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Protective effect ofSpirulina against doxorubicin-induced cardiotoxicity
Phytotherapy Research
Abstract
The generation of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin (DOX)-induced cardiotoxicity. The aim of the present study was to determine whether Spirulina, a blue-green algae, could serve as a cardioprotective agent during DOX treatment in a mouse model. Mice were treated with DOX (4 mg/kg bw, intraperitoneally), weekly, for 4 weeks. Spirulina was administered orally for 3 days twice daily, then for 7 weeks along with the four equal injections of DOX. Cardiotoxicity was assessed, at 3 weeks after the end of the DOX-treatment period, by mortality, volume of ascites, liver congestion, oxidative stress and ultrastructural changes of heart tissue. The DOX-treated animals showed higher mortality (53%) and more ascites. Myocardial damage, as assessed by ultrastructural changes, showed loss of myofibrils, cytoplasmic vacuolization and mitochondrial swelling. Myocardial superoxide dismutase and glutathione peroxidase activities were decreased and lipid peroxidation was increased. Pretreatment with Spirulina significantly protected the mice from DOX-induced cardiotoxic effects as evidenced from lower mortality (26%), less ascites, lower levels of lipid peroxidation, normalization of antioxidant enzymes and ultrastructural studies showing minimal damage to the heart. In vitro cytotoxic studies using ovarian cancer cells demonstrated that Spirulina did not compromise the anti-tumor activity of doxorubicin. These results suggest that Spirulina has a protective effect against cardiotoxicity induced by DOX and it may, therefore, improve the therapeutic index of DOX.
... Studies have shown that Spirulina has potent antioxidant activity (Premkumar et al., 2001;Upasani & Balaraman, 2003) and scavenges hydroxyl and peroxyl radicals both in vitro and in vivo by utilizing its C-phycocyanin component (Bhat & Madyastha, 2000). It has been established that C-phycocyanin not only scavenges hydroxyl, peroxyl, (Vadiraja et al., 1998) and superoxide radicals (Khan et al., 2005a) and peroxynitrite (Bhat & Madyastha, 2001) but also acts as a potent antioxidant by inhibiting membrane lipid peroxidation Remirez et al., 2002a;Romay et al., 1998;. Hence, C-phycocyanin, one of the major biliproteins from Spirulina, is regarded as an effective antioxidant and a free-radical scavenger (Bhat & Madyastha, 2000). ...
... Free radical formation, lipid peroxidation and depletion in myocardial antioxidants may contribute to the development of doxorubicin-induced cardiotoxicity (Doroshow, 1983;Myers et al., 1977). Recently, we have demonstrated the cardioprotective effects of Spirulina in a mouse model of DOX-induced cardiotoxicity (Table 2; Fig 3) (Khan et al., 2005a). In our study, isolated cardiomyocytes pretreated with Spirulina or C-phycocyanin significantly ameliorated the DOX-induced oxidative stress, inhibited the apoptotic pathway and prevented DNA fragmentation, suggesting that these protective effects could be attributed to C-phycocyanin (Fig 4) (Khan et al., 2005a;Khan et al., 2006c). ...
... Recently, we have demonstrated the cardioprotective effects of Spirulina in a mouse model of DOX-induced cardiotoxicity (Table 2; Fig 3) (Khan et al., 2005a). In our study, isolated cardiomyocytes pretreated with Spirulina or C-phycocyanin significantly ameliorated the DOX-induced oxidative stress, inhibited the apoptotic pathway and prevented DNA fragmentation, suggesting that these protective effects could be attributed to C-phycocyanin (Fig 4) (Khan et al., 2005a;Khan et al., 2006c). Spirulina and C-phycocyanin have also caused the inhibition of DOX-induced cell death even after the prolonged treatment with the drug. ...
Humans depend on plants for their survival. In addition to providing us with food, clothing, medicine and cosmetics, they have been of tremendous medicinal importance since the dawn of civilization. Many of these plants, in particular herbs, are rich in unique natural products (active phytochemicals) which make them ideal for use in herbal medicine in successful treatment of several diseases in humans. A wide variety of natural compounds including phytochemicals such as alkaloids, flavonoids, terpenoids, lignans, polyphenolics, coumarins, saponins, furyl compounds, pigments, thiophenes, proteins and peptides have been identified for the therapeutic use. This review focuses on the potential medicinal uses of Spirulina, which have not been comprehensively discussed so far. Spirulina, a fresh water blue green-algal photosynthetic prokaryote, is thought to be in existence for more than 2 billion years. Spirulina contains high levels of amino acids, carbohydrates, proteins, various B-vitamins, ß-carotene, lipids and minerals, including calcium, iron, magnesium, manganese, potassium and zinc, in addition to various other phytochemicals such as the plant pigments. Besides nutritional values, this blue-green alga offers diverse therapeutic uses. Spirulina and its natural products have been shown to exhibit anticancer, antiinflammatory, immunomodulatory and antiviral properties. Although in vitro and in vivo studies show promising health benefits of Spirulina, there is an urgent need to conduct clinical trails to determine safety, dosage, bioavailability and bioefficacy of Spirulina and their components against various human diseases.
... Spirulina is a plentiful source of various minerals, including potassium, calcium, chromium, copper, iron, magnesium, manganese, phosphorus, selenium, sodium, and zinc (Tokusoglu & Uunal, 2003). The administration of Sp has been discovered to mitigate the cardiac damage resulting from chemotherapy (Khan et al., 2005), reduce the severity of strokes, and enhance the recovery of motor function after a stroke (Wang et al., 2005). Additionally, it has shown the ability to reverse age-related declines in memory and learning. ...
... And same findings were stated by Noman et al., (2015) plus renal tubular degeneration and intratubular necrosis. Besides that, while using Sp as an amelioration arsenic affects organs' tissues in current outcomes comes agreement to Khan et al., (2005) state that Sp has antioxidant properties that decrease liver toxicities (Khan et al., 2005). Sp also stimulates antiapoptotic genes to express bcl-2 (Liu and Zhang 2002), and it contains gammalinolenic acid, which has antioxidant properties and reduces heavy metal toxicity in the liver (Saxena and Kumar 2004), as well as stabilizes membrane functions in various tissues (Upasani and Balaraman 2003). ...
... And same findings were stated by Noman et al., (2015) plus renal tubular degeneration and intratubular necrosis. Besides that, while using Sp as an amelioration arsenic affects organs' tissues in current outcomes comes agreement to Khan et al., (2005) state that Sp has antioxidant properties that decrease liver toxicities (Khan et al., 2005). Sp also stimulates antiapoptotic genes to express bcl-2 (Liu and Zhang 2002), and it contains gammalinolenic acid, which has antioxidant properties and reduces heavy metal toxicity in the liver (Saxena and Kumar 2004), as well as stabilizes membrane functions in various tissues (Upasani and Balaraman 2003). ...
Abstract
Background: Arsenic (As) contributes to metabolic disorders, including
diabetes, and disrupts the functions of multiple systems, leading to associated
diseases and dysfunctions. This study aims to investigate the effects of
Arsenic on plasma and liver enzymes, assess liver tissue histopathological
changes, and explore spirulina's potential protective role against As-induced
liver damage. Materials and Methods: Female Wistar rats were divided into
six groups, including control, sodium arsenate-only (5mg/kg body weight),
Sp-only (300mg and 600mg), and combined As and Sp treatment groups.
Plasma and liver samples were collected after four weeks of treatment for
enzyme analysis, and part of the liver tissues were examined histologically.
Results: Arsenic exposure significantly increased aspartate aminotransferase
(AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate
dehydrogenase (LDH) enzyme levels in plasma and liver. However, Sp
supplementation at different doses showed a reduction in enzyme levels,
although not statistically significant. Histological examination revealed liver
damage in the As-exposed group, including congestion, leukocyte infiltration,
and endothelium detachment. Sp supplementation partially attenuated these
changes. Conclusion: This study enhances understanding of As's toxic effects
and suggests that Sp supplementation may offer some protection against As-induced liver damage. Recommendation: To improve the findings,
additional parameters such as oxidative stress markers, inflammatory
markers, and liver function tests should be incorporated. These measurements
will provide a more comprehensive understanding of the effects of arsenate
exposure.
... (GLA), it also contains a host of other phytochemicals that have potential health benefits 1 . Several studies have focused on physiological properties of some valuable antiviral or antioxidant compounds in blue green alga Spirulina [2][3][4] . The occurrence of many compounds possess antioxidant activity in biological systems in higher plants is well documented, while in microalgae are less documented 5 . ...
... This finding suggests that the presence of electron and/or hydrogen donating constituent in algal organic extracts phenol compounds were responsible for reducing power 27 . However, the positive correlations between phenol, phytosterol and carotenoids contents in Spirulina and its antioxidant activity is well documented as reported 3,9,11 . Total phenolic, phycocynin, carotenoids and chlorophyll-derived present in the organic extracts might explain their high antioxidant activity. ...
... Similar antioxidant properties were found for carotenoids compounds that is capable to scavenging of free radicals and quench singlet oxygen primarily by physical mechanism 28 . In addition, phycocyanin, one of the major pigments in Spirulina, possesses significant antioxidant and radical scavenging properties as well as can inhibits lipid peroxidation mediated by ROS and could be act as chelating agent 3 To get maximum antioxidant activity we screened solvents from single extraction and performed sequential extraction. Sequential extraction showed maximum antioxidant activity for all the three methods (% inhibition-317.24 ...
The occurrence of many compounds possessing antioxidant activity in biological systems in higher plants is well documented; while in micro algae are less documented. Spirulina platensis or its extracts show therapeutic properties, such as the ability to prevent the incidence of cancers, decrease blood cholesterol levels, stimulate the immunological system, reduce the nephrotoxicity of pharmaceuticals and toxic metals and provide protection against the harmful effect of radiation. This work was conducted to evaluate the influence of solvents and extraction time on antioxidation activity of Spirulina. Biochemical characteristics of organic extracts obtained from different solvents were analysed. The chromatographic analyses of Spirulina organic extracts with TLC showed that carotenoids, chlorophyll-derived compounds, and phenol compounds were present as main constituents. Hydrophilic solvents and hydrophobic solvents were used for the evaluation of antioxidant property. Water extract of Spirulina showed an Reducing power of 48% followed by butanol with 41% in medium polar solvents.Hydrogen peroxide scavenging activity was significantly high in propanpl with 81% of inhibition.Lower most inhibition of 18% was recorded in benzene extract.Radical modulation assay was superior in diethyl ether extract. Sequential extraction with water, acetone,propanpl and cyclohexane was very effective exhibiting two fold scavenging activity of 200% inhibition compared with the respective solvents used alone. The concentration of pigments were high in hydrophobic solvents and the concentration of polyphenol were high in hydrophilic solvents. Thus, it could be suggested that the Spirulina is a useful bio-system for production of bioactive compounds.
... In the process of investigating the hypolipidemic effects of Arthrospira platensis, Han et al. found that the aqueous extract of it may inhibit the intestinal absorption of dietary fat by inhibiting pancreatic lipase activity [111]. Khan et al. studied whether Spirulina could serve as a cardioprotective agent during doxorubicin-induced cardiotoxicity (DOX) treatment in a mouse model [112]. A similar effect was observed when taking pure phycocyanin extracted from the cyanobacteria. ...
... A similar effect was observed when taking pure phycocyanin extracted from the cyanobacteria. Khan et al. investigated the cardioprotective effect of C-phycocyanin (PC) (an antioxidant biliprotein pigment of a blue-green algae Arthrospira platensis) against ischemia-reperfusion (I/R)-induced myocardial injury and show that PC attenuated I/R-induced cardiac dysfunction through its antioxidant and antiapoptotic actions [112]. ...
Arthrospira platensis is a filamentous cyanobacterium of the class Cyanophyceae and is the most cultivated photosynthetic prokaryote. It is used in the pharmaceutical sector, medicine and the food industry. It has a rich micro- and macro-element composition, containing proteins, lipids, carbohydrates, essential amino acids, polyunsaturated fatty acids, minerals and raw fibers. It is a commonly used ingredient in food products and nutritional supplements. The wide range of biologically active components determines its diverse pharmacological properties (antioxidant, antidiabetic, antimicrobial, antineoplastic, antitumor, anti-inflammatory, photoprotective, antiviral, etc.). This review summarizes research related to the taxonomy, distribution and chemical composition of Arthrospira platensis as well as its potential application in the food and pharmaceutical industries. Attention is drawn to its various medical applications as an antidiabetic and antiobesity agent, with hepatoprotective, antitumor, antimicrobial and antiviral effects as well as regulatory effects on neurodegenerative diseases.
... The use of anti-neoplastic drugs significantly reduces the progression of cancers and prevents their recurrence in many patients. Doxorubicin (DOX) is an agent from anthracyclines used to treat a variety of solid tumors such as breast cancer, sarcoma, leukemia, and lymphoma with beneficial effects in preventing metastasis (2). However, this chemotherapeutic drug is associated with a risk of cardiotoxicity in patients after acute or cumulative doses. ...
... Test sample absorption -Low control absorption High control absorption -Low control absorption × 100 (2) Total oxidant capacity assay Assessment of hydroperoxides concentration as an indicator of total oxidant capacity was performed using a commercial kit based on the FOX-1 (ferrous ion oxidation by xylenol orange) technique (20). In this assay, the supernatant of the cardiomyocytes after being pretreated with different concentrations of PCA and then exposed to DOX or ATO was mixed with FOX-1 solution. ...
Background and purpose: Some chemotherapeutic drugs are associated with an increased risk of cardiotoxicity in patients. Protocatechuic acid (PCA) is a phenolic acid with valuable cardiovascular, chemo-preventive, and anticancer activities. Recent studies have shown the cardioprotective effects of PCA in several pathological conditions. This investigation aimed to assess the possible protective effects of PCA on cardiomyocytes against toxicities caused by anti-neoplastic agents, doxorubicin (DOX), and arsenic trioxide (ATO).
Experimental approach: H9C2 cells were exposed to DOX (1 μM) or ATO (35 μM) after 24 h pretreatment with PCA (1-100 μM). MTT and lactate dehydrogenase (LDH) tests were used to define cell viability or cytotoxicity. Total oxidant and antioxidant capacities were evaluated by measuring hydroperoxides and ferric-reducing antioxidant power (FRAP) levels. Expression of the TLR4 gene was also quantitatively estimated by real-time polymerase chain reaction.
Findings/Results: PCA showed a proliferative effect on cardiomyocytes and significantly enhanced cell viability and reduced cytotoxicity of DOX and ATO during MTT and LDH assays. Pretreatment of cardiomyocytes with PCA significantly decreased hydroperoxide levels and elevated FRAP value. Moreover, PCA meaningfully decreased TLR4 expression in DOX-and ATO-treated cardiomyocytes.
Conclusions and implications: In conclusion, antioxidant and cytoprotective activities were found for PCA versus toxicities caused by DOX and ATO in cardiomyocytes. However, further in vivo investigations are recommended to assess its clinical value for the prevention and treatment of cardiotoxicity induced by chemotherapeutic agents.
... Besides, several studies with spirulina have shown an improvement in insulin sensitivity and glucose uptake mediated by C-phycocyanin activity, and, in some studies spirulina has displayed hypolipidemic properties (Park et al., 2008;Mazokopakis et al., 2014b;Serban et al., 2016). On the other hand, cell culture approaches have demonstrated the ability of spirulina to exhibit anti-atherosclerotic effects by preventing monocyte migration through direct inhibition of P-and Eselectin adhesion molecules (Vo and Kim, 2013;Ren et al., 2018), and to effectively inhibit doxorubicin-induced cardiac damage (Khan et al., 2005;Khan et al., 2006a). However, whether oral supplementation with spirulina is able to limit infarct size and ameliorate cardiac dysfunction in the setting of myocardial infarction remains to be addressed. ...
... So far, the in vivo effects of spirulina on the myocardium have been only investigated in a mice model of doxorubicin-induced cardiotoxicity where oral spirulina supplementation for 7 weeks elicited a decrease in lipid peroxidation, normalized antioxidant enzymes, and limited doxorubicin-induced myocardial ultrastructural changes leading to an overall significant reduction in mortality (Khan et al., 2005). In our study we further expand spirulina-related cardioprotective properties to the setting of coronary artery total occlusion and elucidate the mechanisms behind its action. ...
Background and Aims: Myocardial infarction (MI) is the clinical manifestation of atherosclerotic coronary artery disease. Spirulina is an algae known to ameliorate cardiometabolic disorders and with proven anti-inflammatory and anti-oxidant effects. We investigated, in a highly translatable animal model, whether oral supplementation with spirulina protects against the deleterious effects triggered by ST-elevation MI (STEMI).
Methods: Pigs were fed a regular diet supplemented with spirulina (1 g/animal/bid) or placebo-control for 10 days. Thereafter, animals were subjected to 1.5 h percutaneous balloon-induced coronary occlusion (STEMI) followed by 2.5 h reperfusion and then sacrificed. We assessed infarct size and cardiac function. Blood samples and infarcted and remote myocardial tissue were obtained.
Results: Spirulina supplementation reduced infarct size by 64%, increased myocardial salvage by 18%, and improved cardiac function by 30% vs. controls (p < 0.05). These benefits were associated with attenuation in DNA-oxidative damage and apoptotic markers and increased iNOS in the infarcted myocardium, higher AMPK activation in the remote myocardium, and lower myocardial MCP-1 expression. Systemically, spirulina attenuated Cox-2 expression in STEMI-activated peripheral blood mononuclear cells and enhanced TNF-α release acutely post-STEMI. Additionally, spirulina decreased weight gain progression over time (p < 0.05) without changes in lipids, glucose, liver or kidney parameters.
Conclusion: A 10-day supplementation with spirulina exerts cardioprotection in a preclinical setting of STEMI by limiting cardiac damage and improving ventricular contractility through anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms.
... mg/g of total carotenoids, and 1.69±0.07 mg/g of chlorophyll b. S. platensis also possesses a 27.06% (w/w) overall phycobiliprotein percentage, which is made up of 3.47% (w/w) phycoerythrins, Allophycocyanins: 5.34% (w/w), and 18.25% (w/w) c-phycocyanins(Rahim et al., 2021).Throughout centuries, spirulina has been employed as a conventional dietary staple due to its remarkably varied and nourishing nutritional composition (Parikh et al., 2001).Spirulina having incredibly high concentrations of both macro-and micronutrients, including as minerals, vitamins, unsaturated fatty acids, proteins, and amino acids (Khan et al., 2005). Spirulina is well known for having a large amount of protein content roughly 60% of its total volume (Grosshagauer et al., 2020). ...
The global nutraceuticals market has experienced substantial growth in recent
years, attributed to increasing consumer awareness regarding the importance of
nutritional supplementations for a healthy lifestyle. This market encompasses
many products, including inorganic mineral supplements, vitamin supplements,
digestive enzymes, dietary fibers, antioxidants, and PUFAs (Polyunsaturated
Fatty Acids). This edited book chapter provides a comprehensive analysis of
current trends and future growth prospects in the nutraceutical industry.
Emphasis is placed on the regulatory aspects and adherence to FSSAI (Food
Safety and Standards Authority of India) guidelines in the development of
nutraceuticals. The prominent nutraceuticals and functional foods, such as
Spirulina, Soybean, Ginseng, Garlic, Broccoli, Ginkgo, and Flaxseeds have
been discussed for their marker compounds, chemical nature, medicinal uses,
and health benefits. By exploring the multifaceted aspects of these
nutraceuticals, the chapter aims to offer valuable insights into their potential
applications, supporting a holistic approach to health and wellness through
functional foods. Integrating scientific understanding and regulatory
frameworks underscores the importance of evidence-based advancements in
nutraceutical development to promote consumer well-being and contribute to
the evolving healthcare landscape.
... Lysine as one of the essential amino acids in Spirulina and Chlorella content has been shown to be involved in cytokine production and lymphocyte proliferation, resulting in best immune system performance in the face of disease (Nasr and Kheiri, 2012). The improvement inrelative weight of bursa may indicate that Spirulina enhances immune system function by strengthening immunecells and organs and their resistance to environmental or in fectiousagent stress (Khan et al., 2005). Significant effects of algae were observed in lymphoid organs that are primarily responsible for immune responsesin chicks (El-Gogary et al., 2023). ...
... Cardiac side effects of doxorubicin are reported to be common, especially congestive heart failure and the risk of toxicity is higher when doxorubicin is co-administered with another anticancer agent [17]. The mode of toxicity principally related to redox imbalances resulted from reactive oxygen species generation [18][19][20]. The cardiac tissue is highly vulnerable to free radical toxicity generated by doxorubicin [21,22]. ...
Doxorubicin is the common chemotherapeutic agent that has
been harnessed for the treatment of various types of malignancy
including the treatment of soft tissue and osteosarcoma and
cancers of the vital organs like breast, ovary, bladder, and
thyroid. It is also used to treat leukaemia and lymphoma,
however, this is an obstacle because of their prominent side
effects including cardiotoxicity and lung fibrosis, we do aim to
determine the role of CoQ10 as an antioxidant on the impeding
the deleterious impacts of doxorubicin on tissue degenerative
effects. To do so, 27 rats were subdivided into 3 groups of 9
each; CoQ10 exposed group, Doxorubicin exposed group, and
CoQ10 plus Doxorubicin group. At the end of the study, the
animals were sacrificed and lungs with hearts were harvested,
and slides were prepared for examination under a microscope.
The results indicated that doxorubicin induced abnormal
cellular structure resulting in damaging cellular structures of the
lung and heart while CoQ10 impeded these damaging effects
and nearly restoring normal tissue structure. As a result, CoQ10
will maintain normal tissue of the lung and heart.
Key words. Doxorubicin, CoQ10, histopathology, lung,
cardiotoxicity.
... Iqbal et al. (2008) demonstrated that the administration of TEL significantly decreased the LDH and MDA levels while increasing GSH in doxorubicin-induced cardiotoxicity. Khan et al. (2005a) showed that Sp ameliorated doxorubicininduced cardiotoxicity in mice models via downregulation of MDA and upregulation of SOD and GPx-1; this protective effect of Sp is attributed to its antioxidant constituents C-phycocyanin and β-carotene. ...
... Iqbal et al. (2008) demonstrated that the administration of TEL significantly decreased the LDH and MDA levels while increasing GSH in doxorubicin-induced cardiotoxicity. Khan et al. (2005a) showed that Sp ameliorated doxorubicininduced cardiotoxicity in mice models via downregulation of MDA and upregulation of SOD and GPx-1; this protective effect of Sp is attributed to its antioxidant constituents C-phycocyanin and β-carotene. ...
Background
Cardiotoxicity is one of the limiting side effects of the commonly used anticancer agent cyclophosphamide (Cyclo).
Materials and methods
The possible protective effects of telmisartan and nanoformulated Spirulina platensis (Sp) methanolic extract against Cyclo-induced cardiotoxicity were examined in this study. Experimental groups of rats were randomly divided into nine groups as control vehicle, control polymer, telmisartan (TEL, 10 mg/kg), free Sp extract (300 mg/kg), nano Sp extract (100 mg/kg), Cyclo (200 mg/kg), TEL + Cyclo, free Sp + Cyclo, and nano Sp + Cyclo. The groups with Cyclo combinations were treated in the same manner as their corresponding ones without Cyclo, with a single dose of Cyclo on day 18.
Results
The results indicate that Cyclo causes significant cardiotoxicity, manifesting in the form of notable increases of 155.49%, 105.74%, 451.76%, and 826.07% in the serum levels of glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), and cardiac troponin I (cTnI) enzyme activities, respectively, as compared to the control. In addition, the cardiac glutathione (GSH) content and activity of glutathione peroxidase-1 (GPX-1) enzyme decreased by 65.94% and 73.85%, respectively. Treatment with nano Sp extract showed the most prominent restorations of the altered biochemical, histopathological, and immunohistochemical features as compared with those by TEL and free Sp; moreover, reductions of 30.64% and 43.02% in the p-AKT content as well as 60.43% and 75.30% of the endothelial nitric oxide synthase (eNOS) immunoreactivity were detected in the TEL and free Sp treatment groups, respectively. Interestingly, nano Sp boosted the autophagy signal via activation of beclin-1 (36.42% and 153.4%), activation of LC3II (69.13% and 195%), downregulation of p62 expressions (39.68% and 62.45%), and increased gene expressions of paraoxonase-1 (PON-1) (90.3% and 225.9%) compared to the TEL and free Sp treatment groups, respectively.
Conclusion
The findings suggest the protective efficiency of telmisartan and nano Sp extract against cardiotoxicity via activations of the antioxidant, antiapoptotic, and autophagy signaling pathways.
... As a result, decreased lipid peroxidation in rat liver has been demonstrated [94]. Furthermore, several studies described that after consuming this alga, it relieved the symptoms of liver cirrhosis [95][96] and reduced the oxidative stress of alpha-toxinfed pets [97][98]. ...
Algae, as well as Arthrospira platensis, have a wide range of biologically active constituents that determine different pharmacological properties. They are also the basis for developing various new nutritional compositions and supplements. This review summarizes the application of algae and Arthrospira platensis in pharmaceutical technology and food over the last 20 years with an emphasis on the beneficial effects of spirulina on human health, considering its nutritional value and therapeutic properties. A detailed literature review was conducted in scientific databases for over 20 years, such as PubMed, ScienceDirect, ResearchGate, and Google Scholar. Relevant information is summarized and interpreted. The permanent research process leads to the development of new preparations to inhibit the growth of cancer cells, reduce the aging of cells, increase the immune system's efficiency, protect against infectious diseases, etc. In vivo studies show specific mechanisms of neuroprotection, appetite regulation, and prevention of neurodegenerative and psycho-cognitive pathologies. Algae and Arthrospira platensis, with their biologically active metabolites, are essential raw materials for producing various pharmaceutical products and functional foods with high nutrient content. Their use depends on the preservation of their biodiversity. In connection with their biosafety and the understanding of the biological effects on the human organism, it is necessary to continue their study.
... It has also been reported that Spirulina helps with the digestion of nutrients, the absorption of minerals, and the prevention of diarrhea (Gružauskas et al., 2004). In addition, Spirulina has been shown to boost immunological response and reproduction (Qureshi et al., 1996;Khan et al., 2005). A modest amount of Spirulina in the diet has also been shown to greatly increase the antigen-processing defense system (T-cell) and decrease the harmful microbial community (Qureshi et al., 1996;Kaoud, 2012). ...
The development of antibiotic-resistant microorganisms prompted the investigation of possible antibiotic substitutes. As a result, the purpose of the current study is to assess the effect of dietary Spirulina platensis extract as an antibiotic alternative on Japanese quail (Coturnix japonica) growth, antioxidant status, blood parameters, and cecal microorganisms. There was a total of 150 Japanese quails used in this study, divided equally among 5 experimental groups (10 birds per group with 3 replicates): group 1 (G1) received a basal diet without any S. platensis extract, group 2 (G2) received a basal diet supplemented with 1 mL S. platensis extract/kg, group 3 (G3) received a basal diet supplemented with 2 mL S. platensis extract/kg, group 4 (G4) received a basal diet supplemented with 3 mL S. platensis extract/kg, and group 5 (G5) received a basal diet supplemented with 4 mL S. platensis extract/kg from d 7 until d 35. The results showed that compared to the control birds in G1, Japanese quail supplemented with 4 mL of S. platensis extract/kg of diet (G5) had significantly better live body weight, body weight gain, feed intake, feed conversion ratio, digestive enzymes, blood parameters, liver and kidney functions, lipid profile, antioxidant profile, immunological parameters, and cecal microorganism's count. There were no significant changes in the percentage of carcasses, liver, and total giblets among all the 5 groups. Only gizzard percentage showed a significant increase in G2 compared to birds in G1. In addition, intestinal pH showed a significant drop in G2 and G5 compared to birds in G1. After cooking the quail meat, the juiciness and tenderness increased as S. platensis extract levels increased, whereas aroma and taste declined slightly as S. platensis extract levels increased. Furthermore, when a high concentration of S. platensis extract was used, the lightness of the meat reduced while its redness and yellowness increased. The disk diffusion assay showed that S. platensis extract had significant antibacterial activity against Staphylococcus aureus, Listeria monocytogenes, Campylobacter jejuni, and Salmonella typhi, with inhibition zones ranging from 16 to 42 mm. This activity may be attributable to the volatile chemicals in S. platensis extract, of which Geosmin and 2-methylisoborneol are the primary components. In the diet of Japanese quails, it is possible to draw the conclusion that the extract of S. platensis can be utilized as a feed additive and as an alternative to antibiotics.
... TGF binds to TR-II, activating activin receptor-like kinase4 (ALK4) and receptor-regulated Smad proteins (Smad2/3), which impair the endothelium. The suppression of TGFβ in cardiac cells will reduce left ventricle remodeling, as well as systolic and diastolic dysfunctions [5][6][7]. ...
Doxorubicin (DOX) has been extensively utilized in cancer treatment. However, DOX administration has adverse effects, such as cardiac injury. This study intends to analyze the expression of TGF, cytochrome c, and apoptosis on the cardiac histology of rats induced with doxorubicin, since the prevalence of cardiotoxicity remains an unpreventable problem due to a lack of understanding of the mechanism underlying the cardiotoxicity result. Vernonia amygdalina ethanol extract (VAEE) was produced by soaking dried Vernonia amygdalina leaves in ethanol. Rats were randomly divided into seven groups: K- (only given doxorubicin 15 mg/kgbw), KN (water saline), P100, P200, P400, P4600, and P800 (DOX 15 mg/kgbw + 100, 200, 400, 600, and 800 mg/kgbw extract); at the end of the study, rats were scarified, and blood was taken directly from the heart; the heart was then removed. TGF, cytochrome c, and apoptosis were stained using immunohistochemistry, whereas SOD, MDA, and GR concentration were evaluated using an ELISA kit. In conclusion, ethanol extract might protect the cardiotoxicity produced by doxorubicin by significantly reducing the expression of TGF, cytochrome c, and apoptosis in P600 and P800 compared to untreated control K- (p < 0.001). These findings suggest that Vernonia amygdalina may protect cardiac rats by reducing the apoptosis, TGF, and cytochrome c expression while not producing the doxorubicinol as doxorubicin metabolite. In the future, Vernonia amygdalina could be used as herbal preventive therapy for patient administered doxorubicin to reduce the incidence of cardiotoxicity.
... Spirulina provides many medical benefits, which can be used in the treatment of high cholesterol, hyperlipidemia, and various cancers. These benefits are as a result of spirulina's unique composition, which consists of approximately 60% protein, numerous essential vitamins, high concentrations of ß-carotene, and fatty acids (Khan et al., 2005;Campanella et al., 2002), making this a lucrative organism for cultivation. However, the viability of this species for cultivation is hindered by the high costs of production, which can be largely attributed to the high temperatures, and thus high energy inputs, that are required for optimal growth. ...
One of the major constraints in South African warm-water aquaculture is low water temperatures associated with cold weather and winter months. The extreme cost of heating to raise the water temperature during these times is generally unfeasible; and for this reason, warm-water aquaculture is predominantly confined to one 6-month summer production cycle per year. Geothermal hot springs have thus been proposed as a viable alternative heat source for the support of warm-water aquaculture all year round. A geothermal hot spring at the Brandvlei Correctional Facility in Worcester in the Western Cape, was identified as the start site for this 12-month project. The spring water at Brandvlei is approximately 60°C and emerges from the ground at 126 L/s and complies with all water drinking standards. The overall aim of the project was to investigate a suitable method to use the heat from the Brandvlei geothermal spring to support the warm-water aquaculture of Nile tilapia, with focus on renewable energy, and creating food security and skills development opportunities. The specific aims were to firstly develop an appropriate method to harness the geothermal heat to support tilapia aquaculture; to then determine the costbenefit of utilising geothermal heat for aquaculture; and to also provide a SWOT analysis evaluating the potential use of the test-system for fish production and skills development. The project involved the design and installation of two separate single-tank recirculating aquaculture systems of 10 000 L each, that individually maintained a water temperature of 28°C for optimum Nile tilapia aquaculture. The ‘control’ system included a conventional heating method (a heat pump) and was referred to as the HP system; and the ‘test’ system included a heat exchanger which transferred heat from the Brandvlei geothermal spring to the fish-tank system’s water and was referred to as the HX system. A kilowatt meter was included in each system to monitor and compare the electricity usage of the systems separately. From the power consumption records it was seen that the HX system used significantly less power than the HP system at any given time. Records for monthly power usage for the period from November 2021 to April 2022, showed that the cost savings percentage was as high as 55.7% for the coldest month (April) when comparing the daily power usage for the HX system to that of the HP system. It was seen that the average monthly power usage of the HP system had a strong negative correlation with the minimum average monthly temperature for Worcester, whereas the power usage for the HX system appeared to be relatively consistent over the months, having only a moderate negative correlation with minimum temperature. The power consumption records and historical temperature records for ambient temperature in Worcester were used in simple linear regression analyses to make predictions for what the systems may have cost to run for the full previous year of 2021. In terms of power usage, predictions indicated that the HX system would use 57.8% less power than the HP system for the full year of 2021. In terms of the average monthly cost for running and heating the 10 000 L systems, it was predicted that for 2021 it would cost between R3 838.50 and R3 423.00 monthly for the HP system and between R1 445.60 and R1 411.25 monthly for the HX system. Depending on the electricity user tariffs, this could be a cost-savings percentage of between 57.8 and 63.2% in favour of the HX system. It is expected that in colder weather or in winter months, the cost savings percentage would be higher to a point, and then the HP system would most likely need insulation to keep temperatures from dropping below 28°C. Fish were stocked successfully in both systems, however, due to this being a 12-month project, a full growth cycle (±6 months) was not possible within this project’s timeframe, but the co-management plan between Stellenbosch University and the Department of Correctional Services was established to ensure continued maintenance of the fish and the system until harvest at ±6 months. Based on the results, it was concluded that geothermal energy may be a viable solution to producing warmwater fish species all year around feasibly, as long as there is a good management strategy in place. This project provides a system design that can be applied at other hot springs in South Africa, which in turn will promote the development of the aquaculture sector while also creating food security and skills development opportunities. Besides the cost savings advantage, another major benefit of using a heat exchanger for geothermal aquaculture is that the geothermal water does not come into contact with the water of the aquaculture system. This means that even geothermal hot springs with poor water quality can be used, as it would just be the heat that would be harnessed from these springs. A limitation that was identified during the project was with regard to the data collection, as the power consumption meters only recorded the total power used for each system each day and did not record at smaller intervals. It was therefore not possible to obtain accurate estimates of running and heating power consumption separately. A recommendation for improvement or for future studies would thus be to either set the meters to record power used for heating only, or to find a power recording programme that would record power usage at minute intervals. Installing a roof or cover over the systems is also recommended to protect the systems and managerial staff from the harsh elements of sun and rain during extreme weather. A remote alarm system would also be useful for notifying the manager and core project members about any system failure on their cell phone, as a delayed response to system issues can result in mass fish mortalities
... 13,14 S. platensis has also showed immunomodulatory, cardioprotective, renoprotective, antihyperlipidimic, antioxidant, protective against heavy metals, anti-diabetic, hepatoprotective, neuroprotective effects in different animal models. [15][16][17][18][19][20][21][22][23] Diabetic neuropathic pain (mechanical allodynia and thermal hyperaigesia) was also shown to be significantly decreased after administration of this medicinal algae. 13,24 Based on analgesic and antioxidant properties of S. platensis, the present study has been aimed to evaluate the effect of S. platensis on cold allodynia and chemical allodynia in Streptozotocin (STZ) induced diabetic neuropathic pain rats. ...
Background: Diabetic neuropathic pain exerts strong as well as negative influence on both survival and quality of life of the patient. This pain is difficult to treat with conventional analgesics. Now a days, different medicinal herbs are highlighted due to their wide range of beneficial application with less side effects. In this regards Spirulina platensis is well known for its wide range of biological activities. Objective: To assess the effects of oral administration of Spirulina platensis on cold allodynia and chemical allodynia in diabetic neuropathic pain in Long Evans rats.Materials and Methods: This study was conducted in the Department of Physiology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka from March 2017 to February 2019. Twenty four (24) Long Evans rats, having 150 to 200 grams body weight (on the basis of treatments), the rats were divided into Group I (normal saline 5 ml/kg body weight) and Group II (Spirulina platensis 400 mg/kg body weight). All the supplementations were given once daily for consecutive 21 days orally and last doses were given one hour before the pain evaluation tests. Further on the basis of experiments, previously grouped rats were divided into subgroup ‘a’(cold tail immersion test), and ‘b’ (formalin test). Data were expressed as mean±SEM and were statistically analyzed by SPSS (Version 16) using independent sample ‘t’ test to compare mean value between two groups. (p 0.05 was considered as the level of significance).Results: Spirulina platensis showed significantly higher tail flick latency (p 0.001) in cold tail immersion test. S. platensis demonstrated significantly lowered jerking frequency (p 0.001,p 0.01,p 0.001, respectively); the duration of licking (p 0.001,p 0.05,p 0.001, respectively) and the duration of flexing (p 0.001, non-significant 0.01, respectively) in early, inter and late phases of formalin test in compared to those of control. Conclusion: S. platensis attenuates cold allodynia and chemical allodynia diabetic neuropathic pain in rat model. KYAMC Journal Vol. 13, No. 04, January 2023: 208-213
... Spirulina platensis, Reishi (Ganoderma lucidum), and Moringa oleifera are three nutraceuticals with anti-inflammatory effects that are currently used in cancer patients as complementary and alternative medicines to improve quality of life. In the preclinical models of DOXO-induced cardiotoxicity, these nutraceuticals and their combinations are able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis [234,235]. Table 7. Nutraceuticals and their mechanisms of protection against RIHD (Adapted from [225]). ...
Nutrition has a significant effect and a crucial role in disease prevention. Low consumption of fruit and vegetables and a sedentary lifestyle are closely related with the onset and development of many types of cancer. Recently, nutraceuticals have gained much attention in cancer research due to their pleiotropic effects and relatively non-toxic behavior. In fact, although in the past there have been conflicting results on the role of some antioxidant compounds as allies against cancer, numerous recent clinical studies highlight the efficacy of dietary phytochemicals in the prevention and treatment of cancer. However, further investigation is necessary to gain a deeper understanding of the potential anticancer capacities of dietary phytochemicals as well as the mechanisms of their action. Therefore, this review examined the current literature on the key properties of the bioactive components present in the diet, such as carotenoids, polyphenols, and antioxidant compounds, as well as their use in cancer therapy. The review focused on potential chemopreventive properties, evaluating their synergistic effects with anticancer drugs and, consequently, the side effects associated with current cancer treatments.
... Cardiomyocytes subjected to CP treatment had a significant increase in ROS and superoxide anion buildup, indicating that oxidative stress is intimately linked to its harmful effects [32]. Particular focus is placed on the production of ROS and their harmful effects on myocardial tissue due to the dearth of antioxidant enzymes in cardiac tissue [33]. According to Swamy et al., the production of ROS damages the myocardium and makes cell walls more permeable. ...
Background: While Cisplatin (CP) is a powerful DNA alkylating agent used to treat many malignancies, its clinical use is linked to a number of negative side effects. It has been proposed that vitamin D can shield biological systems against harm caused by CP. The current study's objective was to look into how vitamin D protects the rat heart and lung against cisplatin-induced damage. Material and methods: Thirty adult male Albino rats; 180–220 g body weight were allocated into 3 groups; Group I (n=10) receiving saline, Group II (n=10); rats receiving CP (single dose of 6.5 mg/kg intraperitoneal) and Group III (n=10); receiving CP and 50 ng/kg/day alfacalcidol. Results: Alterations included a significant increase in malondialdehyde (MDA) level in the CP group compared with the other groups (p value for comparing between control and each other group, statistically significant at p ≤ 0.05). Histopathologically, CP induced severe changes were observed. However, the CP-induced disturbances significantly improved by treatment with Vitamin D. Conclusion: According to this study, CP treatment significantly harmed rats' hearts and lungs; however, treatment with vitamin D significantly lessened these harms. Keywords: Cisplatin, Immunohistochemical, Vitamin D, Malondialdehyde, Oxidative stress.
... Scientific interest is directed not only at the antioxidant effect of marine algae, but also at the antioxidant activity of freshwater algae cultivated in bioreactors such as Arthrospira/ Spirulina (Cyanobacteria). According to various studies, Arthrospira/Spirulina (Table 3) has the potential to improve heart health by influencing the blood lipid composition, blood pressure [47,48], and cholesterol profile, by lowering LDL (bad) cholesterol and total triglycerides and increasing good (HDL) cholesterol [49,50]. ...
The current research focused on algae from the waters of the Black Sea—Chaetomorpha linum, Ulva intestinalis, Ericaria crinita, and bioreactors—Chlorella spp. and Arthrospira platensis/cyanobacterium/. Pigment content, total phenolic content, and antioxidant capacity were investigated for their use as pharmaceutical, food, and cosmetic ingredients. E. crinita exhibited the highest antioxidant activity by ORAC and HORAC (463.3 µmol TE/g and 463.3 µmol GAE/g) and the highest total content of polyphenols and rutin of the investigated algae. Lower protein content was found in saltwater algae than in freshwater algae. For the first time, biologically active substances from the Bulgarian A. platensis and Chlorella spp., produced in a bioreactor, have been quantitatively identified. A. platensis contained rutin (141.25 mg/100 g), naringenin (42.17 mg/100 g), quercetin (26.74 mg/100 g), kaempferol, and quercetin-3-β-glycoside. Phenolic acids were isolated: neochlorogenic (172.27 mg/100 g) for lyophilized and 5783 mg/100 g for convection-dried A. platensis. It has been found that the protein content in A. platensis (convection dried) and Chlorella spp. (lyophilized) was nearly 54% higher than that of green algae U. intestinalis from Varna. The lyophilization process reduced the protein content of A. platensis samples by almost 20%. The high protein content of convection-dried A. platensis (43.4%) and lyophilized Chlorella spp. (43.7%) identified them as suitable emulsifiers in colloidal and emulsion systems.
... Many medicinal plants and algae like SPA play a major role in many metabolism and biological reactions through their specific mode of action (Kaoud, 2012 andCheong et al., 2016). Also, FCR was better for birds supplemented with SPA compared to the control treatment, the improvement of FCR as a result of SPA supplementation to broiler chicken diet could be attributed to the increase in BW accompanied by no effect on FC in accordance with Khan et al., (2005); Kharde et al., (2012);Jamil et al., (2015), and Shanmugapriya et al., (2015). Moreover, Nikodémusz et al., (2010) noticed that broiler chickens fed Spirulina containing diets were superior in their productive performance compared to control birds. ...
Spirulina platensis algae (SPA) is a natural feed supplement with 40 to 45% crude protein, 2.44% Ca, and 6.27% P. It contains substances (e.g., β-carotene and zeaxanthin, and high Fe, vitamins and phycocyanin). These substances reveal potential biological properties such as antioxidative, anti-inflammatory, and hypolipidemic contain. The effects of dietary supplementation of SPA on growth performance, antioxidative, immune status, and intestinal histology were investigated. A total of 540 broiler chickens were randomly assigned into 3 treatments of 18 breeding pens each housed in 6 replicates per each experimental treatment (30 birds per pen). Three diets were formulated to contain 0, 3, and 6% of SPA and fed from d 7 to 35. Body weight and body weight gain at 5 wk of age were greater (P ≤ 0.05) in the diet containing 6% SPA compared with the 0% SPA. The supplementation of SPA to a broiler chickens diet improved (P = 0.008) the feed conversion ratio. The obtained results of the experiment showed that broiler chickens fed with 3 and 6% of feed SPA increased (P ≤ 0.05) RBC, Hb, WBC, and lymphocyte values compared to the 0% SPA. Serum total lipid, cholesterol, and triglyceride concentrations in the diet containing 3 or 6% SPA decreased compared with the 0% SPA. Furthermore, the concentration of high-density lipoprotein was increased (P = 0.001), while the opposite is observed with low-density lipoprotein concentration. Serum Ca and P concentrations had greater (P ≤ 0.05) in the diet containing 3 or 6% SPA compared to the 0% SPA. Broiler chickens with both treated groups of SPA had the best antioxidative and immune status. Moreover, the content of Ca and P in tibia ash increased (P ≤ 0.05) in both broiler chickens fed the diets containing 3 and 6% SPA compared with those fed the diet containing 0% SPA. In comparison to the control treatment, all experimental chickens had increased villus height, goblet cells per 100 enterocytes and villus height per crypt depth in the jejunum histology examination. The inclusion of SPA in broiler chicken fed the diet containing of 6% had a considerably positive effect on growth performance and gut health status. In addition, it is a good source of Ca and P to increase tibia strength.
... In our study, addition of Spirulina platensis extract in ration also resulted in improvement immunity indices in broilers such as phagocytic activity, phagocytic index, IgM, IgG. According to, spirulina has been demonstrated to improve immunological function, reproduction, and growth (Khan et al., 2005). It also boosts the ability of hens' cell-mediated and mononuclear phagocytic systems to resist illness. ...
The current study was conducted to assess the consequences of Spirulina platensis extract based on growth performance and immunological response of broiler chicks. There was a total of a hundred and Eighty-one-day-old chicks were assigned at random into three dietary groups undergoing treatment with three replicates of 20 each bird. Control group was given ration without additives. The second and third groups were supplemented with Spirulina platensis extract at doses of 30 and 50 gm./kg. of ration, respectively. Supplementation of broiler chicks with Spirulina platensis extract enhanced their growth performance represented by increasing final body weight, body weight gain, phagocytic activity, and phagocytic index while significantly decreased feed intake and food conversion ratio. Moreover, it increased serum levels of Ig-M, and Ig-G and obviously change in serum level of Insulin like growth factor-1 (IGF-1) but not lead to a significant change as compared to control. This study indicated that Spirulina platensis extract in ration enhanced the growth performance and immunological response of broiler chicks through increasing serum levels of immunoglobulins.
... Spirulina and its antioxidant activity were documented. 27, 40,41 The potent antioxidant activity of the extract of different cyanobacteria might be due to the total phenolics, phycocyanin, triterpenoids present in the extracts. 42 Phycocyanin is a water soluble pigment, which is known to exhibit antioxidant, anti-inflammatory, hepato protective effects. ...
In the present study, efforts were made to reveal the total phenolics and flavanoid
contents and antioxidant activity in the four cyanobacterial species viz., Phormidium
fragile, Lyngbya limnetica, Scytonema bohnerii and Calothrix fusca isolated from a
sulfur spring in the Western Ghats of Karnataka. The cultures were maintained in BG11
medium. In vitro screening for antioxidant activity of ethanol and methanol extracts of
these cultures was determined by total antioxidant capacity by phosphomolybdenum,
DPPH free radical scavenging and ferric ion reducing assays. The study indicates the
significant antioxidant potential in Lyngbya limnetica (P<0.01) followed by Scytonema
bohnerii (P<0.05) and least activity was observed in Calothrix fusca (P>0.05).
Therefore, mass cultivation of such strains for the production of valuable bioproducts
may be a good strategy for future use. The study has revealed the utilization of certain
strains of cyanobacteria for the production of biologically active compounds particularly,
antioxidants.
... Many animal trials revealed additional beneficial properties of Spirulina, such as increased fertility [51], improved wound healing [52], protection against chemical-induced nephrotoxicity [53], and cardiotoxicity [54]. In an animal study by Wang., et al. (2007), the researchers reported Spirulina's neuroprotective effects (in cerebral ischemia) [55]. ...
Spirulina is a cyanobacteria (blue-green alga) rich in vital nutrients, having tremendous potential as a "future food". The utility of algae is not limited to providing nutrition. Specific alga can perform the following functions: immunomodulator, anti-allergic, cleanses the body of toxins, antitumor, anti-inflammatory, antiviral, and abstergent (cleansing the body of toxins). Spirulina has been a vital dietary component for humans for millennia. The United Nations recognizes Spirulina as a potential defense against malnutrition. The current evidence in support of Spirulina points towards perfoming further research regarding the promising applications of Spirulina. These organisms are a rich source of bioactive compounds and, thus, should be considered as an alternative and supplementary therapy-albeit with scientific support and evidence-based studies. The revolution in functional foods continues as the incidence of lifestyle-related diseases is increasing. The most notable experiments have been conducted in studying Spirulina's effect on metabolic disorders, revealing its ability to reduce cholesterol, triglycerides, and blood glucose. Also, Spirulina has particular applications in cancer research, protecting against the adverse effects of specific chemotherapeutic agents. Microalgae can also form special supplements for vegetarians, offsetting the absence of protein in the vegan diet. Nevertheless, Spirulina also has a negative side and potential adverse effects. Self-medication with Spirulina supplements can lead to unwanted complications if a person is taking immunosuppressants or anticoagulants concomitantly or suffering from auto-immune diseases. Children and pregnant women should avoid these products until more applicable data are obtained. Also, some people may have an inherent allergy to algal products.
... The activation of mitochondrial permeability transition causes nonreversible increase in membrane permeability and culminates in cell death (Parsons & Green, 2010). It is worthwhile to find compounds to prevent oxidative stress, caused by high level of ROS, known complication of cardiotoxicity after doxorubicin cancer treatment (Diab et al., 2020;Kazama et al., 2015;Khan et al., 2005), hypertrophy induced by angiotensin II (Yan et al., 2013) or during the ischemiareperfusion process (Adlam et al., 2005;Aon et al., 2003). ...
Using H9C2 cardiomyoblasts, we have shown that all-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A, affects mitochondrial dynamics and functions. The low dose (10 nM) ATRA stimulates the expression of nuclear retinoid receptors and induces mechanisms that are protective against severe local damage caused by laser irradiation at the mitochondrial level. These changes include increased density of the mitochondrial network, higher number of mitochondrial junctions, and enhanced mitochondrial velocity. Moreover, the treated cells had lower basal level of reactive oxygen species (ROS) and could maintain mitochondrial potential (ΔΨm ) after photodamage. Cells treated with 10 nM ATRA had significantly better survival rate after photodamage in comparison to control cells. Cells treated with pharmacological concentration of ATRA (1 µM) expressed higher mitochondrial connectivity without increased motility, which did not lead to better survival or decreased ROS level as was in the case of low-dose ATRA. The proteomics analysis showed changes in proteins related to cellular metabolism (glycolysis) and respiration in ATRA-treated cells. The l-lactate assay confirmed the shift to anaerobic glycolysis in cells treated with 1 µm ATRA, whereas the 10 nM ATRA decreased the level of lactate in medium. The increased levels of cytochrome c or peroxiredoxins 5 level and also lower expression of retinoid and rexinoid receptors were observed in cells treated with 1 µM ATRA. The effect of ATRA is concentration-dependent; the increased mitochondrial dynamics and slower metabolism at 10 nM ATRA contributed significantly to the chance of survival of the cells after photodamage whereas the higher concentration of ATRA overrode the protective effect and led to the unfavorable ones.
... Spirulina helps to improve mineral absorption and nutrient digestion processes and protects the gut from diarrhea (76). Spirulina has antiviral activity and immune stimulatory effects (77). Improvement of performance parameters, like FCR, body weight gain, greater production, and percentage of carcass yield, was observed in the dietary group supplemented with Spirulina platensis compared with the other groups (78)(79)(80)(81)(82)(83). ...
The poultry industry has grown so fast alongside the irrational use of antibiotics to maximize profit and make the production cost-effective during the last few decades. The rising and indiscriminate use of antibiotics might result in the deposition of residues in poultry food products and in the development of resistance to these drugs by microorganisms. Therefore, many diseases are becoming difficult to treat both in humans and animals. In addition, the use of low-dose antibiotics as growth enhancer results in antibiotic residues in food products, which have detrimental effects on human health. On the other hand, many studies have shown that antibiotics administered to poultry and livestock are poorly absorbed through the gut and usually excreted without metabolism. These excreted antibiotics eventually accumulate in the environment and enter the human food chain, resulting in the bioaccumulation of drug residues in the human body. In this regard, to find out alternatives is of paramount importance for the production of safe meat and egg. Therefore, in recent years, much research attention was disarticulated toward the exploration for alternatives to antibiotic as in-feed growth enhancers after its ban by the EU. As a result, probiotics, prebiotics, phytobiotics, spirulina, symbiotic, and their combination are being used more frequently in poultry production. Feed additives therefore gained popularity in poultry production by having many advantages but without any residues in poultry products. In addition, numerous studies demonstrating that such biological supplements compete with antimicrobial resistance have been conducted. Therefore, the purpose of this review article was to highlight the advantages of using biological products instead of antibiotics as poultry in-feed growth enhancers to enhance the production performance, reduce intestinal pathogenic bacteria, and maintain gut health, potentiating the immune response, safety, and wholesomeness of meat and eggs as evidence of consumer protection, as well as to improve the safety of poultry products for human consumption.
... In recent years, there has been a steady growth of scientific interest in blue green microalgae Arthospira platensis, hereafter referred to as Spirulina, as a sustainable source of proteins and other high-value compounds with physiological properties (Ozdemir et al., 2004;Khan et al., 2005Khan et al., , 2006Nuhu, 2013). Spirulina platensis, and its purified extracts, have demonstrated functional properties, of which the most relevant include potential antioxidant, antimicrobial, anti-cancer, and immunomodulatory properties (El-Baky et al., 2008;Nuhu, 2013;Marco Castro et al., 2019). ...
The present study challenges the in vivo assessment of cold atmospheric pressure plasma (CAPP) technology on the bioactive activity (antioxidant/antiaging and antimicrobial potential) of Spirulina powder, using Caenorhabditis elegans as an animal model. Surface microdischarge cold atmospheric pressure plasma (SMD-CAPP) treatment was 3.3 W discharge power for 7 min. C. elegans lifespan and egg laying were used as indicators of antioxidant/antiaging potential of Spirulina (1 mg/mL), when grown with Spirulina CP-treated [E_SCP] and untreated [E_S], compared with a control [E_0] (non-supplemented with Spirulina ). According to our results, under both Spirulina supplemented media [E_SCP and E_S] and for the first 17 days, nematodes experienced an increase in lifespan but without significant differences ( p > 0.05) between control and Spirulina CP-treated. Regarding the in vivo assay of the antimicrobial potential of Spirulina against Salmonella enterica serovar Typhimurium (infected worms), no significant differences ( p > 0.05) were found between the three exposure scenarios (control [S_0]; Spirulina supplemented media [S_S]; CP-treated Spirulina supplemented media [S_SCP]). According to present results, CAPP-treatment do not influence negatively the lifespan of C. elegans but a reduction in the S pirulina antiaging potential was found. No in vivo modifications in antimicrobial activity seem to be linked to CAPP-processed Spirulin a.
... The antioxidant effect of spirulina has been proven in vitro as well as in vivo studies. Spirulina is recognized due to its broad biological 4183 activity, and antimutagenic, anti-inflammatory, immune boosting and cardioprotective features (9)(10)(11) . ...
... На сегодняшний день предметом активного изучения служат рациональность профилактического назначения пациентам кардиоонкологического профиля препаратов с кардиопротекторной активностью. Существует множество работ, описывающих кардиопротекторное влияние различных антиоксидантов на целостность кардиомиоцитов и миокарда, среди таких веществ достойными внимания являются куркумин [6], ресвератрол [7] и спирулина [8]. Однако полученные результаты являются трудносопоставимыми, а иногда и полностью противоречивыми. ...
The aim of this article is to represent the characterization of the clinical case of chemotherapy-related atrial fibrillation (AF) development in the young woman, elaborated as a result of multiple neoadjuvant and adjuvant modes of the intake of chemotherapy (both anthracycline based and non-anthracycline ones). In this case, the noted disturbances of heart rhythm should be recognized as a manifestation of cardiotoxicity. The latter implies the degree of detrimental effect of chemotherapeutical medication on the morphophynctional parameters of the cardiovascular system. Anthracycline drugs, being highly effective chemotherapytical agents, provide well-known toxic effects on the heart and vessels. Anthracycline mediated cardiotoxicity is a well- known veracity that dates back to the 60s of the last century, but up to now this medication sustains irreplaceable components of big volume of chemotherapy modes. Moreover, it should be noted that relatively newer drugs also posses certain cardiotoxicogenic potential.
... На сегодняшний день предметом активного изучения служат рациональность профилактического назначения пациентам кардиоонкологического профиля препаратов с кардиопротекторной активностью. Существует множество работ, описывающих кардиопротекторное влияние различных антиоксидантов на целостность кардиомиоцитов и миокарда, среди таких веществ достойными внимания являются куркумин [6], ресвератрол [7] и спирулина [8]. Однако полученные результаты являются трудносопоставимыми, а иногда и полностью противоречивыми. ...
Данная статья представляет описание клинического случая развития фибрилляции предсердий (ФП), ассоциированной с введением препаратов химиотерапевтического ряда. В данном случае отмеченное нарушение ритма является проявлением кардиотоксичности. Последнее подразумевает степень деструктивного воздействия химиопрепарата на структурно-функциональные параметры сердечно-сосудистой системы. Необходимо отметить, что клиническая манифестация кардиотоксичности может быть как острой, т.е. проявиться непосредственно после введения химиопрепарата (часто при вынужденно высоких кумулятивных дозах), отсроченной, так и иметь поздний характер. Высокоэффективные препараты антрациклинового ряда, кардиотоксичность которых известна достаточно давно, продолжают оставаться практически незаменимыми компонентами многих режимов химиотерапии. Стоит отметить, что сравнительно более новые препараты также обладают кардиотоксическим действием. Целью данной статьи является описание клинического случая ФП на фоне приема множественных неоадъювантных и адъювантных режимов химиотерапии, содержащих препараты как антрациклинового ряда, так и других групп.
... Spirulina platensis supplementation resulted in significant improvements in immune function, oxidative stress and pathology of bursa of Fabricius in the current research. Spirulina has been shown to enhance immune function, and growth parameters (Khan et al., 2005). This might be due to limiting the amount of free radicals generated in cells by its antioxidant scavenging activity (Abdel-Daim, 2014). ...
... Several strains of cyanobacteria are known to produce intracellular and extracellular metabolites that exhibit immune stimulant (Hirahashi et al., 2002) and antibacterial (Kaushik and Chauhan 2008) effects. In addition, antiplatelet (Hsiao et al., 2005), anti-cardiotoxic (Khan et al., 2005), anti-nephrotoxic (Khan et al., 2006), anti-hepatotoxic effects (Al-Qahtani and Binobead, 2019) and hypocholesterolemic (Nagaoka et al., 2005) effects were also reported. ...
Spirulina, the blue green algae is considered to exhibit multifaceted benefits on both human health and animal production. A six weeks study was conducted on white broilers (N = 360) categorized in to five treatment groups each comprising nine replicates of 8 chicks. The experiment was carried out during the hot humid summer season (Mid-April to May) under deep litter rearing system with uniform managemental conditions. Birds were administered orally with spirulina through drinking water (DW) in the morning (06:00–12:00 PM) at 5, 10, 15 and 20 g/L concentration. Spirulina supplementation neither improved nor compromised production performance of broilers reared during hot climatic condition. One way ANOVA results indicated a significant (P < 0.05) effect on haemoglobin and total RBC. Serum lipid content and transaminases were reduced, while serum protein concentration was higher (P < 0.01) in the groups administered with 15 and 20 g/L of Spirulina. The extent of imparting shank pigmentation was improved in all the supplemented groups. Cell mediated and humoral immunity against Phytoheamagglutunin-P and Newcastle disease vaccination respectively was maximum (P < 0.05) at 20 g/L. These findings provide direct evidences of dose-related modulation of production, physiological and immunological attributes by spirulina engendering the further investigation of spirulina as a potential source of drinking water supplement for stress alleviation in broilers.In conclusion, DW supplementation of Spirulina at 15 and 20 g/L is optimum for improving the health and welfare attributes of broilers reared during hot summer without compromising production.
... Due to its high content of protein, calcium, iron, and β-carotene, it is often used in the production of dietary supplements. Its biological activity, and above all its strong antioxidant and antiinflammatory activity, can be attributed to compounds such as fatty acids (n−3, n−6), β-carotene, α-tocopherol, phycocyanin, and phenolic compounds [15]. Recent studies suggest that spirulina counteracts DOX-induced cardiotoxicity and, therefore, may improve the therapeutic index of this drug [84]. ...
Cardiotoxicity is a frequent undesirable phenomenon observed during oncological treatment that limits the therapeutic dose of antitumor drugs and thus may decrease the effectiveness of cancer eradication. Almost all antitumor drugs exhibit toxic properties towards cardiac muscle. One of the underlying causes of cardiotoxicity is the stimulation of oxidative stress by chemotherapy. This suggests that an appropriately designed diet or dietary supplements based on edible plants rich in antioxidants could decrease the toxicity of antitumor drugs and diminish the risk of cardiac failure. This comprehensive review compares the cardioprotective efficacy of edible plant extracts and foodborne phytochemicals whose beneficial activity was demonstrated in various models in vivo and in vitro. The studies selected for this review concentrated on a therapy frequently applied in cancer, anthracycline antibiotic—doxorubicin—as the oxidative stress- and cardiotoxicity-inducing agent.
The cyanobacterium , Spirulina sp. is a photosynthetic blue-green alga with essential nutrients, vitamins nucleic acids, proteins, carbohydrates, fatty acids and pigments carotenes; and phycocyanins are the significant components having immunomodulatory, anti-inflammatory properties, which are used in food and cosmetics industries. Spirulina sp. can play an important role in human and animal nutrition for potential health benefits due to their phycochemical and pharmaceutical significance. This study highlights antibacterial, antifungal, antiviral, antioxidant, nephroprotective, cardioprotective, anticancer, neuroprotective, anti-aging, anti-inflammatory, and immunomodulatory properties. It highlights anti-anemic, antidiabetic, probiotic, anti-malarial, anti-obesity and weight loss, anti-genotoxicity, anti-thrombic, radioprotective, and detoxifying effects of Spirulina sp. Pharmaceutical studies indicate it may improve heart health and add to the treatment of diabetes, obesity and weight loss. It can play a major role in protecting the environment by recycling wastewater and providing food for humans and animals. Spirulina sp. can supply ingredients for aquaculture and agricultural feeds, pigments, antioxidants, and essential omega-3 oils, among other human health and wellness products. The amino acid of Spirulina is among the greatest qualititavely of any plant, even higher than that of soybean. Furthermore, cyanobacterium Spirulina sp. could be a future antimicrobial drug agent.
Graphical Abstract
Interstitial cystitis is a fierce syndrome affecting the quality of life of thousands of individuals around the globe. It causes immense pain in the bladder and associated viscera along with inflammation-like lesions. The current medicinal and pharmacological research focuses on the protective and curative effects of phytochemicals in several ailments. Phytochemicals derived from many medicinal plants have shown potent outcomes in protection against various pathological conditions including interstitial cystitis. This review has summarized the insights of in vitro and in vivo studies regarding the effects of phytochemicals in fading the inflammation in bladder tissue and exhibiting a protective effect on the urothelium. Hemorrhagic cystitis is a common manifestation in patients undergoing chemotherapy with cyclophosphamide and related alkylating agents. Sodium 2-mercaptoethane sulfonate (Mesna) has traditionally been employed in clinical practice to counter cyclophosphamide-induced cystitis in humans. However, cyclophosphamide has been employed in developing animal models of interstitial cystitis in in vivo studies. Phytochemicals including quercetin, beta-caryophyllene, curcumol, boswellic acid, caftaric acid, some flavonoids and other secondary metabolites being a consequential component of numerous medicinal plants, have displayed a significant reduction in the levels of proinflammatory cytokines including TNF-α, NFĸB, IL-1β, NLRP3 inflammasome, IL-6, IL-2, matrix metalloproteinases etc. Uroprotective outcomes of these phytochemicals have been found to result in diminished oxidative stress and restoration of glutathione, superoxide dismutase, and related proteins in the inflamed bladder tissue. Many in vivo studies involving cyclophosphamide-induced interstitial cystitis have confirmed these findings. The coupling of phytotherapy with novel drug delivery systems such as nanoparticles, liposomes, nanotubes, quantum dots, etc. can help translate these beneficial effects of phytochemicals into clinical practice. Further investigations of these phytochemicals can provide intuition regarding the development of newer drug molecules having exclusive activity for attenuating interstitial cystitis.
Background: Diabetic neuropathy is a serious complication of diabetes mellitus and exerts powerful pessimistic effect on patient’s life. This neuropathy induced pain is not relieved by taking usual analgesics. At present, several medicinal herbs have gained attention since these exhibit fewer side effects. In this regard, Spirulina platensis is one such herb that various activities beneficial to human health. Objective: To note the influence of oral Spirulina platensis (S.platensis) on hyperglycaemia and mechanical allodynia following its administration into Long Evans rats that have been induced into diabetic neuropathy. Materials and method: This research work was performed between March of 2017 and February of 2019 in the physiology department of BSMMU ( Bangabandhu Sheikh Mujib Medical University),Dhaka. Long Evan rats (12 in number, weighing 150-200g) were distributed in to 2 groups based on intervention. Group 1 was given oral Spirulina platensis, 400 mg/kg body weight while group 2 received normal saline 5ml/kg body weight once daily and here experiment performed was Von Frey test. The experiment was carried out for 21 days. Mean±SEM was used to express the data that was analyzed with SPSS (version 16.0). Comparison between the 2 groups was done by means of independent sample ‘t’ test and significance level was taken at p 0.05 . Results: In this study, Spirulina platensis demonstrated significant reduction in blood glucose level (p≤0.01) and higher paw withdrawal threshold (p 0.001) of diabetic rats in estimation of random blood glucose level and Von Frey test respectively. Conclusion: The present study concluded that, S. platenis attenuates hyperglycaemia and mechanical allodynia in rats with diabetic neuropathic pain. J Med Coll Women Hosp.2024;20(2): 56-63
Özet: Spirulina cinsi üyelerinin, diğer birçok siyanobakteri türü gibi çok sayıda antimikrobiyal madde üretme potansiyeline sahip olduğu bilinmektedir. Bu çalışmada amaç ticari olarak satın alınan toz formundaki Spirulina platensis’in üç farklı çözücü kullanılarak yedi bakteri ve iki fungusa karşı antimikrobiyal aktivitesinin belirlenmesidir. Spirulina platensis’in üç farklı (aseton, hekzan, metanol) çözücü kullanılarak ekstraktları elde edilmiştir. Ekstraktların yedi patojen bakteri (Bacillus cereus ATCC 10987, Bacillus subtilis ATCC 6623, Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 70060, Pseudomonas aeruginosa ATCC 27853) ve iki fungusa (Candida albicans ATCC 10231, Aspergillus niger ATCC 16404) karşı antimikrobiyal aktivitesi disk difüzyon yöntemi kullanılarak beş farklı konsantrasyonda (30 mg/ml, 15 mg/ml, 6 mg/ml, 3 mg/ml ve 1 mg/ml) belirlenmiştir. Çalışma sonuçları değerlendirildiğinde kullanılan çözücüler arasında en iyi sonucu metanolden elde edilen ekstrakt vermiştir. Metanolden elde edilen ekstrakt Bacillus cereus ATCC 10987, Bacillus subtilis ATCC 6623, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 70060 ve Pseudomonas aeruginosa ATCC 27853 karşı antimikrobiyal aktivite gösterirken, hekzandan elde edilen ekstrakt Bacillus cereus ATCC 10987 ve Bacillus subtilis ATCC 6623 karşı aktivite göstermiş, asetondan elde edilen ekstrakt ise sadece Pseudomonas aeruginosa ATCC 27853 karşı antimikrobiyal aktivite göstermiştir. Metanol, aseton ve hekzandan elde edilen ektraktlar kullanılan funguslara karşı aktivite göstermemiştir.
Cisplatin (CP) is a chemotherapy drug used in a broad spectrum of cancer. The current study investigated the protective effect of vitamin D3 (vit-D3) on CP-induced cardiotoxicity. Forty-two male Balb-c mice (20–25 g) were divided into seven groups (GP), 6 per/group were included: GP1 was considered the control group, GP2 received a single dose of I.V. injection of cisplatin (10 mg/kg). Seven days before cisplatin injection on GP3 and GP4 as pre-treatment, vit-D3 was injected I.P. with the doses of 500 IU/kg and 1000 IU/kg, respectively. GP5 and GP6 were considered the treatment groups, were injected cisplatin (10 mg/kg, I.V), and 15 days later, received vit-D3 (500 IU/kg and 1000 IU/kg, I.P) for 7 days. GP7 was the positive control group, which received vit-D3 at a dose of 500 IU/kg (I.P.) for 7 days. Tissues samples and blood serum were collected for biochemical and histopathological investigations. CP injection significantly increased (p < 0.001) LDH, Troponin I, CK-MB, malondialdehyde (MDA), and nitric oxide (NO) levels, but total antioxidant capacity (TAC) levels were significantly reduced. Histological findings showed cardiac muscle rupture, myocardial fiber necrosis, edema, and pyknotic nuclei, indicating cardiac damage. In both pre-treatment and treatment protocol, vit-D3 could improve the histological and biochemical parameters and prevented from the CP toxicity. Vit-D3 significantly could prevent the CP cardiotoxicity in pre-treatment groups, and partially improve the damage of chemotherapy in treatment group. However, further research is necessary to establish the potential of vit-D3 in preventing or ameliorating cisplatin-induced cardiotoxicity.
Background-Freshwater microalgae called spirulina have been consumed for many years as a dietary supplement. This algae possesses a diversified concentration of nutrients and has been known as a wonder medicine due to its many applications. It promotes immunity and resistance to several illness. Spirulina possesses a high content of proteins, essential amino acid, lipids, polysaccharides, dietary minerals, vitamins, and fatty acids which is responsible for its pharmacological action like antimicrobial effect, anticancer and metaloprotective effect, potent immunostimulant and antioxidant effects. Methodology-The experimental analysis and data reported on the species of spirulina were reviewed since the year 2005 to 2021.Various database were used as article source like Medline and Pubmed and literature review was done by using the key words spirulina, habitat, species, pharmacological action, toxicities and traditional uses. Result-This article provides an outline of this algae's basic biochemical makeup before moving on to its potential uses in medicine. The fundamental description of the illness, the mechanism of harm, the specific Spirulina spp. content for therapy, in vivo and/or in vitro usage, variables related with therapeutic role, challenges encountered, and benefits are presented for each application.
A hemorrhagic fever caused by the Marburg virus (MARV) belongs to the Filoviridae family and has been classified as a risk group 4 pathogen. To this day, there are no approved effective vaccinations or medications available to prevent or treat MARV infections. Reverse vaccinology-based approach was formulated to prioritize B and T cell epitopes utilizing a numerous immunoinformatics tools. Potential epitopes were systematically screened based on various parameters needed for an ideal vaccine such as allergenicity, solubility, and toxicity. The most suitable epitopes capable of inducing immune response were shortlisted. Epitopes with population coverage of 100% and fulfilling set parameters were selected for docking with human leukocyte antigen molecules, and binding affinity of each peptide was analyzed. Finally, 4 CTL and HTL each while 6 B cell 16-mers were used for designing multiepitope subunit (MSV) and mRNA vaccine joined via suitable linkers. Immune simulations were used to validate the constructed vaccine’s capacity to induce a robust immune response whereas molecular dynamics simulations were used to confirm epitope-HLA complex stability. Based on these parameter’s studies, both the vaccines constructed in this study offer a promising choice against MARV but require further experimental verification. This study provides a rationale point to begin with the development of an efficient vaccine against Marburg virus; however, the findings need further experimental validation to confirm the computational finding of this study.
This study was performed to examine the influences of Spirulina platensis powder (SPP) on growth performance, physiological status, blood biochemistry, and intestinal microbial population in quail. 240-10-days old Japanese quail chicks were distributed into five groups. Each group had four replicate pens with 12 birds each. The first group received a basal diet (control group). Groups from two to five received the basal diet with SPP at levels of 1.5, 3.0, 4.5, and 6.0% as dietary ingredients, respectively. Results clarified significantly higher live body weight and body weight gain (p < 0.001) with significant enhancements (p < 0.001) in feed conversion values for groups that received SPP levels, especially 4.5% compared with the control and other groups. Birds fed on a diet containing SPP had significantly higher amylase, trypsin and lipase levels (p < 0.001) than the control. Intestinal Lactobacillus sp. was significantly increased, and Escherichia coli and Salamonella populations were significantly decreased by dietary SPP levels (p < 0.001). Liver function, total lipid profile, antioxidant parameters and immune response were significantly affected by SPP levels compared with the control (p < 0.001). In conclusion, the inclusion of SPP until 4.5% in quail diets could improve the growth performance, intestinal microbial population and serum biochemical constituents of growing quail.
The major contributor for various diseases like cardiac failures, diabetes, obesity, cancer, etc., is unhealthy diets followed in frequently changing lifestyle of consumers. Nowadays, they need food not only as a source of energy but to treat and cure diseases. Those substances or compounds said to provide energy, nutritional, and health benefits are known as nutraceuticals and functional foods. This opened up the need to recognize spirulina as nutraceuticals because of its promising health promoting nutrients and bioactive compounds. It is a filamentous photosynthetic blue-green algal biomass that can be industrially cultivated, harvested, and processed. Some of the nutraceutical properties of spirulina are promoting growth, immune booster, antimicrobial, antioxidant, anticancer, antidiabetic property. Also,spirulina can be incorporated into various food products to enhance its nutraceutical value.
Anthracyclines (ANTs) continue to play an irreplaceable role in oncology treatment. However, the clinical application of ANTs has been limited. In the first place, ANTs can cause dose-dependent cardiotoxicity such as arrhythmia, cardiomyopathy, and congestive heart failure. In the second place, the development of multidrug resistance (MDR) leads to their chemotherapeutic failure. Oncology cardiologists are urgently searching for agents that can both protect the heart and reverse MDR without compromising the antitumor effects of ANT. Based on in vivo and in vitro data, we found that natural compounds, including saponins, may be active agents for other both natural and chemical compounds in the inhibition of anthracycline-induced cardiotoxicity (AIC) and the reversal of MDR. In this review, we summarize the work of previous researchers, describe the mechanisms of AIC and MDR, and focus on revealing the pharmacological effects and potential molecular targets of saponins and their derivatives in the inhibition of AIC and the reversal of MDR, aiming to encourage future research and clinical trials.
Hypertension is one of the major issues worldwide and one of the main factors involved in heart and kidney failure. Angiotensinogen and renin are key components of the renin–angiotensin–aldosterone system, which plays an indispensable role in hypertension. The aim of this study was to find out the non‐synonymous mutations and structure‐based mutation‐function correlation in the renin–AGT complex and reveal the most deleterious mutations to accelerated hypertension. In the current study, we employed computational modeling and molecular simulation approaches to demonstrate the impact of specific mutations in the REN‐AGT interface in hypertension. Computational algorithms, that is, PhD‐SNP, PolyPhen‐1, MAPP, Sorting Intolerant from Tolerant, Screening of non‐acceptable polymorphism, PredictSNP, PolyPhen‐2, and Protein Analysis Through Evolutionary Relationships predicted 20 mutations as deleterious in AGT while only five mutations were confirmed as deleterious in the renin protein. Investigation of the bonding analysis revealed that two mutations S107L and V193F in renin altered the hydrogen‐bonding paradigm at the interface site. Furthermore, exploration of structural‐dynamic behaviors demonstrated by that these mutations also increases the structural stability to regulate the expression of disease pathway. The flexibility index of each residues and structural compactness analysis further validated the findings by portraying the difference in the dynamic behavior in contrast to the wild type. Binding energy calculations based on molecular mechanics/generalized Born surface area methods were used which further established the binding differences between the wild type, S107L, and V193F mutant variants. The total binding energy for wild type, S107L, and V193F was reported to be −27.79, −47.72, and −38.25, respectively. In conclusion, these two mutations increase the binding free energy alongside the docking score to enhance the binding between renin and AGT to overexpress this pathway in a hypertension disease condition. Patients with these mutations may be screened for potential therapeutic intervention.
The current state of the food system is an important problem, the solution of which is aimed at meeting the needs of the food market and the population in food products of domestic production at the level of necessary consumption. To increase the sustainability of the development of the food system, it is necessary to stimulate economic activity, create conditions for accessibility to attracted resources and economic activity. The promotion of new business models of production with the participation of microalgae Spirulina platensis and products based on it can play a certain role in solving the problem of food supply.
There are several reasons to assign a special role to cyanobacteria in the main challenges facing humanity in the 21st century. Their utilization and production are increasing, in a rapidly evolving situation, with maintenance and increasing of health in a central place. Although there are several indications that in the near future these microorganisms may play a key role, in accordance with lifestyle and dietary changes, their nutritional and pharmacological importance is still underestimated. Nevertheless, the scientific evidence in this area is now a reference in respect of the increased use and the growing economic interest of cyanobacteria. In this chapter, it will be explored why these organisms are necessary in several fields, from nutraceutical to pharmacological utilizations. In fact, despite the large number of species, the current market and interest are mainly focused on Spirulina, Alga Klamath, and Nostoc raw materials, although other species may be considered of potential interest. However, in contrast with the current commercial tendency and consumers attitude, there are several differences in constitution and properties of each species, which therefore are here carefully reported. It is also necessary to emphasize some exaggerations due to marketing, which gives cyanobacteria the impressive role of “superfood,” instead of specifying their real capabilities. Finally, a special attention must be dedicated to the quality control of the raw materials and the marketed products, since several factors can deeply influence their quality and therefore their adequate utilization. The first part of this chapter will be dedicated to the general aspects of cyanobacteria, whereas in the second part a monograph will concern each of the aforementioned species. Finally, general thoughts on the future utilization of cyanobacteria are presented to the consideration of everyone.
Cyanobacteria are among the most successful and ancient forms of life ever known. These photosynthetic autotrophs have been studied for decades as model organisms in various aspects, from photosynthesis to biotechnological applications and, more recently, for their pharmacological potential in umpteen fields. In fact, cyanobacteria are now recognized as top metabolic producers of a huge number of bioactive compounds with medical interest and that can revolutionize drug discovery and development. Allied to their metabolic capabilities, cyanobacteria benefit from a cost-effective energy-capturing ability, and high cultivation yields with minimum nutritional requirements, being extremely attractive in terms of industrial-scale production processes. This book was designed to bring together fields in which cyanobacteria derived compounds most stood out, with a special focus on those related to therapeutics, cosmetics, and nutrition, emphasizing unique molecules not found in higher organisms. Of the most promising compounds isolated so far, those acting as anti-inflammatories, anti-carcinogens, antimicrobials, and UV protectors fill a prominent place within drug discovery programs. The metabolic richness of cyanobacteria has also been upholding their key role in the field of cosmetics and nutraceuticals, with the last occupying a prominent place in a rapidly expanding market. Apart from the pharmacological and biotechnological approach, this book does not set aside the well-known cyanobacterial toxins, warning to their substantial economic and social impacts, and drawing attention to the urgency of fully addressing algal blooms and their systematic monitoring. Additionally, and given its extreme importance, this book provides a distinctive approach to cyanobacteria systematics, by exploring general aspects and biodiversity of these organisms to discuss trends in cyanobacterial taxonomy. Overall, The Pharmacological Potential of Cyanobacteria is intended to be a useful resource for students, researchers, and professionals working in the field of cyanobacteria, serving as a guide in the discovery, research, and application of these unique microorganisms. Graciliana Lopes, Marisa Silva and Vitor Vasconcelos
PREFACE
Cyanobacteria are among the most successful and ancient forms of life ever
known. These photosynthetic autotrophs have been studied for decades as model
organisms in various aspects, from photosynthesis to biotechnological applications
and, more recently, for their pharmacological potential in umpteen fields. In fact,
cyanobacteria are now recognized as top metabolic producers of a huge number
of bioactive compounds with medical interest and that can revolutionize drug discovery
and development. Allied to their metabolic capabilities, cyanobacteria benefit
from a cost-effective energy-capturing ability, and high cultivation yields
with minimum nutritional requirements, being extremely attractive in terms of
industrial-scale production processes.
This book was designed to bring together fields in which cyanobacteria derived
compounds most stood out, with a special focus on those related to therapeutics,
cosmetics, and nutrition, emphasizing unique molecules not found in
higher organisms. Of the most promising compounds isolated so far, those acting
as anti-inflammatories, anti-carcinogens, antimicrobials, and UV protectors fill a
prominent place within drug discovery programs. The metabolic richness of cyanobacteria
has also been upholding their key role in the field of cosmetics and
nutraceuticals, with the last occupying a prominent place in a rapidly expanding
market. Apart from the pharmacological and biotechnological approach, this book
does not set aside the well-known cyanobacterial toxins, warning to their substantial
economic and social impacts, and drawing attention to the urgency of fully
addressing algal blooms and their systematic monitoring. Additionally, and given
its extreme importance, this book provides a distinctive approach to cyanobacteria
systematics, by exploring general aspects and biodiversity of these organisms to
discuss trends in cyanobacterial taxonomy.
Overall, The Pharmacological Potential of Cyanobacteria is intended to be a
useful resource for students, researchers, and professionals working in the field of
cyanobacteria, serving as a guide in the discovery, research, and application of
these unique microorganisms.
Graciliana Lopes, Marisa Silva and Vitor Vasconcelos
An enzyme which catalyzes the dismutation of superoxide radicals (O2·⁻ + O2·⁻ + 2H⁺ → O2 + H2O2) has been purified by a simple procedure from bovine erythrocytes. This enzyme, called superoxide dismutase, contains 2 eq of copper per mole of enzyme. The copper may be reversibly removed, and it is required for activity. Superoxide dismutase has been shown to be identical with the previously described copper-containing erythrocuprein (human) and hemocuprein (bovine).
Stable solutions of the superoxide radical were generated by the electrolytic reduction of O2 in an aprotic solvent, dimethylformamide. Slow infusion of such solutions into buffered aqueous media permitted the demonstration that O2·⁻ can reduce ferricytochrome c and tetranitromethane, and that superoxide dismutase, by competing for the superoxide radicals, can markedly inhibit these reactions.
Superoxide dismutase was used to show that the oxidation of epinephrine to adrenochrome by milk xanthine oxidase is mediated by the superoxide radical.
An assay of several tissues indicates that superoxide dismutase is widely distributed within mammalian organisms.
The purpose of this study was to determine the acute effects of doxorubicin and its less cardiotoxic epimer, 4'-epirubicin, on the contractile response of isolated myocytes, and to assess similarities or differences with respect to active oxygen-derived mechanisms. Calcium-tolerant myocytes from rat ventricle were field stimulated at 1.0 Hz, and the maximum extent of cell shortening, peak shortening velocity, and peak relaxation velocity of single twitches were measured by video edge detection. The contractile responses of the myocytes to the two anthracyclines were approximately equal. Exposure of the cells to 10 mu M of either anthracycline for 20 min decreased all indices of contractility by 28% (p < 0.05). The active oxygen scavengers, superoxide dismutase and catalase, distinguished the extent to which active oxygen was involved in modifying cellular contractility. Paradoxically, superoxide dismutase done (10 U/mL) decreased contractility by 21%. Nevertheless, superoxide dismutase (10 U/mL) prevented the decreases in contractility produced by doxorubicin. In contrast, superoxide dismutase only mildly (32%) protected against 4'-epirubicin. Catalase (10 U/mL), however, provided substantial (82-93%) protection against both anthracyclines. Hydrogen peroxide therefore, and presumably hydroxyl radicals, were involved in mediating the decreases in contractility from both doxorubicin and 4'-epirubicin. These results show that an acute exposure to clinically relevant concentrations of these anthracyclines significantly depresses myocyte contractility and that, in this respect, 4'-epirubicin is as potentially cardiotoxic as doxorubicin. The results with antioxidant enzymes also strongly support a free radical mechanism for the toxicity of doxorubicin and 4'-epirubicin to cardiomyocytes.
Free radicals are potentially dangerous for the cell, although in vivo they may be generated by metabolism. These radicals can be classified into two groups: (1) oxygen-derived radicals and active oxygen species, including superoxide anion radical, hydroxyl radical, hydrogen peroxide, and singlet molecular oxygen and (2) organic radicals that usually originate in the course of lipid peroxidation. According to the location in which they are generated, oxygen-derived radicals react mainly with components in the aqueous phases, such as extra- and intracellular fluids, while organic radicals interact mainly with constituents of the hydrophobic membranous phase. This chapter investigates the antioxidant activity of carotenoids and retinoids compared to α-tocopherol and its homologs. For the assay in the aqueous phase, a modified method of a phycoerythrin fluorescence-based procedure is used, whereas for the assay in the hydrophobic phase, a new cis-parinaric acid fluorescence-based assay is developed.
Adult houseflies fed a low-selenium diet showed a 73% decrease in total Se compared to those given 1.0 ppm Se in their drinking water. This decrease was associated with a 84.4% increase in thiobarbituric acid reactants and a 16.3% increase in conjugated dienes. These increases were unrelated to activities of glutathione S-transferases, superoxide dismutases and catalase and to levels of reduced and oxidized glutathione, all of which were unaltered by Se deficiency. Since houseflies lack glutathione peroxidase, Se apparently modulates peroxidation in these animals independent of the antioxidant enzymes and glutathione.
In the accompanying paper (Davies, K. J. A., and Doroshow, J. A. (1986) J. Biol. Chem. 261, 3060-3067), we have demonstrated that anthracycline antibiotics are reduced to the semiquinone form at Complex I of the mitochondrial electron transport chain. In the experiments presented in this study we examined the effects of doxorubicin (Adriamycin), daunorubicin, and related quinonoid anticancer agents on superoxide, hydrogen peroxide, and hydroxyl radical production by preparations of beef heart submitochondrial particles. Superoxide anion formation was stimulated from (mean +/- S.E.) 1.6 +/- 0.2 to 69.6 +/- 2.7 or 32.1 +/- 1.5 nmol X min-1 X mg-1 by the addition of 90 microM doxorubicin or daunorubicin, respectively. However, the anthracycline 5-iminodaunorubicin, in which an imine group has been substituted in the C ring quinone moiety, did not increase superoxide production over control levels. In the presence of rotenone, initial rates of oxygen consumption and superoxide formation were identical under comparable experimental conditions. Furthermore, H2O2 production increased from undetectable control levels to 2.2 +/- 0.3 nmol X min-1 X mg-1 after treatment of submitochondrial particles with doxorubicin (200 microM). The hydroxyl radical, or a related chemical oxidant, was also detected after the addition of an anthracycline to this system by both ESR spectroscopy using the spin trap 5,5-dimethylpyrroline-N-oxide and by gas chromatographic quantitation of CH4 produced from dimethyl sulfoxide. Hydroxyl radical production, which was iron-dependent in this system, occurred in a nonlinear fashion with an initial lag phase due to a requirement for H2O2 accumulation. We also found that two quinonoid anti-cancer agents which produce less cardiotoxicity than the anthracyclines, mitomycin C, and mitoxantrone, stimulated significantly less or no hydroxyl radical production by submitochondrial particles. These experiments suggest that injury to cardiac mitochondria which is produced by anthracycline antibiotics may result from the generation of the hydroxyl radical during anthracycline metabolism by NADH dehydrogenase.
This investigation examined the potential of N-acetylcysteine (NAC) and ICRF-187, alone and in combination, to protect against chronic doxorubicin cardiotoxicity. Adult beagles of either sex (7.3 to 12.5 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 30 min after either ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), or ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.), or 0.9% NaCl solution without doxorubicin. The experiment was terminated 3 weeks after the seventh injection (total doxorubicin dose, 12.25 mg/kg). Three animals pretreated with NAC and one pretreated with ICRF-187 before receiving doxorubicin died or were in poor condition and were killed before the end of the study. The frequency and extent of myocardial lesions (vacuolization and myofibrillar loss) were assessed on a scale of 0 to 4+. Such lesions were present in all six dogs given doxorubicin alone and were marked to severe (3+ to 4+) in five of these dogs and moderate (2+) in one. Lesions of comparable severity (2+ to 4+) were also apparent in the hearts of dogs given the combination of NAC and doxorubicin. In contrast, no abnormalities (lesion score 0) were found in the hearts of three of six dogs given doxorubicin and ICRF-187 and in four of six dogs given doxorubicin following the combination of ICRF-187 and NAC; the remaining animals in these two groups had minimal lesions. At the dosage regimen used in the present experiments, doxorubicin, NAC, or ICRF-187 alone or in combination did not cause alterations in lungs, liver, kidney, or small intestine. Decreases in WBC count, RBC count, and hemoglobin occurred in dogs given doxorubicin with or without the various pretreatments. Thus, pretreatment with ICRF-187 was effective and pretreatment with NAC was ineffective in reducing chronic doxorubicin cardiotoxicity.
PURPOSETo test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer.PATIENTS AND METHODS
Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients).RESULTSWe previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less ...
A method for the screening of antioxidant activity is reported as a decolorization assay applicable to both lipophilic and hydrophilic antioxidants, including flavonoids, hydroxycinnamates, carotenoids, and plasma antioxidants. The pre-formed radical monocation of 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS*+) is generated by oxidation of ABTS with potassium persulfate and is reduced in the presence of such hydrogen-donating antioxidants. The influences of both the concentration of antioxidant and duration of reaction on the inhibition of the radical cation absorption are taken into account when determining the antioxidant activity. This assay clearly improves the original TEAC assay (the ferryl myoglobin/ABTS assay) for the determination of antioxidant activity in a number of ways. First, the chemistry involves the direct generation of the ABTS radical monocation with no involvement of an intermediary radical. Second, it is a decolorization assay; thus the radical cation is pre-formed prior to addition of antioxidant test systems, rather than the generation of the radical taking place continually in the presence of the antioxidant. Hence the results obtained with the improved system may not always be directly comparable with those obtained using the original TEAC assay. Third, it is applicable to both aqueous and lipophilic systems.
In order to test the possible cardiac-sparing effect of doxorubicin admininstered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall In resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m² was 0.06 (p <0.005); at 301 to 449 mg/m² it was 0.09 (p <0.0005); and at 450 mg/m² or greater it was 0.15 (p <0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the “normal range” (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 nM. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus Infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should Include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to Include deteriorations In function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage.
Adriamycin (ADR) is a potent, broad-spectrum chemotherapeutic agent whose clinical use is limited by its cardiotoxicity. Since the pathogenesis of ADR-induced cardiomyopathy may involve free radicals and lipid peroxidation, the antioxidant, melatonin (MEL) may protect against toxic effects of ADR. We therefore tested this hypothesis using a rat model of ADR-induced cardiomyopathy. Sprague-Dawley rats were given ADR (cumulative dose, 15 ), MEL (cumulative dose, 84 ), ADR + MEL, ADR plus probucol (PRB, cumulative dose, 90 ), or vehicle alone, according to known regimens. The rats were maintained for 3 weeks following treatment, after which their cardiac performance was measured. Following sacrifice, their myocardial ultrastructure was examined, and their myocardial lipid peroxidation was assessed. Mortality was observed only in rats treated with ADR alone. When compared to control rats, surviving rats in the ADR group showed significant decreases in ratio of heart to body weight, arterial pressure, and left ventricular fractional shortening, as well as a significant accumulation of ascites. The amount of myocardial thiobarbituric acid reactive substances was significantly higher in ADR-treated than in control rats. Both antioxidants, MEL and PRB, significantly prevented these ADR-induced changes. Electron microscopic examination revealed myocardial lesions indicative of ADR-induced cardiomyopathy in the ADR-treated rats. In contrast, treatment of these rats with MEL or PRB preserved myocardial ultrastructure. By preventing lipid peroxidation, MEL may be highly effective in protecting against ADR-induced cardiomyopathy.
In view of the important role of superoxide in cellular injury, there has been a great need for methods suitable for quantitation of superoxide production from cells. Previous methods have had limited sensitivity or specificity as well as problems with side reactions in cellular systems. Recently, we have shown that the new spin trap 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide has ideal properties for quantitative superoxide measurement in chemical/biochemical systems; however, its suitability and potential for measurements in cellular systems has not been determined. Therefore, we evaluated the use of DEPMPO for quantitative measurement of superoxide formed by polymorphonuclear leukocytes. After activation of these cells with the phorbol ester (PMA, 200 ng/ml) or opsonized zymosan (1 mg/ml) at 24 degrees C a strong signal of the superoxide adduct, DEPMPO-OOH, was observed. This technique was highly sensitive and enabled measurement of superoxide generation from as few as 2 x 10(3) cells. The kinetics of adduct formation and decay were measured which enabled quantitation of superoxide formation. Spin label electron paramagnetic resonance (EPR) oximetry was used to measure the oxygen consumption from these cells. With PMA activation rapid onset of superoxide generation occurred with a rate of 0.78 nmol/min/10(6) cells while with zymosan a slower gradual onset of activation was seen to a peak rate of 0.061 nmol/min/10(6) cells. With both stimulators the ratios of superoxide production to oxygen consumption were similar with values of approximately 50% obtained. Thus, EPR spin trapping with DEPMPO together with EPR oximetry methods can be used to provide sensitive and specific quantitation of cellular superoxide generation and oxygen consumption. These methods provide a promising new approach for the measurement of oxygen reduction and superoxide generation in cellular systems.
A review is presented of cardiac pathologic changes associated with acute and chronic toxicity of anthracyclines. These changes consist of cardiac dilatation, degeneration and atrophy of the muscle cells, and interstitial edema and fibrosis. The degeneration of cardiac muscle cells is a complex phenomenon that involves the myofibrils, the nucleus, the mitochondria and the membrane systems of the T-tubules, the sarcoplasmic reticulum, and the intercellular junctions. The pathogenesis of these alteration is discussed in terms of the biochemical effects of anthracyclines.
Potential risk factors responsible for development of doxorubicin-induced congestive heart failure were examined through retrospective analysis of 4018 patient records. The overall incidence of drug-induced congestive heart failure was 2.2% (88 cases). The probability of incurring doxorubicin-induced congestive heart failure was related to the total dose of doxorubicin administered. There was a continuum of increasing risk as the cumulative amount of administered drug increased. A weekly dose schedule of doxorubicin was associated with a significantly lower incidence of congestive heart failure than was the usually employed every 3-week schedule. An increase in drug-related congestive heart failure was also seen with advancing patient age. Performance status, sex, race, and tumor type were not risk factors. These data will enable clinicians to better estimate the risk/benefit ratio in individual patients receiving prolonged administration of doxorubicin. They also provide a basis for the investigation of less cardiotoxic anthracycline analogues or for designing measures to prevent doxorubicin-induced cardiomyopathy.
Seventy-six endomyocardial biopsies obtained from 60 patients receiving adriamycin (ADM) and other anthracycline analogs were studied. The biopsies were studied by light and electron microscopy. Two main types of myocyte degeneration were consistently present, the lesions were focal, and inflammatory infiltrate was absent. The severity of pathologic changes was graded on a scale from 0 (normal) to 3 (marked abnormality). Twelve patients receiving previous mediastinal irradiation (600-5700 rads) showed a mean pathology grade (2.0 +/- 0.89) that was significantly higher than in those patients receiving a comparable dose of ADM but who were not irradiated (1.18 +/- 0.23) (P less than 0.01). This study indicated that radiation, even if remote, enhances ADM-induced cardiotoxicity and evokes a "recall" phenomenon of latent acute irradiation changes. Our data suggest that a specific, progressive, subclinical injury to the heart occurs with anthracycline therapy that cannot be detected reliably by conventional tests. Anthracycline-induced cardiotoxicity in rabbits, monkeys, and dogs shows the same basic cellular lesions as in man. The analogs, adria-DNA and rubidazone, also show lesions similar to those produced by ADM in the human heart. The endomyocardial biopsy is a reliable method for monitoring cardiac damage due to anthracyclines in man.
The antitumor antibiotic, adriamycin, induces severe cardiac toxicity associated with peroxidation of cardiac lipids in mice. Both this lipid peroxidation and cardiac toxicity of adriamycin are reduced by prior treatment of the animals with the free radical scavenger tocopherol. Such treatment with tocopherol does not, however, alter the magnitude or duration of the adriamycin-induced suppression of DNA synthesis in P388 ascites tumor, nor does it diminish the antitumor responsiveness of P388 ascites tumor. These results suggest that adriamycin has at least two mechanisms of tissue damage: one, which involves lipid peroxidation, is blocked by tocopherol and results in cardiac toxicity; the other, which involves binding to DNA, is not antagonized by tocopherol and is responsible for tumor response.
The cardiotoxicity of seven anthracycline antibiotics was evaluated in small groups of rats treated with repeated intraperitoneal injections. The electrocardiogram showed a widening of the QRS complex often with the appearance of a distinct S-wave trough and occasionally with an increase or flattening of the T wave. Ventricular extrasystoles, intraventricular block, bradycardia, and heart failure developed either during treatment or after discontinuation of therapy. Based on the cumulative dose required to induce significant electrocardiographic changes, the compounds were ranked in the following order of decreasing cardiotoxicity: adriamycin, daunorubicin, NSC-149584, rubidazone, NSC-143496, daunomycin-semicarbazone, and NSC-118714. For three of these compounds used in humans (adriamycin, daunorubicin, and rubidazone) the rat screening results are in good agreement with the clinically observed cardiotoxicity.
The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S alpha T-segment widening and T-wave flattening) and by impairment of the contractile responses (Fmax, +/- dF/dtmax) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S alpha T segment in vivo and a significant impairment of the -dF/dtmax value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR.
To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer.
Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients).
We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity.
By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.
The role of free radicals in adriamycin (Adr)-induced acute myocardial changes was examined by using different antioxidants. Exposure of papillary muscles to Adr (100 microM) in a tissue bath for 60 min reduced developed force by 42%, increased lipid peroxidation by 200%, and resulted in characteristic ultrastructural changes. Catalase (4 x 10(4) U/l), an enzyme effective in the hydrolysis of hydrogen peroxide (H2O2), was more effective in maintaining the developed force than mannitol (20 mM), a hydroxyl radical scavenger. A small protection of developed force seen with superoxide dismutase (1.2 x 10(5) U/l), a quencher of superoxide radical, was evident for the first 15 min only. Only catalase and mannitol showed significant protection against Adr-induced increase in lipid peroxidation. Ultrastructural changes due to Adr alone included mitochondrial swelling, intramitochondrial granules, vacuolization, and disruption of sarcomeres. All of these changes were reduced in the presence of both catalase and mannitol, whereas superoxide dismutase was without any effect. Complete structural or functional protection was not seen with any of the antioxidants used in the study. Although both H2O2 and hydroxyl radical appear to be involved in Adr-induced deleterious effects, data on developed force also indicate that H2O2 may have a major role in mediating the acute effects of Adr in vitro.
Alteration in oxidant-antioxidant balance is a key feature of many common vascular diseases. Using an isolated perfused heart model, we found that (a) xanthine oxidase-derived oxygen radicals contributed to ischemia-reperfusion injury; (b) addition of antioxidants within or outside erythrocytes decreased injury following ischemia-reperfusion; (c) endotoxin pretreatment increased myocardial catalase activity and decreased injury following ischemia-reperfusion; (d) interleukin pretreatment increased myocardial glucose-6-phosphate activity and decreased ischemia-reperfusion injury, and (e) neutrophils mediated tolerance to a subsequent oxidative stress by causing a small oxidant stress that in turn increased antioxidant protection mechanisms.
Doxorubicin (Adriamycin) and the related anthracycline antibiotic daunorubicin play a central part in cancer therapy because of their efficacy in the treatment of hematologic cancers (both acute leukemias and lymphomas), as well as carcinomas of the breast, lung, and thyroid and bone and soft-tissue sarcomas.1 Furthermore, these drugs are widely used in both adults and children in treatment regimens aimed at the cure of neoplasms as well as at palliation. The discovery more than 20 years ago that therapy with anthracyclines could produce irreversible and possibly life-threatening cardiac injury has led to limitations on the use of these drugs in . . .
The effects of Spirulina platensis on lipoprotein lipase activity and hepatic triglyceride lipase activity in post-heparin plasma were studied in fructose-induced hyperlipidemic rats. Male Wistar rats aged 3 weeks old (body weight, 54 g) were fed on the high-fructose diet (68%) or the high-fructose diets containing Spirulina at the level of 5, 10, and 15%, respectively, for 4 weeks. The dietary hyperlipidemia caused by the high-fructose diet was improved by Spirulina feeding, accompanied by a significant increase in the lipoprotein lipase activity in post-heparin plasma.
Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents that produce a well-described but incompletely understood cardiac toxicity. According to a popular hypothesis, anthracyclines injure the heart by generating oxygen-centered free radicals. This free radical hypothesis, however, appears to be inconsistent with many observations, such as the frequent failure of anthracyclines at cardiotoxic doses to produce evidence of increased free radical generation. Other explanations of cardiotoxicity involve platelet-activating factor, prostaglandins, histamine, calcium, and C-13 hydroxy anthracycline metabolites. These C-13 hydroxy metabolites, on the basis of in vitro data, are considerably more potent than parent compounds as myocardial depressants and as inhibitors of ATPases of sarcoplasmic reticulum, mitochondria, and sarcolemma. Further studies will be required to determine whether metabolites or the other putative injurious agents discussed contribute substantially to the cardiomyopathy of anthracycline therapy. The hypotheses presented in this paper should provide a useful framework for subsequent investigations into the mechanisms of anthracycline cardiotoxicity.
The effect of algae extract on tumor regression was studied. Phycotene (extract of Spirulina and Dunaliella algae) 250 micrograms in 0.1 ml MEM (minimum essential medium) was injected locally into DMBA (7, 12 dimethylbenz(a)anthracene)-induced squamous cell carcinomas of hamster buccal pouch in 20 animals. DMBA-induced carcinomas in 20 hamsters were injected locally with beta carotene 250 micrograms in 0.1 ml MEM; DMBA-induced carcinomas in 20 animals were injected locally with canthaxanthin, 250 micrograms in 0.1 ml MEM, and DMBA-induced carcinomas in 20 animals were injected locally with 13-cis-retinoic acid, 250 micrograms in 0.1 ml MEM. Twenty animals with DMBA-induced carcinomas were sham-injected controls using 0.1 ml MEM. The various agents were injected into the tumor bearing right buccal pouches twice-weekly for four weeks. Total tumor regression was found in 30% of phycotene animals, 20% of beta carotene animals and 15% of canthaxanthin animals after four weeks. Partial tumor regression was found in the remaining 70% of phycotene animals, 80% of beta carotene animals and 85% of canthaxanthin animals. None of the 13-cis-retinoic acid animals had total tumor regression, but 70% showed partial regression. No tumor regression was found in the DMBA control group and the sham-injected group.
An extract of Spirulina-Dunaliella algae was shown to prevent tumor development in hamster buccal pouch when a 0.1% solution of 7,12-dimethylbenz[a]anthracene (DMBA) in mineral oil was applied topically three times weekly for 28 weeks. The algae extract was delivered by mouth in continued dosages of 140 micrograms in 0.4 ml mineral oil three times per week. After 28 weeks, the animals given vehicle and untreated controls all presented gross tumors of the right buccal pouch. Animals fed canthaxanthin presented a notably and statistically significant reduction in tumor number and size compared with controls. Animals fed beta-carotene demonstrated a smaller but statistically significant reduction in tumor number and size. The algae animals presented a complete absence of gross tumors. However, microscopic sections of the buccal pouch in the algae group showed localized areas of dysplasia and early carcinoma-in-situ undergoing destruction.
Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions.
Regression of established hamster buccal pouch carcinoma has recently been demonstrated in association with an induction of tumor necrosis factor alpha in macrophages. Regression of hamster buccal pouch tumors has also been demonstrated following the local injection of alphatocopherol, canthaxanthin and an extract of Spirulina-Dunaliella algae. The current study demonstrates that cancer regression is also accompanied by a significant induction of tumor necrosis factor in macrophages in the tumor area, suggesting a possible mechanism of tumor destruction. One hundred and forty young, male adult hamsters were divided into seven equal groups of 20 animals. Epidermoid carcinomas were induced in right buccal pouches by 14 weeks of painting, three times per week, of a 0.5% solution of 7,12-dimethylbenz(a)anthracene. Groups 1 and 2 were untreated and sham injected controls. Groups 3-7 had injected twice weekly into the right buccal pouches 0.1 ml (1.9 mg/ml of 13-cis-retinoic acid, canthaxanthin, algae extract, beta-carotene and alphatocopherol. After 4 weeks the tumors in groups 3-7 demonstrated varying degrees of regression and the animals were sacrificed and the right buccal pouches excised. Tumor necrosis factor alpha (TNF-alpha) was demonstrated by immunohistochemical techniques. A very significant increase in TNF-alpha positive macrophages was found in the tumor-bearing pouches of animals in groups 5-7. Smaller numbers of TNF-alpha-positive macrophages were found in group 4 pouches and a very slight increase in group 3 pouches.
In order to test the possible cardiac-sparing effect of doxorubicin administered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall in resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m2 was 0.06 (p less than 0.005); at 301 to 449 mg/m2 it was 0.09 (p less than 0.0005); and at 450 mg/m2 or greater it was 0.15 (p less than 0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the "normal range" (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 nM. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to include deteriorations in function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage.
Adriamycin was given to 234 patients with leukemia and other types of neoplastic diseases. In children with acute leukemia previously treated, adriamycin produced complete remissions (12%) and good partial remissions (26%). Tumor regressions were seen in 60% of the patients with solid tumors. These included lymphoma, embryonal rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, Wilms' tumor, ovarian tumor, hepatoma, embryonal carcinoma, malignant teratoma, and retinoblastoma. The therapeutic responses in adults have been less consistent and were confined to lymphomas and soft tissue sarcomas. The dose in children was 0.5 mg/kg daily to a total of 2-4 mg/kg per course. In adults, the single dose was 0.4 mg/kg to a total of about 2.5 mg/kg in 10 days. Adriamycin at half the dose of daunomycin produced comparable toxicities, except for earlier and more frequent oral ulcers and alopecia. Varying degrees of transient electrocardiographic changes have been seen in children. Adriamycin may have contributed to cardiac failure and death in one child, who had recurrent pulmonary metastases.
The cardiotoxic effects of adriamycin were studied in 399 patients treated for far-advanced carcimma. Forty-five patients (11%) exhibited transient electrocardiographs changes. Eleven others developed severe congestive heart failure. Eight of these latter patients died within 3 weeks of the onset of the cardiac decompensation. The diffuse nature of this myocardiopathy was suggested by: 1. a conspicuous decrease in the QRS voltage on the electrocardiograms; 2. rapidly occurring cardiac dilatation and ventricular failure, and 3. refractoriness to inoiropic drugs and mechanical ventricular assistance. Postmortem examination of the hearts in two cases showed a striking decrease in the number of cardiac: muscle cells present, degeneration of the remaining myocardial cells, loss o contractile substance, mitochondrial swelling, and intramitochondrial dense inclusion bodies. Congestive heart failure occurred only once in the 366 patients who were treated with less than 550 mg/m2 of adriamycin (0.27%), but there were 10 cases of cardiac failure in the 33 patients who received more than 550 mg/m2 of this drug (30%). Therefore, until more direct means are established to prevent adriamycin-induced congestive heart failure, it is suggested that the total dose of adriamycin should be limited to less than 550 mg/m2 to permit safer use of this efficacious cancer chemotherapeutic agent.
Four hundred and seventy-two patients with disseminated neoplasia were treated with two or more doses of adriamycin. The initial dose for “good risk” patients was 75 mg/m2 every 3 weeks, and for “poor risk” patients was 60 mg/m2 every 3 weeks. Objective remissions were seen in 118/472 patients, with best results noted in lymphomas (21/48), sarcomas (21/64), and carcinoma of the breast (16/50). Eighty-nine per cent of remissions occurred within three courses. Hematopoietic toxic effects were seen in 73% of patients; nausea, vomiting, and/or stomatitis were observed in 43%. Changes in electrocardiograms were seen in 42/472 patients after cumulative doses of adriamycin ranging from 45 mg/m2 to 600+mg/m2. Irreversible congestive heart failure occurred in two patients after cumulative doses of 555 mg/m2 and 825 mg/m2, respectively. It is concluded that adriamycin is an active agent, most remissions occur promptly, and significant cardiotoxic reactions appear to be cumulative.
An assay procedure is described in which blood cell glutathione peroxidase may be accurately measured by a direct spectrophotometric procedure. Glutathione peroxidase activity is found to be associated with a relatively stable, nondialyzable, heat-labile, intracellular component which is separable from hemoglobin, by gel filtration and ammonium sulfate precipitation. The activity appears to be dependent upon active sulfhydryl groups and is unaffected by low concentrations of azide, cyanide, or ferricyanide.
The antitumor drug, adriamycin, enhances NADPH-dependent lipid peroxidation in liver microsomes via the formation of superoxide anion radicals (O2) and hydrogen peroxide (H2O2). In the presence of metal ions additional reactive species are generated, causing stimulation of lipid peroxidation. However, in this study it was found that the stimulation of NADPH-dependent lipid peroxidation by adriamycin was not only affected by the production of O2 and H2O2. Adriamycin also enhances the catalysis by metal ions of the formation of those reactive oxygen species which initiate peroxidation. This was inferred from the fact that adriamycin stimulated malondialdehyde production at low ferrous ion concentrations, whereas at high ferrous ion concentrations no stimulation was found. Additional evidence was found in experiments in which the enzymic redox cycle of adriamycin in microsomes was abolished by heat-inactivation of the microsomes, and O2 and H2O2 were only produced with xanthine and xanthine oxidase. In this case in the presence of ferrous ions, adriamycin stimulated lipid peroxidation.
The superoxide free radical has been spin trapped in microsomal incubations containing adriamycin, daunorubicin, and mitomycin C. The time sequence of the appearance of the spin-trapped superoxide and the semiquinone radical metabolite of these quinone-containing anticancer drugs indicates that air oxidation of the semiquinone is responsible for the superoxide formation. Superoxide dismutase prevents the formation of the superoxide spin adducts. Microsomal incubations containing anthracyclines intercalated in DNA produce much less superoxide than incubations free of DNA. The first unambiguous ESR evidence for the semiquinone metabolite of mitomycin C in a biological system is also presented.
This study investigated the effect of the anthracycline antibiotics on oxygen radical metabolism by cardiac mitochondrial reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase [NADH:(acceptor) oxidoreductase, EC 1.6.99.3]. Superoxide formation by NADH dehydrogenase after anthracycline treatment appeared to follow saturation kinetics with an apparent Km of 167.3, 73.3, 64.0, or 47.6 microM for doxorubicin, daunorubicin, rubidazone, or aclacinomycin A, respectively. Superoxide formation by NADH dehydrogenase after doxorubicin treatment occurred with a pH optimum of 7.6 and was accompanied by the production of hydrogen peroxide. Furthermore, drug-related hydroxyl radical generation was detected in this enzyme system by the evolution of methane gas from dimethyl sulfoxide. Hydroxyl radical production proceeded only in the presence of superoxide anion, hydrogen peroxide, and trace amounts of iron or a chelate of iron and ethylenediaminetetraacetate and thus was probably the by-product of a transition metal-catalyzed Haber-Weiss reaction. The antitumor agents mitoxantrone and actinomycin D did not significantly enhance reactive oxygen metabolism by NADH dehydrogenase. These results suggest that the specific activation of the anthracycline antibiotics to free radicals by NADH dehydrogenase leads to the formation of a variety of reactive oxygen species that may contribute to the mitochondrial toxicity of these drugs.
Direct and spin-trapping electron spin resonance methods have been used to study the reactivity of semiquinone radicals from the anthracycline antibiotics daunorubicin and adriamycin towards peroxides (hydrogen peroxide, t-butyl hydroperoxide and cumene hydroperoxide). Semiquinone radicals were generated by one-electron reduction of anthracyclines, using xanthine/xanthine oxidase. It is shown that the semiquinones are effective reducing agents for all the peroxides. From spin-trapping experiments it is inferred that the radical product is either OH (from H2O2) or an alkoxyl radical (from the hydroperoxides) which undergoes beta-scission to give the methyl radical. The rate constant for reaction of semiquinone with H2O2 is estimated to be approx. 10(4)-10(5) M-1 X s-1. The reduction does not appear to require catalysis by metal ions.