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The potential role of boswellic acids in cancer prevention and treatment

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... Oxidative stress results in disorders that include chronic intestinal damage. Radiation can also increase the oxidative stress in the intestinal epithelial cells (Roy et al., 2016). ...
... Boswellic acid can be defined as a phytochemical (Deng et al., 2019), which includes a series of pentacyclic triterpene molecules. It can be isolated from the gum resin of Boswellia carteri and Boswellia serrata produced by the trees called as Indian olibanum (Roy et al., 2016). Boswellic acids are potent, novel, specific anti-inflammatory agents, which can be attributed to the nonredox inhibition pertaining to 5-lipoxygenase enzyme (Iram et al., 2017). ...
... As a traditional remedy, it has wide application pertaining to different ailments, particularly inflammatory diseases, asthma (Roy et al., 2016), treatment of colds, coughs, bronchitis, hoarseness, and dyspnea (Vuddanda et al., 2016). Table 1 ...
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Phytochemicals accessible in food have demonstrated efficiency against impairment by gamma radiation. The review presented here is an attempt to show the pharmacological outline of the activity of the natural antioxidants and its primary action of molecular mechanism against the damage induced by gamma rays. This research focused on the results of the in vitro dosage of natural antioxidants relationship, and on the correlation of this information with the statistical variables. Moreover, it deliberated the natural compounds which could decrease the unwelcome impacts of gamma radiation and safeguard biological systems from radiation‐stimulated genotoxicity. The outcomes indicated that natural compounds can be utilized as an adjunct to orthodox radiotherapy and cultivate it as an effectual drug for the clinical administration of ailments. This is the first comprehensive review that collected all naturally occurring antioxidants in foods that act as protective agents against damage caused by exposure to gamma rays. There was no such comprehensive study reviewing the effectiveness of natural antioxidants present in food against the danger of gamma‐ray. This review focused on the antioxidants that act as preventive and therapeutic agents against the danger resulting from radiation.
... Commonly known as Indian frankincense or olibanum, salai guggal, loban or kundur, Boswellia have long-standing application as traditional remedies for various ailments, especially inflammatory diseases (asthma, arthritis and chronic bowel diseases), cerebral oedema and chronic pain syndrome, and have been shown to exhibit immense potential in combating cancer [15e17]. At the molecular level, BAs modulate multiple molecular targets, functionally characterised as kinases, transcription factors, enzymes, receptors, growth factors and others, which are directly or indirectly associated with carcinogenesis [17]. The anticancer potential of BAs has been demonstrated against multiple cancer types and has been shown to induce cell cycle arrest and apoptosis as well as inhibit cell proliferation, survival, angiogenesis, tissue invasion and metastasis. ...
... The anticancer potential of BAs has been demonstrated against multiple cancer types and has been shown to induce cell cycle arrest and apoptosis as well as inhibit cell proliferation, survival, angiogenesis, tissue invasion and metastasis. Molecularly, BAs exert their anticancer actions by inhibition of growth factoremediated activation of AKT and extracellular signal-regulated kinase (ERK), inactivation of the transcription factors nuclear factor-kB (NF-kB) and signal transducer and activator of transcription (STAT) 3, inhibition of cell cycle regulatory proteins cyclin D and cyclin E and downregulation of antiapoptotic proteins Bcl-2, Bcl-xL and Mcl-1 ( Table 2 and Fig. 2) [17,18]. AKBA induced apoptosis of prostate cancer cells in death receptor 5 (DR5)e and caspase-8edependent, but DR4-or Fas-independent, mechanisms [19]. ...
... Tumourassociated cell surface receptors and downstream molecules have become targets of many natural agents. For example, BA induces apoptosis through inhibition of growth factoremediated activation of AKT and ERK, resulting in inactivation of NF-kB and STAT3, and inhibition of cyclin D and E, Bcl-2, Bcl-xL and Mcl-1 proteins [17,18]. Others include AKBA-induced apoptosis through activation of the DR5ecaspase-8 pathway [19] and deguelin-induced apoptosis by disrupting the PI3K/Akt pathway [63e66]. ...
Article
Cancer is the second deadliest disease worldwide. Although recent advances applying precision treatments with targeted (molecular and immune) agents are promising, the histological and molecular heterogeneity of cancer cells and huge mutational burdens (intrinsic or acquired after therapy) leading to drug resistance and treatment failure are posing continuous challenges. These recent advances do not negate the need for alternative approaches such as chemoprevention, the pharmacological approach to reverse, suppress or prevent the initial phases of carcinogenesis or the progression of premalignant cells to invasive disease by using non-toxic agents. Although data are limited, the success of several clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational, appealing and viable strategy to prevent carcinogenesis. Particularly among higher-risk groups, the use of safe, non-toxic agents is the utmost consideration because these individuals have not yet developed invasive disease. Natural dietary compounds present in fruits, vegetables and spices are especially attractive for chemoprevention and treatment because of their easy availability, high margin of safety, relatively low cost and widespread human consumption. Hundreds of such compounds have been widely investigated for chemoprevention and treatment in the last few decades. Previously, we reviewed the most widely studied natural compounds and their molecular mechanisms, which were highly exploited by the cancer research community. In the time since our initial review, many promising new compounds have been identified. In this review, we critically review these promising new natural compounds, their molecular targets and mechanisms of anticancer activity that may create novel opportunities for further design and conduct of preclinical and clinical studies.
... Boswellia serrata (BS) or frankincense from the Arabian Peninsula belonging to the Burseraceae family. It possesses various therapeutic activities, for example, bactericidal and anti-inflammatory properties, due to the precence of many aromatic compounds with boswellic acid the most active molecule (5)(6)(7)(8)(9). Mono and diterpenes, ethyl acetate, octyl acetate, and methylanisole are natural anti-oxidants that constitute the major components of BS (5,6). ...
... The BS has beneficial therapeutic features in abundant pathological situations favored by natural medicine scientists in European countries, because of its possible nutritional and medical applications. It reveals an assortment of beneficial properties, which is related to the many aromatic compounds such as boswellic acid (7,8). ...
... Previous studies have been shown the similar positive impact of phytogenic feed additives in animal production (1,4,8,9,21). The enhancement in LBW and BWG by BS, as a natural growth promoter, may be attributed to the presence of some active compounds (such as boswellic acid) which stimulates the ability to absorb and digest nutrients (5)(6)(7)(8)(9). Our findings revealed that dietary supplementation with BS significantly increased LBW compared with control ( Table 2). ...
... Boswellia serrata (BS) or frankincense from the Arabian Peninsula belonging to the Burseraceae family. It possesses various therapeutic activities, for example, bactericidal and anti-inflammatory properties, due to the precence of many aromatic compounds with boswellic acid the most active molecule (5)(6)(7)(8)(9). Mono and diterpenes, ethyl acetate, octyl acetate, and methylanisole are natural anti-oxidants that constitute the major components of BS (5,6). ...
... The BS has beneficial therapeutic features in abundant pathological situations favored by natural medicine scientists in European countries, because of its possible nutritional and medical applications. It reveals an assortment of beneficial properties, which is related to the many aromatic compounds such as boswellic acid (7,8). ...
... Previous studies have been shown the similar positive impact of phytogenic feed additives in animal production (1,4,8,9,21). The enhancement in LBW and BWG by BS, as a natural growth promoter, may be attributed to the presence of some active compounds (such as boswellic acid) which stimulates the ability to absorb and digest nutrients (5)(6)(7)(8)(9). Our findings revealed that dietary supplementation with BS significantly increased LBW compared with control ( Table 2). ...
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The present study aimed to examine the impact of dietary supplementation of Boswellia serrata (BS) (frankincense) resin on growth and carcass traits, blood hematology, serum metabolites and cecal microbiota of growing rabbits. One hundred New Zealand White (NZW) growing male rabbits (6-weeks old) were divided randomly into five groups using different levels of BS (0.00, 0.25, 0.50, 0.75, 1.00 g/kg diet, respectively). When compared to the control diet, daily body weight gain (BWG) and feed conversion ratio (FCR) of rabbits fed BS enriched-diets were improved, while feed intake was significantly decreased. A gradual depression (P < 0.01) in serum triglycerides (TG), total cholesterol (TC) and low density lipoproteins (LDL) were observed with increasing BS level the in diet. Total bacteria count, E. coli and salmonella populations were lower (P < 0.05) in rabbit groups fed diet enriched with BS than that of the control group. Based on these findings, the dietary supplementation of Boswellia serrata enhanced growth, feed efficiency, anti-oxidant status, and minimize cecal pathogenic bacteria in rabbits.
... Boswellia serrata (BS) or frankincense from the Arabian Peninsula belonging to the Burseraceae family. It possesses various therapeutic activities, for example, bactericidal and anti-inflammatory properties, due to the precence of many aromatic compounds with boswellic acid the most active molecule (5)(6)(7)(8)(9). Mono and diterpenes, ethyl acetate, octyl acetate, and methylanisole are natural anti-oxidants that constitute the major components of BS (5,6). ...
... The BS has beneficial therapeutic features in abundant pathological situations favored by natural medicine scientists in European countries, because of its possible nutritional and medical applications. It reveals an assortment of beneficial properties, which is related to the many aromatic compounds such as boswellic acid (7,8). ...
... Previous studies have been shown the similar positive impact of phytogenic feed additives in animal production (1,4,8,9,21). The enhancement in LBW and BWG by BS, as a natural growth promoter, may be attributed to the presence of some active compounds (such as boswellic acid) which stimulates the ability to absorb and digest nutrients (5)(6)(7)(8)(9). Our findings revealed that dietary supplementation with BS significantly increased LBW compared with control ( Table 2). ...
Article
Full-text available
The present study aimed to examine the impact of dietary supplementation of Boswellia serrata (BS) (frankincense) resin on growth and carcass traits, blood hematology, serum metabolites and cecal microbiota of growing rabbits. One hundred New Zealand White (NZW) growing male rabbits (6-weeks old) were divided randomly into five groups using different levels of BS (0.00, 0.25, 0.50, 0.75, 1.00 g/kg diet, respectively). When compared to the control diet, daily body weight gain (BWG) and feed conversion ratio (FCR) of rabbits fed BS enriched-diets were improved, while feed intake was significantly decreased. A gradual depression (P < 0.01) in serum triglycerides (TG), total cholesterol (TC) and low density lipoproteins (LDL) were observed with increasing BS level the in diet. Total bacteria count, E. coli and salmonella populations were lower (P < 0.05) in rabbit groups fed diet enriched with BS than that of the control group. Based on these findings, the dietary supplementation of Boswellia serrata enhanced growth, feed efficiency, anti-oxidant status, and minimize cecal pathogenic bacteria in rabbits.
... It has now been established that boswellic acid is a multi-targeted drug [12]. It regulates a variety of molecular targets, including enzymes, growth factors, kinases, transcription factors, receptors, and other substances involved in cell survival and proliferation [13,14]. ...
... After scraping, cells were crushed by sonication and centrifuged (13,200 rpm, 10 min, 4 °C). Protein concentrations were determined using Pierce Protein Assay Kit (Pierce, Rockford, IL, USA). ...
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Boswellic acids, triterpenoids derived from the genus Boswellia (Burseraceae), are known for their anti-inflammatory and anti-tumor efficacy. Atopic dermatitis is a chronic, non-infectious inflammatory skin disease. However, the effects of α-boswellic acid on atopic dermatitis have not been studied. Therefore, in this study we examined the expression level of pro-inflammatory cytokines, histopathological analysis, and physiological data from BALB/c mice with atopic-like dermatitis induced by 2,4-dinitrochlorobenzene and TNF-α/IFN-γ-stimulated HaCaT cells to better understand the agent’s anti-atopic dermatitis efficacy. First, we found that α-boswellic reduced the epidermal thickening, mast cell numbers, and dermal infiltration of 2,4-dinitrochlorobenzene-induced atopic-like dermatitis in BALB/c mice. Furthermore, we also found that α-boswellic acid can restore transepidermal water loss and skin reddening in mice. In human keratinocytes inflamed by TNF-α/IFN-γ, α-boswellic acid inhibited MAP kinase activation and showed a reduction in NF-κB nuclear translocation. Finally, α-boswellic acid can reduce the expression level of cytokines (IL-1β, IL-6, and IL-8) following the stimulation of TNF-α/IFN-γ in HaCaT cells. Taken together, our study suggests that α-boswellic acids are a potential component for the development of anti-atopic dermatitis drugs.
... It is mainly collected from the forest areas of Madhya Pradesh, Jharkhand, Chhattisgarh, Maharashtra, Uttarakhand, and sold in the adjacent local markets (Shah et al., 2009;Garg et al., 2015;Gupta et al., 2016). Oleo-gum-resin extract is been utilized for several diseases including chronic bowel disease, inflammation, colitis cerebral edema, cancer, analgesia, asthma, and arthritis (Takahashi et al., 2012;Shamraiz et al., 2019;Roy et al., 2016). Furthermore, the extracts have antibacterial, anti-carcinogenic, and anti-neoplastic properties (Parsonidis et al., 2021). ...
... BS-N1 was displayed moderate activity against the A549 cell line due to lower amounts of BAs (15.56%), while other samples were observed as non-significant in this cell line due to poor amounts of KBA (0.8-3.8%) and AKBA (0.7-3.5%). Various studies have shown the efficacy of BAs in the prevention and treatment of breast, bladder, cervical, prostate, colorectal, head and neck, liver, lung, and pancreatic cancers, etc. (Roy et al., 2016). BS-M1 was most significant against the A431 cell line with IC 50 6.01 µg/mL, and the cytotoxic effect of BS-M1 at 50 µg/mL is 93.67% it may be a higher percentage of AKBA (6.9%). ...
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Background : Boswellia serrata, an economically vital ethnic tree of dry deciduous forests to provides oleo-gum-resin of pharmaceutical significance. The marker molecules of this resin are penta-cyclic tri-terpenoids commonly known as boswellic acids (BAs). Methods : The topographical oleo-gum-resin samples were used for chemo-profiling of the BAs in methanol extracts by HPLC analysis. The anti-proliferative potential of extracts was evaluated on eight cell lines by MTT assay. The antibacterial activity was evaluated by the disc diffusion process and Minimum inhibitory concentrations (MIC) of extracts were performed by the microdilution assay. The antioxidant potentials of extract samples were accomplished by DPPH scavenging and ABTS assays. Results : The sample collected from Haldwani (BS-H) has been given the good yield of the extract (65.1%) with the lowest percentage of BAs (9.6%). Shivpuri, Neemuch, and Mandsaur are topographical locations in the state of Madhya Pradesh (M.P.) and are distinguished as the oleo-gum-resin trading sites in India. The methanol extract of Neemuch collection (BS-N2) was contained enhanced percentage of KBA (keto-β-boswellic acid) (8.4%) with highest yield of the extract (70.1%), while Mandsaur collection (BS-M1) was contained the highest percentage of AKBA (6.9%) with enhanced amount of BAs (39.89%). The extracts of M.P. samples have been shown inhibition of lung cancer cell-line with IC50: 2.34-13.06 µg/mL, and the percent inhibition is ranged from 7.0 to 93.67%. All these extracts have been displayed significant antimicrobial activity against Mycobacterium smegmatis (MS) (MIC: 2.4-156 µg/mL). Most importantly, Mandsaur (BS-M1) and Neemuch (BS-N2) collections have shown significant activity against Methicillin-resistant Staphylococcus epidermidis (SE) strain with MIC of 2.4 µg/mL. All the extracts were shown significant antioxidant activity with IC50: 2.7-9.9 µg/mL, and BS-N2 was displayed 78.4% of free radical scavenging reduction activity. Similarly, ABTS was complemented the DPHH scavenging assay. Cluster correlation analyses of chemo-types with biological activities were performed among the different topographical samples. Conclusion : The variations of activities among the extracts were related to their chemical compositions. The topographical samples with the improved percentage of KBA and AKBA were shown highly significant anticancer, antibacterial and antioxidant activities. Cluster correlation analyses of all samples were assisted to compare the BAs contents with bioactivities.
... Chemotherapeutic drugs are often associated with numerous side effects and the patient may slowly develop chemo-resistance. β-Boswellic acid and its derivatives rich extract have shown antitumor and anti-carcinogenic activities (Roy et al., 2016). ...
... These results substantiated the previous reports that boswellic acid derivatives, such as KBA, acetyl-β-boswellic acid, and β-boswellic acid have been associated with the marked anti-proliferative potential on several cancer cell lines such as colon, leukemia, lung and breast. (Liu et al., 2006;Shao et al., 1998;Roy et al., 2016;Khan et al., 2016). ...
Article
Since time immemorial Boswellia serrata has been a useful traditional plant and its oleo-gum-resin is regularly used as an important constituent in herbal medicines for inflammation, cancer sufferers and cosmetics. This study focuses on the antibacterial and anticancer activities of B. serrata oleo-gum-resin extract, fractions and isolates. Time kill kinetic assay, combination study and ethidium bromide efflux pump inhibitory assay of the leading molecule 3-hydroxy-11-keto-β-boswellic acid (KBA) have been evaluated. The extract, fractions and the isolated molecule have shown anti-proliferative activity in different cancer cell lines, and the inhibition ranged from 13% to 93%. KBA caused anti-proliferative dose-dependent impacts on all human malignant cells (IC50 4.10–37.9 µg/ml). In antibacterial study of the extract, fractions and isolated molecules have shown minimum inhibitory concentration MIC range from 31.25 to 1000 μg/ml against 8 different Gram-positive and Gram-negative bacterial strains. KBA exhibited synergistic effect with a oxacillin against different drug resistant clinical isolates with fractional inhibitory concentration index (FICI) in the range of 0.325–0.450 µg/ml. KBA exhibited bacteriostatic killing mechanism and could also modulate ethidium bromide efflux pump to find its potential in combination therapy against multi-drug resistant Staphylococcal infections. KBA in the extract was quantified using HPLC-PDA and its structure was validated for the first time by X-ray crystallography. This study reinforced the promising treatment of KBA for cancer and S. aureus infections. KBA can be further explored to develop potential lead combinations of anti-cancer and anti-Gram-positive bacterial herbal formulations.
... Hence, the corresponding boswellic acids represent constitutional isomers. It was assumed that the pharmacologically interesting keto-boswellic acids, 11-keto-β-boswellic acid (β-KBA, or commonly abbreviated as KBA) and acetyl-11-keto-β-boswellic acid (β-AKBA, commonly abbreviated as AKBA), only occur as β-isomers [3,7,15,16]. However, in 2005, 70 years after the discovery of the first boswellic acids, we could demonstrate that in addition to β-AKBA, the α-isomer acetyl-11-keto-α-boswellic acid (α-AKBA) naturally occurs in Boswellia oleogum resins [17,18]. ...
... The geographical delineation by the Arabian Sea isolates B. serrata from other Boswellia species [1]. Frankincense from B. serrata represents probably the best investigated Boswellia oleogum resin and it has been used in Ayurvedic medicine for centuries [3,7,15,43]. ...
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Boswellic acids, and particularly 11-keto-boswellic acids, triterpenoids derived from the genus Boswellia (Burseraceae), are known for their anti-inflammatory and potential antitumor efficacy. Although boswellic acids generally occur as α-isomers (oleanane type) and β-isomers (ursane type), 11-keto-boswellic acid (KBA) was found only as the β-isomer, β-KBA. Here, the existence and natural occurrence of the respective α-isomer, 11-keto-α-boswellic acid (α-KBA), is demonstrated for the first time. Initially, α-KBA was synthesized and characterized by high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy, and a highly selective, sensitive, and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) method was developed by Design of Experiments (DoE) using a pentafluorophenyl stationary phase. This method allowed the selective quantification of individual 11-keto-boswellic acids and provided evidence for α-KBA in Boswellia spp. oleogum resins. The contents of α-KBA as well as further boswellic acids and the composition of essential oils were used to chemotaxonomically classify 41 Boswellia oleogum resins from 9 different species. Moreover, α-KBA exhibited cytotoxicity against three treatment-resistant triple-negative breast cancer (TNBC) cell lines in vitro and also induced apoptosis in MDA-MB-231 xenografts in vivo. The respective β-isomer and the acetylated form demonstrate higher cytotoxic efficacies against TNBC cells. This provides further insights into the structure–activity relationship of boswellic acids and could support future developments of potential anti-inflammatory and antitumor drugs.
... Inflammation results in the release of many free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), which cause oxidative stress and contribute to the development of various pathological conditions, such as atherosclerosis, cardiovascular disease, and cancer [167][168][169][170][171][172][173]. Cancer growth, progression, and chemotherapy treatment can all induce inflammation in cancer patients [174][175][176][177][178]. Therefore, as compared to synthetic drugs and formulations, natural bioactive metabolites that target different kinds of cancer may substantially alleviate side effects and offer new alternatives to the standard of care for cancer patients [179][180][181][182]. Currently, only a few bioactive compounds isolated from various natural sources have been tested clinically for cancer treatment, and one of these bioactive compounds, withaferin A, isolated from W. somnifera, has potential anticancer, anti-inflammatory, and antioxidant properties [183][184][185]. ...
Article
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Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential.
... Currently, clinical drugs (especially biological agents) are generally used to treat chronic diseases, but these drugs generally have the disadvantages of side effects and high cost (Gautam & Jachak, 2009). Studies have shown that many natural compounds can provide better options for the treatment of chronic diseases (Roy et al., 2016), and a large number of studies have confirmed that compounds derived from a variety of natural products can be used as active drugs against different chronic diseases Tang et al., 2014;Yarla et al., 2016;Harsha et al., 2017;Hasanpourghadi et al., 2017;Banik et al., 2018;Tewari et al., 2018). These plant-derived compounds provide additional and prominent options for existing drug systems. ...
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Abstract The feasibility of human nutritional supplementation is imperative. As a part of daily diet, edible fungus polysaccharides have a variety of health promoting effects, especially for the prevention of chronic diseases. Based on the extensive collection and collation of relevant research datas, the beneficial effects of edible fungus polysaccharides on various chronic diseases were analyzed, and the structure and functional mechanism of edible fungus polysaccharides with anti-chronic disease properties were summarized in this current review. Based on a comprehensive analysis of the current researchs on edible fungus polysaccharides, it was considered that edible fungus polysaccharides can be used as the material basis of anti-chronic disease drugs. In addition, the relevant contents can also provide some reference for the selection and development of anti-chronic disease drugs.
... Recently, both herbal and phytochemical-based medicines have attracted attention for their effectiveness against cancer, as well as a wide variety of other diseases [7][8][9][10][11][12][13][14][15]. Indeed, researchers around the world are focusing on the chemopreventive, antioxidant, and antiinflammatory properties of bioactive compounds [16][17][18], and natural products and their derivatives account for one-third of all new drugs approved by the United States Food and Drug Administration (FDA) [19][20][21]. Plant-based medicines contain multiple bioactive compounds (e.g., alkaloids, carotenoids, diterpenoids, flavonoids, phenolic compounds, and tannins) that impart unique medicinal properties [22,23], and accordingly, plantderived compounds play important roles in increasing the sensitivity of cells to standard chemotherapy and in reducing cancer risk, invasion, and metastasis [22,[24][25][26]. ...
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The flavonoid apigenin (4′,5,7-trihydroxyflavone), which is one of the most widely distributed phytochemicals in the plant kingdom, is one of the most thoroughly investigated phenolic components. Previous studies have attributed the physiological effects of apigenin to its anti-allergic, antibacterial, antidiabetic, anti-inflammatory, antioxidant, antiviral, and blood-pressure-lowering properties, and its documented anticancer properties have been attributed to the induction of apoptosis and autophagy, the inhibition of inflammation, angiogenesis, and cell proliferation, and the regulation of cellular responses to oxidative stress and DNA damage. The most well-known mechanism for the compound’s anticancer effects in human cancer cell lines is apoptosis, followed by autophagy, and studies have also reported that apigenin induces novel cell death mechanisms, such as necroptosis and ferroptosis. Therefore, the aim of this paper is to review the therapeutic potential of apigenin as a chemopreventive agent, as well as the roles of programmed cell death mechanisms in the compound’s chemopreventive properties.
... The extract of B.serrata resin and its major constituent's boswellic acids are unique in Boswellia species. They are known to exhibit pharmacological activities such as anti-inflammatory, arthritis, asthma, cerebral oedema, chronic pain syndrome, chronic bowel diseases, antiulcer, immunomodulatory, hypolipidemic, antibacterial, antiobesity and anticancer [7][8][9]. Terpenoids of B. serrata oleo-gum resin possess anti-plasmodial activity [10] but the mechanism of action in malaria parasites was not evaluated to date. ...
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Malaria eradication is still a major global health problem in developing countries, which has been of more concern ever since the malaria parasite has developed resistance against frontline antimalarial drugs. Historical evidence proves that the plants possess a major resource for the development of novel anti-malarial drugs. In the present study, the bioactivity guided fractionation of the oleogum-resin of Boswellia serrata Roxb. yielded the optimum activity in the ethyl acetate fraction with an IC50 of 22 ± 3.9 μg/mL and 26.5 ± 4.5 μg/mL against chloroquine sensitive (NF54) and resistant (K1) strains of Plasmodium falciparum respectively. Further, upon fractionation, the ethyl acetate fraction yielded four major compounds, of which 3-Hydroxy-11-keto-β-boswellic acid (KBA) was found to be the most potent with IC50 values 4.5 ± 0.60 µg/mL and 6.25 ± 1.02 μg/mL against sensitive and resistant strains respectively. KBA was found to inhibit heme detoxification pathways, one of the most common therapeutic targets, which probably lead to an increase in reactive oxygen species (ROS) and nitric oxide (NO) detrimental to P. falciparum. Further, the induced intracellular oxidative stress affected the macromolecules in terms of DNA damage, increased lipid peroxidation, protein carbonylation as well as loss of mitochondrial membrane potential. However, it did not exhibit any cytotoxic effect in VERO cells. Under in vivo conditions, KBA exhibited a significant reduction in parasitemia, retarding the development of anaemia, resulting in an enhancement of the mean survival time in Plasmodium yoelii nigeriensis (chloroquine-resistant) infected mice. Further, KBA did not exhibit any abnormality in serum biochemistry of animals that underwent acute oral toxicity studies at 2000 mg/kg body weight.
... The modification in transduction signaling pathways gives rise to previously mentioned chronic conditions that might impact population of all ages [51,52]. In such diseases, BAs exerts its therapeutic benefits by modulating various targets like growth factors, transcription factors, enzymes, kinases, and receptors that may initiate apoptosis and finally arrest the cell cycle [53]. It inhibits various pathways [54] associated with cell durability [55], metastasis [56], proliferation [57]. ...
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The resin/gum of Boswellia species belonging to the family of Burseraceae is a naturally occurring mixture of bioactive compounds, which was traditionally used as a folk medicine to treat conditions like chronic inflammation. Several research studies have also explored its' therapeutic potential against multiple neurodegenerative diseases such as Alzheimer's disease (AD). The main chemical constituents of this gum include boswellic acids (BAs) like 3-O-acetyl-11-keto-β boswellic acid (AKBA) that possess potent anti-inflammatory and neuroprotective properties in AD. It is also involved in inhibiting the acetylcholinesterase (AChE) activity in the cholinergic pathway and improve choline levels as well as its binding with nicotinic receptors to produce anti-inflammatory effects. Multiple shreds of evidence have demonstrated that BAs modulate key molecular targets and signalling pathways like 5-lipoxygenase/cyclooxygenase, Nrf2, NF-kB, cholinergic, amyloid-beta (Aβ), and neurofibrillary tangles formation (NFTs) that are involved in AD progression. The present review focuses on the possible mechanistic therapeutic role of BAs in modulating the 5-LOX/COX pathway in arachidonic acid metabolism, activating Nrf2 through binding of ARE, inhibiting NF-kB and AChE activity. In addition, an inhibition of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) induced neurotoxicity and neuroinflammation in AD by BAs is also discussed in this review. We have also highlighted that BAs possess beneficial effects in AD by targeting multiple molecular pathways and makes it an emerging drug candidate for treating neurodegenerative diseases.
... Furthermore, there are some reports showing the effect of Boswellia resins on brain oedema and brain tumours. The main active constituents of Boswellia resin are boswellic acids, which are mainly used in cancer treatment (Roy et al. 2016). ...
... Regardless of the notable progress achieved in cancer diagnosis and treatment, it is still considered as one of the most dreadful and prevalent diseases having very high morbidity and mortality rate [1][2][3][4][5][6][7][8][9][10]. There are diverse types of cancer, all of which are associated with atypical growth and proliferation of cells leading to approximately 10 million deaths per year [11][12][13][14][15][16]. ...
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In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn., which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, nuclear factor-kappa B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.
... Roy et al. [115] have studied the possible role of BA in the prevention and treatment of cancer and observed or highlighted the findings concerning the anti-cancer potential of boswellic acid against different cancer types and the molecular processes underlying the targets of boswellic acid responsible for its potent anti-cancer activity are also discussed. Overall, this study explores the evidence that reveals the assurance that boswellic acid can be appropriately formulated and transformed into a viable cancer drug as an appropriate candidate [116,117]. ...
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Abstract Glioblastoma multiforme is one of the most deadly malignant tumors, with more than 10,000 cases recorded annually in the United States. Various clinical analyses and studies show that certain chronic diseases, including cancer, interact between cell-reactive radicals rise and pathogenesis. Reactive oxygen and nitrogenous sources include endogenous (physiological processes), and exogenous sources contain reactive oxygen and nitrogen (xenobiotic interaction). The cellular oxidation/reduction shifts to oxidative stress when the regulation mechanisms of antioxidants are surpassed, and this raises the ability to damage cellular lipids, proteins, and nucleic acids.
... Cancer has become one of the major universal challenges due to its rising burden and mortality [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. According to the report of GLOBOCAN 2018, an estimate of 18.1 million new cases and 9.6 million deaths occurred annually due to this disease worldwide [15,16]. ...
Article
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Cancer is one of the lethal diseases that arise due to the molecular alterations in the cell. One of those alterations associated with cancer corresponds to differential expression of Farnesoid X receptor (FXR), a nuclear receptor regulating bile, cholesterol homeostasis, lipid, and glucose metabolism. FXR is known to regulate several diseases, including cancer and cardiovascular diseases, the two highly reported causes of mortality globally. Recent studies have shown the association of FXR overexpression with cancer development and progression in different types of cancers of breast, lung, pancreas, and oesophagus. It has also been associated with tissue-specific and cell-specific roles in various cancers. It has been shown to modulate several cell-signalling pathways such as EGFR/ERK, NF-κB, p38/MAPK, PI3K/AKT, Wnt/β-catenin, and JAK/STAT along with their targets such as caspases, MMPs, cyclins; tumour suppressor proteins like p53, C/EBPβ, and p-Rb; various cytokines; EMT markers; and many more. Therefore, FXR has high potential as novel biomarkers for the diagnosis, prognosis, and therapy of cancer. Thus, the present review focuses on the diverse role of FXR in different cancers and its agonists and antagonists.
... Acetyl-11-keto-β-boswellic acid Boswellic acids are PTs present in the resin of Boswellia species [60]. Boswellic acids have reported anti-inflammatory [60,61], antimicrobial [60,61], antiparasitic [60], anticancer [62], anti-arthritic [61], and immunomodulatory [61] actions. Although more than 12 different boswellic acids have been identified in resin extracts, 11-keto-β-boswellic acid and AKBA [(3R,4R,4aR,6aR, 6bS,8aR,11R,12S,12aR,14aR,14bS)-3-acetyloxy-4,6a,6b,8a,11,12, 14b-heptamethyl-14-oxo-1,2,3,4a,5,6,7,8,9,10,11,12,12a,14atetradecahydropicene-4-carboxylic acid] appear to have the greatest pharmacological significance [60]. ...
Article
Retinal diseases are a leading cause of impaired vision and blindness but some lack effective treatments. New therapies are required urgently to better manage retinal diseases. Natural pentacyclic triterpenoids and their derivatives have a wide range of activities, including antioxidative, anti-inflammatory, cytoprotective, neuroprotective, and antiangiogenic properties. Pentacyclic triterpenoids have great potential in preventing and/or treating retinal pathologies. The pharmacological effects of pentacyclic triterpenoids are often mediated through the modulation of signalling pathways, including nuclear factor erythroid-2 related factor 2, high-mobility group box protein 1, 11β-hydroxysteroid dehydrogenase type 1, and Src homology region 2 domain-containing phosphatase-1. This review summarizes recent in vitro and in vivo evidence for the pharmacological potential of pentacyclic triterpenoids in the prevention and treatment of retinal diseases. The present literature supports the further development of pentacyclic triterpenoids. Future research should now attempt to improve the efficacy and pharmacokinetic behaviour of the agents, possibly by the use of medicinal chemistry and targeted drug delivery strategies.
... Mother Nature has bestowed us with various promising medicinal plants as well as plant-based products such as fruits, vegetables, herbs, and spices that are abundantly consumed [186], [187], [188], [189], [190], [191], [192], [193], [194]. Apart from their high nutritional value, these are also rich in therapeutic properties [189], [193], [195], [196], [197], [198], [199], [200]. ...
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Background Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India is low (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. Aim To evaluate the literature available on the anti-inflammatory properties of some spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. Method A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19 and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. Key findings The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. Significance As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.
... To date, most studies on their mechanisms of action have focused on AKBA and KBA. For example, AKBA inhibits several enzymes, including MAT2A, 5-lipoxygenase, and cyclooxygenase-1 (23)(24)(25), and interferes with signaling pathways such as NF-kB and Ca 2+ signaling (26). However, acetylated aBA and acetylated bBA (AbBA) shows strong clinical potential with a higher peak concentration value than KBA and AKBA after oral administration (27). ...
Article
IL-17-secreting Th17 cells play an important role in the pathogenesis of various inflammatory and autoimmune diseases. IL-17-targeted biologics and small molecules are becoming promising treatments for these diseases. In this study, we report that SZB120, a derivative of the natural compound 3-acetyl-β-boswellic acid, inhibits murine Th17 cell differentiation by interacting with the α-subunit of eukaryotic initiation factor 2 (eIF2α). We showed that SZB120 directly interacts with eIF2α and contributes to serine 51 phosphorylation of eIF2α. The suppressive effect of SZB120 on Th17 cell differentiation was reversed by GSK2606414, an inhibitor of eIF2α phosphokinase. Phosphorylation of eIF2α induced by SZB120 decreased the protein expression of IκBζ, which is important for Th17 cell differentiation. Notably, interaction with eIF2α by SZB120 also impaired glucose uptake and glycolysis in T cells. In vivo, SZB120 treatment of C57BL/6 mice significantly attenuated IL-17/Th17-mediated autoimmune disease. Our study indicates that SZB120 is a promising drug candidate for IL-17/Th17-mediated inflammatory diseases.
... However, cancer is still responsible for many deaths around the world (9.6 million deaths annually) [11]. A variety of factors account for the high mortality of cancer, including metastasis, uncontrolled growth, drug-resistance, and the inefficiency of current diagnostic strategies leading to relatively late diagnosis [12][13][14][15][16][17][18]. Therefore, novel therapeutic and diagnostic methods should be developed for cancer therapy. ...
Article
Cancer still remains as one of the leading causes of death worldwide. Metastasis and proliferation are abnormally increased in cancer cells that subsequently, mediate resistance of cancer cells to different therapies such as radio-, chemo- and immune-therapy. MicroRNAs (miRNAs) are endogenous short non-coding RNAs that can regulate expression of target genes at post-transcriptional level and capable of interaction with mRNA-coding genes. Vital biological mechanisms including apoptosis, migration and differentiation are modulated by these small molecules. MiRNAs are key players in regulating cancer proliferation and metastasis as well as cancer therapy response. MiRNAs can function as both tumor-suppressing and tumor-promoting factors. In the present review, regulatory impact of miRNA-338-3p on cancer growth and migration is discussed. This new emerging miRNA can regulate response of cancer cells to chemotherapy and radiotherapy. It seems that miRNA-338-3p has dual role in cancer chemotherapy, acting as tumor-promoting or tumor-suppressor factor. Experiments reveal anti-tumor activity of miRNA-338-3p in cancer. Hence, increasing miRNA-338-3p expression is of importance in effective cancer therapy. Long non-coding RNAs, circular RNAs and hypoxia are potential upstream mediators of miRNA-338-3p in cancer. Anti-tumor agents including baicalin and arbutin can promote expression of miRNA-338-3p in suppressing cancer progression. These topics are discussed to shed some light on function of miRNA-338-3p in cancer cells.
... Therefore, with the increase in the incidence of chronic diseases, the development of highly efficacious and affordable drugs to impart a healthy and productive lifestyle to patients, without needless complications, becomes imperative. Hence, the challenge here is to develop clinically-productive compounds that would naturally blend into the body and improve the therapy, reduce long-term side effects and impart positive effects (Bulaj et al., 2016;Roy et al., 2016;Banik et al., 2018). ...
Article
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Although chronic diseases are often caused by the perturbations in multiple cellular components involved in different biological processes, most of the approved therapeutics target a single gene/protein/pathway which makes them not as efficient as they are anticipated and are also known to cause severe side effects. Therefore, the pursuit of safe, efficacious, and multitargeted agents is imperative for the prevention and treatment of these diseases. Cardamonin is one such agent that has been known to modulate different signaling molecules such as transcription factors (NF-κB and STAT3), cytokines (TNF-α, IL-1β, and IL-6) enzymes (COX-2, MMP-9 and ALDH1), other proteins and genes (Bcl-2, XIAP and cyclin D1), involved in the development and progression of chronic diseases. Multiple lines of evidence emerging from pre-clinical studies advocate the promising potential of this agent against various pathological conditions like cancer, cardiovascular diseases, diabetes, neurological disorders, inflammation, rheumatoid arthritis, etc., despite its poor bioavailability. Therefore, further studies are paramount in establishing its efficacy in clinical settings. Hence, the current review focuses on highlighting the underlying molecular mechanism of action of cardamonin and delineating its potential in the prevention and treatment of different chronic diseases.
... Therefore, looking for highly safe and effective compounds to prevent or treat cancers is necessary. AKBA, the main derivative of boswellic acids, is considered as a promising therapeutic agent due to its natural anticancerous properties (Roy et al. 2016;Yadav et al. 2012). TWIST1 and FOXM1 are two important molecules, which are involved in proliferation, migration, invasion and metastasis of glioma cancer cells when upregulated. ...
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Background Glioblastoma multiforme (GBM) is a highly aggressive and poor prognosis brain tumor with about 12- to 18-month median survival period and high mortality rate in human. Glioma cells are able to disseminate and migrate far away from the primary tumor and display treatment resistance. Therefore, upgrading our knowledge regarding the genetic aspects of GBM and also applying a safe and promising source of therapeutic agent to prevent GBM might bring some new hopes to treat this disease. TWIST1 and FOXM1 upregulations are associated with migration and metastasis in gliomas. 3-Acetyl-11-keto-β-boswellic acid (AKBA) has been shown to inhibit the growth of a wide variety of cancer cells, such as gliomas. The aim of this study was to investigate the possible inhibitory effects of AKBA on the TWIST1 and FOXM1 gene expression levels and the migration of glioblastoma cancer cells. Methods U87MG cells were treated with or without 50 µM of AKBA. The expression levels of TWIST1 and FOXM1 were assessed using real-time PCR. The migration of cells in the presence or absence of AKBA was examined through the wound healing assay. Results AKBA significantly downregulated both TWIST1 and FOXM1 gene expression levels. The migration of U87MG cancer cells was significantly declined when AKBA was applied. Conclusion AKBA potentially prevents FOXM1 and TWIST1 axis in glioblastoma cancer cells and also inhibits cell migration.
... It is now well established that boswellic acids are multitargeting agents. They can modulate several molecular targets, including enzymes, growth factors, kinases, transcription factors, receptors, and others related to the survival and proliferation of cells [375]. Studies revealed that boswellic acids induced their antitumoral activity through inhibition of topoisomerases I and II leading to apoptosis in different cell lines [376,377]. ...
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Cancer is one of the main causes of death globally and considered as a major challenge for the public health system. The high toxicity and the lack of selectivity of conventional anticancer therapies make the search for alternative treatments a priority. In this review, we describe the main plant-derived natural products used as anticancer agents. Natural sources, extraction methods, anticancer mechanisms, clinical studies, and pharmaceutical formulation are discussed in this review. Studies covered by this review should provide a solid foundation for researchers and physicians to enhance basic and clinical research on developing alternative anticancer therapies.
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The antidiabetic action of traditional plants is mostly attributed to their antioxidant and anti-inflammatory properties. These plants are still having some secrets, making them an attractive source that allows for investigating new drugs or uncovering precise pharmacologic antidiabetic functions of their constituents. In diabetes, which is a lipid disease, long-term exposure of pancreatic islet beta cells to fatty acids (FAs) increases basal insulin release, reduces glucose-stimulated insulin secretion, causes islet beta cell inflammation, failure and apoptosis. Pancreatic islet beta cells express fatty acid binding protein 3 (FABP3) that receives long-chain FAs and traffics them throughout different cellular compartments to be metabolized and render their effects. Inhibition of this FABP3 may retard FA metabolism and protect islet beta cells. Since FAs interact with FABPs by their carboxylic group, some traditionally-known antidiabetic plants were reviewed in the present study, searching for their components that have common features of FABP ligands, namely carboxylic group and hydrophobic tail. Many of these carboxylic acids were computationally introduced into the ligand-binding pocket of FABP3 and some of them exhibited FABP3 ligand possibilities. Among others, the naturally occurring ferulic, cleomaldeic, caffeic, sinapic, hydroxycinnamic, 4-p-coumaroylquinic, quinoline-2-carboxylic, chlorogenic, 6-hydroxykynurenic, and rosmarinic acids in many plants are promising candidates for being FABP3-specific inhibitors. The study shed light on repurposing these phyto-carboxylic acids to function as FABP inhibitors. However, more in-depth biological and pharmacological studies to broaden the understanding of this function are needed.
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Most diseases are preventable, and they are related to what we eat. Moreover, most doctor visits are for lifestyle-based diseases, which means they can be prevented by adopting a healthy lifestyle. Treating the causes of illness rather than symptoms of the disease is not only safer and cheaper, but it can work better. In this context, the Special Issue on “Nutraceuticals in Immune System” for the journal Molecules was launched in January 2020. Soon after that, the world was ravaged by the COVID-19 pandemic causing a grave health threat. Paradoxically, the immune system can be both friend and foe of COVID-19. The COVID-19 manifests only mild to moderate symptoms for most infected people who recover without hospitalisation, demonstrating the proper functioning of the immune system in fighting such an infection. For some, however, the overactivation of the immune response causing “cytokine storm” has dire consequences, with severe respiratory failure leading to multiple organ failure, which could be fatal. In fact, most deaths from COVID-19 came from organ inflammation due to undesirable immune system responses. As such, the COVID-19 is a good case in point, demonstrating the importance of a healthy immune system. Nutraceuticals are products derived from food sources with health benefits in addition to the basic nutritional values. Many of them can positively affect and enhance the immune system, which is particularly pertinent in the current turbulent times of COVID-19. Not surprisingly, nutraceutical sales rose dramatically during the pandemic period. However, much research is still needed to understand how natural products interact with the immune system to clarify their chemical compositions, mechanisms of action and effects on health and illnesses. This Special Issue provided an open forum for researchers to share their research findings in the growing interest of nutraceuticals. We received an overwhelming response with a total of 33 submissions, of which only nine original research papers and ten reviews were accepted after rigorous peer-review. The included articles research into natural substances of interest in nutraceuticals ranging from herbal medicine to vitamins to microbiota-derived metabolites. The investigated immune-related responses include cancer, neurological diseases, gastroenterological disorders, inflammatory conditions, and infections. We thank the publisher for this excellent opportunity to serve the research community. As academic editors for this Special Issue, it is our pleasure to review these insightful manuscripts first-hand. We thank all the authors for their contributions. The collected works represent our current understanding and latest findings of nutraceuticals in immune system, which we hope will continue to inspire knowledge quests into the field of nutraceuticals.
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This study aimed to compare the effect of Boswellic acid derivatives on the viability, apoptosis, and epigenomic profiling of breast cancer. According to the viability assays, 3-O-acetyl-11-keto-β-Boswellic acid (AKBA) showed more toxicity against MDA-MB-231 cells when compared with the 3-O-acetyl-β-Boswellic acid (ABA). In contrast, ABA revealed less toxicity against MCF-10A. Cell cycle and apoptosis assays determined the maximum apoptotic effect of AKBA on MCF-7, and MDA-MB-231 cells. Interestingly, β-Boswellic acid (BA) and ABA did not promote the apoptosis in MCF-10A cells. Transwell migration assay indicated the greatest normalized inhibition (around 160%) in the migration of MDA-MB-231 cells induced by AKBA. The expression of P53, BAX, and BCL2 genes in cancerous cell lines has affirmed that both AKBA and ABA could induce the maximal apoptosis. Western-blot investigation demonstrated that the maximum over-expression of P53 protein (1.96 times) was caused by AKBA in MDA-MB-231 cells, followed by ABA in MCF-7 cells. The BCL2 protein expression was in agreement with the previously reported results. The global DNA methylation in both cancerous cells was reduced by ABA. These results suggest that ABA represented more epigenetic modulatory effect while AKBA shows more cytotoxic and apoptotic effect against breast cancer cell lines.
Article
Boswellic acid (BA)s are pentacyclic triterpenic acids present in gum resin of Boswellia species (such as B. serrata and B. carterii). They possess a variety of pharmacological effects such as anti-inflammatory, anti-oxidant, and anti-excitotoxic effects. These properties may have potential therapeutic implication in neurological disorders. Notably, the BAs-induced neuroprotection is proposed to be associated with the ability to reduce neurotoxic aggregates, decrease oxidative stress, and improve cognitive dysfunction. Recently, BAs have been suggested as potential agents for the treatment of brain tumors due to their potential to attenuate cell proliferation, migration, metastasis, angiogenesis, and promote apoptosis during both in vitro and in vivo studies. The present review aims to address these studies and highlights the possible underlying mechanisms of the observed effects. Besides, novel formulations and improving pharmacokinetic properties may enhance the therapeutic efficacy of BAs.
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Breast cancer (BC) is one of the most common cancers in females and is responsible for the highest cancer-related deaths following lung cancer. The complex tumor microenvironment and the aggressive behavior, heterogenous nature, high proliferation rate, and ability to resist treatment are the most well-known features of BC. Accordingly, it is critical to find an effective therapeutic agent to overcome these deleterious features of BC. Resveratrol (RES) is a polyphenol and can be found in common foods, such as pistachios, peanuts, bilberries, blueberries, and grapes. It has been used as a therapeutic agent for various diseases, such as diabetes, cardiovascular diseases, inflammation, and cancer. The anticancer mechanisms of RES in regard to breast cancer include the inhibition of cell proliferation, and reduction of cell viability, invasion, and metastasis. In addition, the synergistic effects of RES in combination with other chemotherapeutic agents, such as docetaxel, paclitaxel, cisplatin, and/or doxorubicin may contribute to enhancing the anticancer properties of RES on BC cells. Although, it demonstrates promising therapeutic features, the low water solubility of RES limits its use, suggesting the use of delivery systems to improve its bioavailability. Several types of nano drug delivery systems have therefore been introduced as good candidates for RES delivery. Due to RES’s promising potential as a chemopreventive and chemotherapeutic agent for BC, this review aims to explore the anticancer mechanisms of RES using the most up to date research and addresses the effects of using nanomaterials as delivery systems to improve the anticancer properties of RES. Graphical abstract
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The antidiabetic action of traditional plants is mostly attributed to their antioxidant and anti-inflammatory properties. These plants are still having some secrets, making them an attractive source that allows for investigating new drugs or uncovering precise pharmacologic antidiabetic functions of their constituents. In diabetes, which is a lipid disease, long-term exposure of pancreatic islet beta cells to fatty acids (FAs) increases basal insulin release, reduces glucose-stimulated insulin secretion, causes islet beta cell inflammation, failure and apoptosis. Pancreatic islet beta cells express fatty acid binding protein 3 (FABP3) that receives long-chain FAs and traffics them throughout different cellular compartments to be metabolized and render their effects. Inhibition of this FABP3 may retard FA metabolism and protect islet beta cells. Since FAs interact with FABPs by their carboxylic group, some traditionally-known antidiabetic plants were reviewed in the present study, searching for their components that have common features of FABP ligands, namely carboxylic group and hydrophobic tail. Many of these carboxylic acids were computationally introduced into the ligand-binding pocket of FABP3 and some of them exhibited FABP3 ligand possibilities. Among others, the naturally occurring ferulic, cleomaldeic, caffeic, sinapic, hydroxycinnamic, 4-p-coumaroylquinic, quinoline-2-carboxylic, chlorogenic, 6-hydroxykynurenic, and rosmarinic acids in many plants are promising candidates for being FABP3-specific inhibitors. The study shed light on repurposing these phyto-carboxylic acids to function as FABP inhibitors. However, more in-depth biological and pharmacological studies to broaden the understanding of this function are needed.
Preprint
Full-text available
The antidiabetic action of traditional plants is mostly attributed to their antioxidant and anti-inflammatory properties. These plants are still having some secrets, making them an attractive source that allows for investigating new drugs or uncovering precise pharmacologic antidiabetic functions of their constituents. In diabetes, which is a lipid disease, long-term exposure of pancreatic islet beta cells to fatty acids (FAs) increases basal insulin release, reduces glucose-stimulated insulin secretion, causes islet beta cell inflammation, failure and apoptosis. Pancreatic islet beta cells express fatty acid binding protein 3 (FABP3) that receives long-chain FAs and traffics them throughout different cellular compartments to be metabolized and render their effects. Inhibition of this FABP3 may retard FA metabolism and protect islet beta cells. Since FAs interact with FABPs by their carboxylic group, some traditionally-known antidiabetic plants were reviewed in the present study, searching for their components that have common features of FABP ligands, namely carboxylic group and hydrophobic tail. Many of these carboxylic acids were computationally introduced into the ligand-binding pocket of FABP3 and some of them exhibited FABP3 ligand possibilities. Among others, the naturally occurring ferulic, cleomaldeic, caffeic, sinapic, hydroxycinnamic, 4-p-coumaroylquinic, quinoline-2-carboxylic, chlorogenic, 6-hydroxykynurenic, and rosmarinic acids in many plants are promising candidates for being FABP3-specific inhibitors. The study shed light on repurposing these phyto-carboxylic acids to function as FABP inhibitors. However, more in-depth biological and pharmacological studies to broaden the understanding of this function are needed.
Article
With rising technological advancements, several factors influence the lifestyle of people and stimulate chronic inflammation that severely affects the human body. Chronic inflammation leads to a broad range of physical and pathophysiological distress. For many years non-steroidal drugs and corticosteroids were most frequently used in treating inflammation and related ailments. However, long-term usage of these drugs aggravates the conditions of chronic diseases and is presented with morbid side effects, especially in old age. Hence, the quest for safe and less toxic anti-inflammatory compounds of high therapeutic potential with least adverse side effects has shifted researchers' attention to ancient medicinal system. Resveratrol (RSV) - 3,4,5' trihydroxystilbene is one such naturally available polyphenolic stilbene derivative obtained from various plant sources. For over 2000 years, these plants have been used in Asian medicinal system for curing inflammation-associated disorders. There is a wealth of in vitro, in vivo and clinical evidence that shows RSV could induce anti-aging health benefits including, anti-cancer, anti-inflammatory, anti-oxidant, phytoesterogenic, and cardio protective properties. However, the issue of rapid elimination of RSV through the metabolic system and its low bio-availability is of paramount importance which is being studied extensively. Therefore, in the present article, we scientifically reviewed the molecular targets, biological activities, beneficial and contradicting effects of RSV as evinced by clinical studies for the prevention and treatment of inflammation-mediated chronic disorders.
Article
Background Regardless of major advances in diagnosis, prevention and treatment strategies, cancer is still a foreboding cause due to factors like chemoresistance, radioresistance, adverse side effects and cancer recurrence. Therefore, continuous development of unconventional approaches is a prerequisite to overcome foregoing glitches. Natural products have found their way into treatment of serious health conditions, including cancer since ancient times. The compound oroxylin A (OA) is one among those with enormous potential against different malignancies. It is a flavonoid obtained from the several plants such as Oroxylum indicum, Scutellaria baicalensis and S. lateriflora, Anchietea pyrifolia, and Aster himalaicus. Purpose The main purpose of this study is to comprehensively elucidate the anticancerous effects of OA against various malignancies and unravel their chemosensitization and radiosensitization potential. Pharmacokinetic and pharmacodynamic studies of OA have also been investigated. Method The literature on antineoplastic effects of OA was searched in PubMed and Scopus, including in vitro and in vivo studies and is summarized based on a systematic review protocol prepared according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The term “oroxylin A” was used in combination with “cancer” and all the title, abstracts and keywords appeared were considered. Results In Scopus, a total of 157 articles appeared out of which 103 articles that did not meet the eligibility criteria were eliminated and 54 were critically evaluated. In PubMed, from the 85 results obtained, 26 articles were eliminated and 59 were included in the preparation of this review. Mounting number of studies have illustrated the anticancer effects of OA, and its mechanism of action. Conclusion OA is a promising natural flavonoid possessing wide range of pleiotropic properties and is a potential anticancer agent. It has a great potential in the treatment of multiple cancers including brain, breast, cervical, colon, esophageal, gall bladder, gastric, hematological, liver, lung, oral, ovarian, pancreatic and skin. However, lack of pharmacokinetic studies, toxicity assessments, and dose standardization studies and adverse effects limit the optimization of this compound as a therapeutic agent.
Article
Withaferin A (WFA), a withanolide, is isolated from plants of Withania somnifera (L.) Dual (Solanaceae), known as Indian ginseng, Indian winter cherry or Ashwagandha. It has been reported to exert multifaceted anti-neoplastic effects. Here, we analyzed the impact of WFA on apoptosis and autophagy activation in different human colorectal cancer cell lines. We observed that WFA exposure caused an increased aggregation of cells in the subG1 arrest in cell cycle, and increased the number of late apoptotic cells. WFA also induced the apoptosis via PARP and caspase-3 cleavage accompanied with suppression of levels of anti-apoptotic proteins like Bcl-2 and Bcl-xl. The influence of WFA on autophagy was validated by acridine orange, MDC staining, and immunocytochemistry of LC3. It was found that 24 h treatment of WFA increased the acridine and MDC stained autophagosome with induced the LC3 and other autophagy markers Atg7 and beclin-1 activation. We used Z-DEVD-FMK, a caspase-3 blocker, and 3-MA, an autophagy inhibitor, to confirm whether these effects were specific to apoptosis and autophagy, and observed the recovery of both these processes upon exposure to WFA. Moreover, the activation of β-catenin protein was attenuated by WFA. Interestingly, small interfering RNA (siRNA)-promoted β-catenin knockdown augmented the WFA-induced active form of p-GSK-3β, and stimulated autophagy and apoptosis through PARP and LC3 activation. These findings suggested that WFA could stimulate activation of both apoptosis and autophagy process via modulating β-catenin pathway.
Article
Cyclophosphamide (CP) is a chemotherapeutic agent that belongs to the alkylating agent group that is widely used in the treatment of cancer. Cardiotoxicity is often a side effect of using CP in medical therapy. In this study, 24 Sprague Dawley rats were randomly divided into 4 groups. Group 1 (K1) was given injection with aqua pro injection intraperitoneally (IP) once a week for 21 days. Group 2 (K2) was given IP CP with a dose of 50 mg/kg BW, once a week for 21 days. Group 3 (K3) was given boswellic acid extract at a dose of 250 mg/kg BW orally, every day for 21 days. Group 4 (K4) was given boswellic acid nanoparticles at a dose of 250 mg/kg BW orally, every day for 21 days. During the treatment the body weight of the rats was weighed every day. At the end of the treatment, the rats were euthanized and blood samples were taken for blood biochemical evaluation, namely CPK, LDH, AST, and ALT. The results showed that the levels of CPK, LDH, AST, and ALT in K2 were significantly higher (p<0.05) than K1, K3 and K4. Statistically, the results of CPK, LDH, AST and ALT in K3 and K4 were not significantly different (p<0.05) compared to K1. The two groups (K3 and K4) were not significantly different (p<0.05) but on average the CPK, LDH, AST, and ALT results in K4 had lower scores than K3. This can indicate the protective effect of boswellic acid and boswellic acid nanoparticles on the heart against cyclophosphamide-induced cardiotoxicity.
Article
Renal cell carcinoma (RCC), also called kidney cancer, is one of the most common malignancies worldwide, including the United States and China. Because of the characteristics of RCC that are both insidious and largely insensitive to chemo-radiation, the incidence and mortality of RCC are increasing every year. However, there are few studies describing anti-cancer effects of the natural compounds on RCC as compared to other cancers. Here, we analyzed the anti-neoplastic impact of Tanshinone IIA (TSN) on RCC cells. We noted that TSN increased the expression of LC3 proteins while having little effect on PARP and Alix protein expression. We found that TSN up-regulated the expression of autophagy-related proteins such as Atg7 and Beclin-1. Moreover, TSN promoted the formation of autophagic vacuoles such as autophagosomes and autolysosomes. However, treatment with 3-Methyladenine (3-MA) or Chloroquine (CQ), slightly decreased the ability of TSN to induce autophagy, but still autophagy occurred. In addition, TSN inhibited translocation of β-catenin into the nucleus, and β-catenin deletion and TSN treatment in RCC increased the expression of LC3 protein. Overall our findings indicate that TSN can exert significant anti-tumor effects through down-regulation of β-catenin to induce autophagic cell death.
Article
The use of complementary and alternative veterinary medicine (CAVM) continues to become more widespread, especially for the management of chronic pain conditions such as canine osteoarthritis. Many patients have comorbidities that preclude traditional medical options, have not adequately responded to conventional therapies, or have owners interested in pursuing a complementary approach. Evidence-based CAVM can serve as a safe and effective adjunct to manage chronic pain conditions. There is growing evidence in the veterinary literature for the use of acupuncture and some herbal supplements in the multimodal management of canine osteoarthritis. The majority of evidence supporting chiropractic is limited to equine and human literature.
Article
Chronic diseases are a serious health concern worldwide, especially in the elderly population. Most chronic diseases like cancer, cardiovascular ailments, neurodegenerative disorders, and autoimmune diseases are caused due to the abnormal functioning of multiple signaling pathways that give rise to critical anomalies in the body. Although a lot of advanced therapies are available, these have failed to entirely cure the disease due to their less efficacy. Apart from this, they have been shown to manifest disturbing side effects which hamper the patient's quality of life to the extreme. Since the last few decades, extensive studies have been done on natural herbs due to their excellent medicinal benefits. Components present in natural herbs target multiple signaling pathways involved in diseases and therefore hold high potential in the prevention and treatment of various chronic diseases. Embelin, a benzoquinone, is one such agent isolated from Embelia ribes, which has shown excellent biological activities toward several chronic ailments by upregulating a number of antioxidant enzymes (e.g., SOD, CAT, GSH, etc.), inhibiting anti-apoptotic genes (e.g., TRAIL, XIAP, survivin, etc.), modulating transcription factors (e.g., NF-κB, STAT3, etc.) blocking inflammatory biomarkers (e.g., NO, IL-1β, IL-6, TNF-α, etc.), monitoring cell cycle synchronizing genes (e.g., p53, cyclins, CDKs, etc.), and so forth. Several preclinical studies have confirmed its excellent therapeutic activities against malicious diseases like cancer, obesity, heart diseases, Alzheimer's, and so forth. This review presents an overview of embelin, its therapeutic prospective, and the molecular targets in different chronic diseases.
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Inflammatory responses are the consequences of infection, injury, and tissue dysfunctions. In general, these responses associate with the inception of several diseases such as rheumatoid arthritis, diabetes, allergy, asthma, cancer, epilepsy, and Alzheimer's disease. To enhance such responses a number of synthetic drugs are widely used, including steroidal/non-steroidal components, antibodies, and cytokine inhibitors. However, prolonged use of these components may generate some side effects, including the malfunction of digestive tract, liver intoxication, kidney damage, and cardiovascular disorders. Therefore, alternative application of natural compounds, such as herbal components, against inflammatory responses might be safer and more effective. Frankincense is a gum resin with potential therapeutic effects on various diseases with signs of inflammation. Therefore, frankincense can decrease the indications of numerous illnesses with the least side effects. The identification of critical active constituents in frankincense may be useful for the development of new components with desired biological effects. In this review, the potential therapeutic effects of frankincense will be described based on its anti-inflammatory effects.
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Cancer is one of the leading causes of mortality in the world. The conventional treatment strategies of cancer are surgery, radiation, and chemotherapy. However, in the advanced stage of the disease chemotherapy is the prime treatment and it is effective in only less than 10% of the patients. Therefore, there is an urgent need to find out novel therapeutic targets and delineate the mechanism of action of these targets for better management of this disease. Recent studies have shown that some of the proteins have differential role in different cancers. Therefore, it is pertinent that the targeting of these proteins should be based on the type of cancer. The nuclear receptor, FXR, is one of the vital proteins that regulate cell apoptosis. Besides, it also regulates other processes such as cell proliferation, angiogenesis, invasion, and migration. Studies suggest that the low or high expression of FXR is associated with the progression of carcinogenesis depending on the cancer types. Due to the diverse expression, it functions as both tumor suppressor and promoter. Previous studies suggest the overexpression of FXR in breast, lung, esophageal, and prostate cancer, which is related to poor survival and poor prognosis in patients. Therefore, targeting FXR with agonists and antagonists play different outcome in different cancers. Hence, this review describes the role of FXR in different cancers and the role of its inhibitors and activators for the prevention and treatment of various cancers.
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Background Despite the remarkable advances made in the diagnosis and treatment of cancer during the past couple of decades, it remains the second largest cause of mortality in the world, killing approximately 9.6 million people annually. The major challenges in the treatment of the advanced stage of this disease are the development of chemoresistance, severe adverse effects of the drugs, and high treatment cost. Therefore, the development of drugs that are safe, efficacious, and cost-effective remains a ‘Holy Grail’ in cancer research. However, the research over the past four decades shed light on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action. Apigenin is one such compound, which is known to be safe and has significant potential in the prevention and therapy of this disease. Aim To assess the literature available on the potential of apigenin and its analogs in modulating the key molecular targets leading to the prevention and treatment of different types of cancer. Method A comprehensive literature search has been carried out on PubMed for obtaining information related to the sources and analogs, chemistry and biosynthesis, physicochemical properties, biological activities, bioavailability, and toxicity of apigenin. Key findings The literature search resulted in many in vitro, in vivo, and a few cohort studies that evidenced the effectiveness of apigenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK/ERK, Wnt/β-catenin, etc., which play a crucial role in the development and progression of cancer. In addition, apigenin was also shown to inhibit chemoresistance and radioresistance and make cancer cells sensitive to these agents. Reports have further revealed the safety of the compound and the adaptation of nanotechnological approaches for improving its bioavailability. Significance Hence, the present review recapitulates the properties of apigenin and its pharmacological activities against different types of cancer, which warrants further investigation in clinical settings.
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Cancer is the most dreadful disease worldwide in terms of morbidity and mortality. The exact cause of cancer development and progression is not fully known. But it is thought that cancer occurs due to the structural and functional changes in the genes. The current approach to cancer treatment based on allopathic is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a safe and effective mode of treatment is needed to control the cancer development and progression. Some medicinal plants provide a safe, effective and affordable remedy to control the progression of malignant cells. The importance of medicinal plants and their constituents has been documented in Ayurveda, Unani medicine, and various religious books. Curcumin, a vital constituent of the spice turmeric, is an alternative approach in the prevention of cancer. Earlier studies have shown the effect of curcumin as an antioxidant, antibacterial, antitumor and it also has a noteworthy role in the control of different diseases. In this review, we summarize the understanding of chemopreventive effects of curcumin in the prevention of cancer via the regulation of various cell signaling and genetic pathways.
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This case report is aimed to investigate the effects of Korean medicine therapy (KMT) including oral herbal medicine and herb nebulizer therapy in treating metastatic bladder cancer in the lungs. A 74-year-old man was diagnosed with metastatic bladder cancer in both lungs in August 2013. He refused any chemotherapy and was admitted to our hospital in a much progressed state on January 11, 2014. Since then, he was treated with KMT until May 17, 2014. The main oral herbal medicines were Hyunamdan made of heat-processed ginseng, Hangamdan S made of Cordyceps militaris, Panax ginseng radix, Commiphora myrrha, calculus bovis, margarita, Boswellia carteri, Panax notoginseng radix and Cremastra appendiculata tuber, and nebulizer therapy with Soram nebulizer solution made of wild ginseng and Cordyceps sinensis distillate. Their effect was evaluated considering the change of the main symptoms and using serial chest X-ray. The size and number of multiple metastatic nodules in both lungs were markedly decreased and the symptoms had disappeared. These results suggest that KMT can be an effective method to treat metastatic bladder cancer in the lungs.
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The study investigated the growth-inhibiting and apoptosis mediating effects of B. serrata extract as monotherapy and combination therapy with DOX against hepatocellular carcinoma cell lines. Boswellic acid rich fraction of B. serrata extract was prepared. MTT assay on HepG2 and Hep3B cells was carried out using B. serrata alone and in combination with DOX. Further, caspase-3 activity, TNF-α level, and IL-6 level were estimated. Isobolographic analysis was carried out to evaluate the effect of combination therapy. Additionally, protective effect of B. serrata extract on DOX induced hepatic toxicity was also evaluated in Wistar rats. B. serrata extract inhibited growth of HepG2 (IC50 value of 21.21 ± 0.92 μg/mL) as well as HepG2 (IC50 value of 18.65 ± 0.71 μg/mL). DOX inhibited growth in HepG2 and Hep3B cells with an IC50 of 1.06 ± 0.04 μg/mL and 1.92 ± 0.09 μg/mL. Isobolographic analysis showed combination index (CI) of DOX and B. serrata extract of 0.53 ± 0.03 to 0.79 ± 0.02 suggesting synergistic behavior against the two cell lines. B. serrata extract also caused dose dependent increase in caspase-3 activity, TNF-α level, and IL-6 level which was higher (P < 0.001) with DOX (1 μM) and B. serrata extract (20 μg/mL) combination. B. serrata extract also protected Wistar rats against DOX induced hepatic toxicity.
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Boswellic acid (BA)-containing extracts such as BSE have anti-inflammatory and immunomodulatory activity. In chronic schistosomiasis, the hepatic granuloma and fibrosis induced by egg deposition in the liver is the most serious pathological manifestations. However, little is known regarding the role of BAs in Schistosoma japonicum (S. japonicum) egg-induced liver granuloma and fibrosis. In order to investigate the effect of a water-soluble complex preparation of BSE, BSE-CD, on S. japonicum egg-induced liver pathology, liver granuloma and fibrosis were induced by infecting C57BL/6 mice with 18-22 cercariae of S. japonicum. S. japonicum cercariae infected mice were injected with BSE-CD at the onset of egg granuloma formation (early phase BSE-CD treatment after 4 weeks infection) or after the formation of liver fibrosis (late phase BSE-CD treatment after 7 weeks infection). Our data show that treatment of infected mice with BSE-CD significantly reduced both the extent of hepatic granuloma and fibrosis. Consistent with an inhibition of NF-κB signaling as evidenced by reduced IκB kinase (IKK) activation, the mRNA expression of VEGF (vascular endothelial growth factor, VEGF), TNF-α (tumor necrosis factor-alpha TNF-α) and MCP-1 (monocyte chemotactic protein 1, MCP-1) was decreased. Moreover, immunohistochemical analysis (IHC) revealed that the content of α-SMA in liver tissue of BSE-CD treated mice was dramatically decreased. Our findings suggest that BSE-CD treatment attenuates S. japonicum egg-induced hepatic granulomas and fibrosis, at least partly due to reduced NF-κB signaling and the subsequently decreased expression of VEGF, TNF-α, and MCP-1. Suppression of the activation of hepatic stellate cells (HSC) may also be involved in the therapeutic efficacy of BSE-CD.
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Frankincense ( Rǔ Xiāng; Boswellia Species), the resinous extract from the trees of the genus Boswellia, has been used for centuries in cultural ceremonies, as a cosmetic agent, and as a traditional medicine to treat a variety of ailments, especially inflammatory diseases including asthma, arthritis, cerebral edema, chronic pain syndrome, chronic bowel diseases, cancer, and some other illnesses. Boswellic acids are the active compounds of frankincense and AKBA (3-O-acetyl-11-keto-β-boswellic acid) is the most important and effective acid among them. Some studies have shown that the use of frankincense can also improve the learning and enhance the memory in animals and human beings. It seems that frankincense might have a potential ability to be used as an alternative natural medicine not only for chronic and inflammatory diseases but also for brain and memory disorders.
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Chemotherapy is one of the standard methods of treatment in many cancers. While chemotherapy is often capable of inducing cell death in tumors and reducing the tumor bulk, many cancer patients experience recurrence and ultimately death because of treatment failure. In recent years, cancer stem cells (CSCs) have gained intense interest as key tumor-initiating cells that may also play an integral role in recurrence following chemotherapy. As such, a number of mechanisms of chemoresistance have been identified in CSCs. In this review, we describe a number of these mechanisms of chemoresistance including ABC transporter expression, aldehyde dehydrogenase (ALDH) activity, B-cell lymphoma-2 (BCL2) related chemoresistance, enhanced DNA damage response and activation of key signaling pathways. Furthermore, we evaluate studies that demonstrate potential methods for overcoming chemoresistance and treating chemoresistant cancers that are driven by CSCs. By understanding how tumor-initiating cells such as CSCs escape chemotherapy, more informed approaches to treating cancer will develop and may improve clinical outcomes for cancer patients.
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The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-β-boswellic acid (C-KβBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KβBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eIF4E, cyclin D1, and induces G(1) cell cycle arrest. In contrast to conventional mTOR inhibitors, C-KβBA downregulates the phosphorylation of S6K1, the major downstream target of mTORC1, without concomitant activation of mTORC2/Akt and ERK pathways, and independently of protein phosphatase 2A, LKB1/AMPK/TSC, and F12-protein binding. At the molecular level, the compound binds to the FRB domain of mTOR with high affinity thereby competing with the endogenous mTOR activator phosphatidic acid. C-KβBA represents a new type of proapoptotic mTOR inhibitor that due to its special mechanistic profile might overcome the therapeutic drawbacks of conventional mTOR inhibitors.
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It is well established that glucans enhance the efficacy of anti-cancer and anti-infection immunotheraphy, both in clinical and experimental conditions. However, the considerable variations among batches of natural glucan in molecular weight, branching frequency, as well as linkage to chitins and mannoproteins, make the clinical applications of natural glucan questionable. The future might be in the use of small synthetic oligosaccharides prepared on the basis of natural glucans. Some of these non natural oligosaccharides showed biological activities such as stimulation of phagocytosis, modulation of gene expression and anti-cancer activity, which were superior to natural glucans. The recent studies strongly suggest the possibility of small chemical changes in the structure of these oligoglucans oriented towards their improved biological activities. This review highlights recent achievements in the immunological effects of synthetic, glucan-based oligosaccharides.
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The anti-inflammatory potential of Boswellia serrata gum resin extracts has been demonstrated in vitro and in animal studies as well as in pilot clinical trials. However, pharmacokinetic studies have evidenced low systemic absorption of boswellic acids (BAs), especially of KBA and AKBA, in rodents and humans. This observation has provided a rationale to improve the formulation of Boswellia extract. We present here the results of a murine comparative bioavailability study of Casperome™, a soy lecithin formulation of standardized Boswellia serrata gum resin extract (BE), and its corresponding non-formulated extract. The concentration of the six major BAs [11-keto-ß-boswellic acid (KBA), acetyl-11-keto-ß-boswellic acid (AKBA), ß-boswellic acid (ßBA), acetyl-ß-boswellic acid (AßBA), α-boswellic acid (αBA), and acetyl-α-boswellic acid (AαBA)] was evaluated in plasma and in a series of tissues (brain, muscle, eye, liver and kidney), providing the first data on tissue distribution of BAs. Weight equivalent and equimolar oral administration of Casperome(TM) provided significantly higher plasma levels (up to 7-fold for KBA, and 3-fold for ßBA quantified as area under the plasma concentration time curve, AUC(last)) compared to the non-formulated extract. This was accompanied by remarkably higher tissue levels. Of particular relevance was the marked increase in brain concentration of KBA and AKBA (35-fold) as well as ßBA (3-fold) following Casperome(TM) administration. Notably, up to 17 times higher BA levels were observed in poorly vascularized organs such as eye. The increased systemic availability of BAs and the improved tissue distribution, qualifies Casperome(TM) for further clinical development to fully exploit the clinical potential of BE.
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Colorectal cancer (CRC) is a complex disease with genetic and epigenetic alterations in many key oncogenes and tumor suppressor genes. The active principle of a gum resin from Boswellia serrata, 3-acetyl-11-keto-β-boswellic acid (AKBA), has recently gained attention as a chemopreventive compound due to its ability to target key oncogenic proteins such as 5-lipoxygenase and nuclear factor-kappaB. AKBA has been shown to inhibit the growth of CRC cells; however, the precise molecular mechanisms underlying its anticancer activities in CRC remain unclear. We hypothesized that boswellic acids may achieve their chemopreventive effects by modulating specific microRNA (miRNA) pathways. We found that AKBA significantly up-regulated expression of the let-7 and miR-200 families in various CRC cell lines. Both let-7 and miR-200 are putative tumor-suppressive miRNAs. AKBA modulated the expression of several downstream targets of the let-7 and miR-200 families, such as CDK6, vimentin and E-cadherin. These data were further strengthened by miRNA knockdown studies, which revealed that inhibition of let-7i facilitated enhanced cancer cell proliferation, migration and invasion. In addition, AKBA also induced similar modulation of the let-7 and miR-200 downstream genes in CRC tumors orthotopically implanted in nude mice. These results indicate that AKBA-induced antitumor effects in CRC occur, at least partly through the up-regulation of specific miRNA pathways. Our data provide novel evidence that anticancer effects of boswellic acids are due in part to their ability to regulate cellular epigenetic machinery and further highlight the promise for this phytochemical in the preventative and therapeutic applications of CRC.
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Apoptotic induction in cancer cells has become a major focus of anticancer therapeutics. In this regard, β-boswellic acids, naturally occurring pentacyclic triterpenes, have demonstrated antiproliferative and cytotoxic effects against different types of cancers. Surprisingly, not much has been reported regarding the chemical modifications or preparation of structural analogs of the key constituents of β-boswellic acid. Aim: The anticancer activity of 3-α-propionyloxy-β-boswellic acid (POBA) was investigated and this article reports for the first time that the triterpenoid ring of the boswellic acid derivative POBA is targeting the PI3K pathway. Induction of apoptosis of the semi-synthetic derivative of β-boswellic acid-POBA in vitro was analyzed using a battery of human cancer cell lines followed by cell cycle phase distribution, further validated by DNA fragmentation, and was found to cause mitochondrial membrane potential loss with ultrastructural changes, as observed by electron microscopy studies and expression study using PARP cleavage, as well as validated by in vivo anti-tumor activity. The cytotoxicity data revealed the sensitivity of various human cancer cell lines of varied tissue origin to β-boswellic acid, which robustly induced cell cycle arrest, DNA fragmentation and loss of mitochondrial membrane potential. Morphological studies of the effects of POBA revealed loss of surface projections, chromatin condensation, apoptotic body formation and POBA-mediated PARP cleavage. For in vivo therapeutic experiments, murine tumor models were treated with POBA and the treatment resulted in a significantly higher level of growth inhibition and apoptosis was significantly induced. These findings demonstrate that acyl substituents/groups in the main skeleton of β-boswellic acid have the potential to be potent chemotherapeutic agents.
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The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.
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Pancreatic cancer (PaCa) is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA), an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation). These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg) significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.
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Triterpenoids are pentacyclic secondary metabolites present in many terrestrial plants. Natural triterpenoids have been reported to exhibit anti-inflammatory and anti-carcinogenic activities. Here, we show that modifications of ring A of boswellic acid (2 cyano, 3 enone) resulted in a highly active growth inhibitory, anti-inflammatory, prodifferentiative and anti-tumour triterpenoid compound called cyano enone of methyl boswellates (CEMB). This compound showed cytotoxic activity on a number of cancer cell lines with IC₅₀ ranging from 0.2 to 0.6 μM. CEMB inhibits DNA synthesis and induces apoptosis in A549 cell line at 0.25 μM and 1 μM concentrations, respectively. CEMB induces adipogenic differentiation in 3T3-L1 cells at a concentration of 0.1 μM. Finally, administration of CEMB intra-tumourally significantly inhibited the growth of C6 glioma tumour xenograft in immuno-compromised mice. Collectively, these results suggest that CEMB is a very potent anti-tumour compound.
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Boswellic acids have long been considered the main bioactive components of frankincense, and many studies in vitro and in animals as well as several clinical studies have confirmed their various bioactivities. In particular, a large number of mechanistic studies have confirmed their anti-inflammatory and antitumor activities. However, not every boswellic acid exhibits a satisfactory pharmacological performance, which depends on the chemical structure and functional groups of the acid. To enhance the pharmacological values of boswellic acids, derivatization has been specifically applied with the aim of discovering more active derivatives of BAs. In addition, the preliminary pharmacokinetic studies of these compounds using various standard methods show their poor bioavailability in humans and rodents, which has led to questions of their pharmacological relevance and potentially limits their use in clinical practice and pharmaceutical development. To improve these effects, some approaches have shown some improvements in effectiveness, and the new formula compatibility approach is considered a very reasonable method for improving the bioavailability of boswellic acids. Georg Thieme Verlag KG Stuttgart · New York.
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