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![Structure of Z-guggulsterone [trans-4,17(20)-pregnadiene-3,16-dione] [12].](profile/Yih-Huei-Uen/publication/230739679/figure/fig11/AS:669665101639707@1536672010840/Structure-of-Z-guggulsterone-trans-4-1720-pregnadiene-3-16-dione-12.png)
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![Structure ofZ-guggulsterone [trans-4,17(20)-pregnadiene-3,16-dione][12].](profile/Yih-Huei-Uen/publication/230739679/figure/fig1/AS:195707383357440@1423671684094/Structure-ofZ-guggulsterone-trans-4-1720-pregnadiene-3-16-dione12_Q320.jpg)
Background
Doxorubicin (DOX) is an effective antineoplastic drug; however, clinical use of DOX is limited by its dose-dependent cardiotoxicity. It is well known that reactive oxygen species (ROS) play a vital role in the pathological process of DOX-induced cardiotoxicity. For this study, we evaluated the protective effects of guggulsterone (GS), a...
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Context 1
... (GS) is a steroid compound that has been isolated from myrrh [10,11]; the structure of which is shown in Figure 1 [12]. In 1972, two isomer derivatives, Z-GS and E-GS, were identified in Commi- phora mukul (containing 4.50% (Z)-isomer and 1.42% (E)-isomer) [13] as antagonist ligands for the bile acid receptor farnesoid X receptor and as active ingredients responsible for hypolipidemic activity [14,15]. ...
Context 2
... determine whether GS influences DOX in cancer therapy, GS and DOX were combined to treat DLD-1 cells (human colon adenocarcinoma). As shown in Figure 10A, the morphology of DLD-1 cells indicated that they were injured after treatment with 1 μM of DOX; however, GS (10, 20 and 30μM) did not reverse this re- sponse. As shown in Figure 10B, GS (1-50 μM) did not cause cytotoxicity in the DLD-1 cells. ...
Context 3
... shown in Figure 10A, the morphology of DLD-1 cells indicated that they were injured after treatment with 1 μM of DOX; however, GS (10, 20 and 30μM) did not reverse this re- sponse. As shown in Figure 10B, GS (1-50 μM) did not cause cytotoxicity in the DLD-1 cells. DOX (1 μM) can in- duce 42.6% cell death; however, the cell viability did not significantly increase after co-treatment of GS (1-50 μM) and DOX. ...
Context 4
... addition, we assessed PARP, caspase-3, and bax by Western blotting. As shown in Figure 10C, DOX induced PARP and caspase-3 protein degradation, in- creased cleaved-PARP and cleaved-caspase-3 expression, and induced bax expression. However, these effects were not influenced by co-treatment with GS. ...
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Background
Endoplasmic reticulum stress (ERS) is part of the cardiovascular pathological processes, including atherosclerosis. Nuclear factor IA (NFIA) influences atherosclerosis development; however, its effects on ERS remain unknown. This study investigated the effect of NFIA on oxidized low-density lipoprotein (ox-LDL)-induced ERS and apoptosis...
Citations
... In another article, guggulsterone has been significantly reported to inhibit and restrain the proliferation of cancer cells (Gupta et al., 2023). G-Z has been examined to exert a negative regulatory effect on microglia-mediated neuroinflammation (Huang et al., 2016), cardioprotective effect against DOX-induced cardiotoxicity (Wang et al., 2012), anti-inflammatory efficacy through the inhibition of nuclear factor-κB (NF-κB) activation (Deng, 2007) and stimulatory effect on thyroid function in rats (Tripathi et al., 1988). ...
... For the determination of the effect of PCA, DOX, and ATO on H9C2 cell viability, an MTT kit was used (19). In Brief, 1 × 10 5 cells per mL were cultivated in every well of a plate and incubated for 24 h. ...
... For evaluation of the effect of PCA against DOX-and ATO-induced cytotoxicity, LDH releases assay kit was used following the manufacturer's instructions (19). The released LDH in collected culture media which reflects a direct measurement of the dead fraction of cells was quantified by microplate reader/spectrophotometer at 560 nm. ...
Background and purpose: Some chemotherapeutic drugs are associated with an increased risk of cardiotoxicity in patients. Protocatechuic acid (PCA) is a phenolic acid with valuable cardiovascular, chemo-preventive, and anticancer activities. Recent studies have shown the cardioprotective effects of PCA in several pathological conditions. This investigation aimed to assess the possible protective effects of PCA on cardiomyocytes against toxicities caused by anti-neoplastic agents, doxorubicin (DOX), and arsenic trioxide (ATO).
Experimental approach: H9C2 cells were exposed to DOX (1 μM) or ATO (35 μM) after 24 h pretreatment with PCA (1-100 μM). MTT and lactate dehydrogenase (LDH) tests were used to define cell viability or cytotoxicity. Total oxidant and antioxidant capacities were evaluated by measuring hydroperoxides and ferric-reducing antioxidant power (FRAP) levels. Expression of the TLR4 gene was also quantitatively estimated by real-time polymerase chain reaction.
Findings/Results: PCA showed a proliferative effect on cardiomyocytes and significantly enhanced cell viability and reduced cytotoxicity of DOX and ATO during MTT and LDH assays. Pretreatment of cardiomyocytes with PCA significantly decreased hydroperoxide levels and elevated FRAP value. Moreover, PCA meaningfully decreased TLR4 expression in DOX-and ATO-treated cardiomyocytes.
Conclusions and implications: In conclusion, antioxidant and cytoprotective activities were found for PCA versus toxicities caused by DOX and ATO in cardiomyocytes. However, further in vivo investigations are recommended to assess its clinical value for the prevention and treatment of cardiotoxicity induced by chemotherapeutic agents.
... Anticancer activity enhance the antitumour activities of gemcitabine through the suppression of NF-B activation Reference Chen et al., 2021Younes, 2020Leo et al., 2019Agbay et al., 2018Che et al., 2018Azhar et al., 2016Zhong et al., 2015Guan et al., 2014Kim et al., 2013Koo et al., 2012Wang et al., 2012Yang et al., 2012 Table 1: Clinical studies on guggulsterone in the past decade to treat many diseases mevalonate pathway leading to the synthesis of isoprenoids. The C 30 Squalene is produced by joining six isoprenoid units (6 X C 5 units) and Squalene synthase (SS) catalyzes the first step to form squalene from FPP (Nes, 2011); it is the first enzymatic step towards the biosynthesis of sterols and triterpenoids (Abe et al., 1993). ...
Bambusa bambos (L.) Voss is an Indian Thorny Bamboo doesn't require any management strategies for propagation. It is a multipurpose bamboo species. Its edible shoots are being used as vegetable, leaves for forage and seeds for famine food to valuable culms (wood and construction material) and highly adaptive to tropical subtropical and temperate regions. Its most sustainable resource in making Bamboo charcoal so called "Black Diamond" an environmental-friendly material helps in mitigating energy crisis and preventing deforestation. Bamboo charcoal has extremely good absorbing property, known for cleansing applications. Basically, as air and water purifier, it conceivably has a higher enrichment capacity for heavy metal ions due to its micro-porous structure and large surface area. In this paper we are reviewing a reliable species for Bambusa bambos charcoal production and some of its applications
... Anticancer activity enhance the antitumour activities of gemcitabine through the suppression of NF-B activation Reference Chen et al., 2021Younes, 2020Leo et al., 2019Agbay et al., 2018Che et al., 2018Azhar et al., 2016Zhong et al., 2015Guan et al., 2014Kim et al., 2013Koo et al., 2012Wang et al., 2012Yang et al., 2012 Table 1: Clinical studies on guggulsterone in the past decade to treat many diseases mevalonate pathway leading to the synthesis of isoprenoids. The C 30 Squalene is produced by joining six isoprenoid units (6 X C 5 units) and Squalene synthase (SS) catalyzes the first step to form squalene from FPP (Nes, 2011); it is the first enzymatic step towards the biosynthesis of sterols and triterpenoids (Abe et al., 1993). ...
Bambusa bamboo (L.) Voss is an Indian Thorny Bamboo that does not require any managementstrategies for propagation. It is a multipurpose bamboo species. Its edible shoots are being usedas vegetables, leaves for forage, and seeds for famine food to valuable culms (wood and constructionmaterial) and are highly adaptive to tropical subtropical and temperate regions. Its most sustainableresource in making Bamboo charcoal (BC) is the so-called ‘Black Diamond’ an environmental-friendlymaterial that helps in mitigating the energy crisis and preventing deforestation. BC has extremely goodabsorbing property, which is known for cleansing applications. Basically, as an air and water purifier,it conceivably has a higher enrichment capacity for heavy metal ions due to its microporous structureand large surface area. In this article, we are reviewing a reliable species for B. bamboo charcoalproduction and some of its applications
... Acute toxicity study of Z-GS demonstrated that Z-GS did not show any sign of toxicity or abnormal symptom in the rats of dosing up to 1600 mg/kg, suggesting the potential clinical safety of Z-GS [8]. Increasing evidence suggests that Z-GS possesses strong antioxidant property by inhibiting intracellular ROS level [9]. A recent research has reported that Z-GS attenuated glucocorticoid-induced osteoporosis by activating the Nrf2/HO-1 signaling [10]. ...
Ischemic stroke is a serious and life-threatening cerebrovascular thrombotic disease; however, the therapeutic strategy is limited for the complicated mechanism and narrow therapeutic window. Our previous study suggested that Z-Guggulsterone (Z-GS), an active component derived from myrrh, is a good candidate for cerebral injury. The object of this study is to investigate the exact mechanisms of Z-GS in cerebral ischemic stroke. Rats were used to conduct middle cerebral artery occlusion (MCAO) model and were treated with different dosage of Z-GS. Morphological results showed that Z-GS significantly alleviated neurological deficits, infarct volume and histopathological damage in MCAO rats. A total of 8276 differentially expressed genes were identified based on microarray analysis. Oxidation-reduction process and inflammatory response were enriched as the significant gene ontology items. TXNIP and NLRP3 were screened as the potential target genes by Series Test of Cluster (STC) analysis. The results were validated by immunohistochemistry and immunofluorescence staining. Besides, Z-GS successfully inhibited oxidative stress and inflammatory response in oxygen-glucose deprivation (OGD) treated neurons. Knockdown of TXNIP significantly decreased the expression of NLRP3 in OGD-induced neurons. In addition, Z-GS treatment scarcely changed the expressions of NLRP3 in siRNA-TXNIP pretreated cells compared with the siRNA-TXNIP alone treatment group, suggesting that the neuroprotective effect of Z-GS was dependent on TXNIP-NLRP3 axis. Taken together, this study revealed that Z-GS exerted neuroprotective property through alleviated oxidative stress and inflammation via inhibiting the TXNIP/NLRP3 axis. Z-GS could be considered as a promising candidate for the treatment of ischemic stroke.
... There is evidence showing that the use of guggulsterone at the doses of 10-30 μM significantly reduced the formation of MDA and suppressed caspase-3 activity to reference levels in doxorubicin-induced cytotoxicity and cell death in H9C2 cell line. 36 The beneficial effects of EEM found in the present study might be attributed to its phytochemical compounds. ...
Background: The oleo-gum-resin of Commiphora myrrha (myrrh) has a long history of therapeutic use in traditional medicine. The aim of this study was to seek for the scientific evidence to determine whether the ethanolic extract of myrrh (EEM) has any beneficial effects on Streptozotocin (STZ) induced testicular impairments, and explore the possible mechanisms underlying such actions. Methods: Forty-eight severe and complicated diabetic rats (fasting blood glucose above 350 mg/dL), randomly were divided into six equal groups (n=8). Besides, eight healthy rats allocated as a normal control group and only treated with vehicle solution. The diabetic animals orally received the extract (100, 200, 300, and 500 mg/kg), metformin (500 mg/kg) or vehicle solution for 28 days. As a final point, plasma glucose and insulin, circulatory sex hormones, sperm parameters including sperm concentration, motility and viability and also testicular malondialdehyde (MDA) levels were assessed. Furthermore, quantitative histological evaluation of seminiferous tubules area and determination of germinal cells apoptosis were performed. Results: None of the studied doses of EEM showed anti-diabetic effects. However, the extract mainly at the maximum dose (500 mg/kg) exhibited beneficial effects on reproductive impairments. The EEM treated rats mainly at 500 mg/kg had significantly higher sperm concentration, sperm motility, sperm viability, sex hormones and lower testicular MDA and germ cell apoptosis index than untreated diabetic rats. Conclusion: These results indicated that EEM may have beneficial effects against reproductive dysfunction induced by diabetes. The mechanisms behind the effects might be associated with the EEM sex hormone booster potential, antioxidant and anti-apoptotic properties.
... A marked activity was shown by guggulsterone on cardiac enzymes and P450 system against myocardial necrosis induced by isoproterenol in rats (Kaul and Kapoor 1989). Guggulsterone decreased DOX-induced apoptosis in cardiomyocyte H9C2 (Wang et al. 2012). siRNA-mediated silencing of endogenous FXR or post-ischaemic myocardial apoptosis showed reduction by guggulsterone in murine myocardial ischaemia. ...
Guggulsterone is a plant sterol isolated from gum resin of some members of family Burseraceae. The gum resin from these plants has been used for thousands of years to treat various ailments like obesity, tumours, intestinal worms, liver problems, cancer, leucoderma, etc. An important bioactive component of this natural resin has been identified as guggulsterone. There is a great demand for large amounts of the guggulsterones for further in vitro and in vivo studies. As this demand is not met by natural sources, which only provide the compounds in low yield, synthetic mechanisms were recently developed for synthesis of this important sterol to make it available in sufficient quantities to put in evidence its valuable biological effects. The aim of this review is to examine the chemistry and pharmacology of this compound.
... In addition, Commiphora and Boswellia showed potent cardioprotective as well as thyroid-stimulatory effects (Singh et al., 1982;Deng, 2007). For instance, GS inhibited DOX induced cytotoxicity, reduced apoptosis, and intracellular ROS and formation of MDA in DOX-treated H9C2 cells (Wang et al., 2012). In addition, triterpenes and prenylaromadendranetype diterpenes from the gum resin of B. carterii was shown to exert hepatoprotective effect against d-galactosamine-induced liver cell damage . ...
Extensive research during last 2 decades has revealed that most drugs discovered today, although costs billions of dollars for discovery, and yet they are highly ineffective in their clinical response. For instance, the European Medicines Agency has approved 68 anti-cancer drugs, and out of which 39 has reached the market level with no indication of increased survival nor betterment of quality of life. Even when drugs did improve survival rate compared to available treatment strategies, most of these were found to be clinically insignificant. This is a fundamental problem with modern drug discovery which is based on thinking that most chronic diseases are caused by alteration of a single gene and thus most therapies are single gene-targeted therapies. However, extensive research has revealed that most chronic diseases are caused by multiple gene products. Although most drugs designed by man are mono-targeted therapies, however, those designed by “mother nature” and have been used for thousands of years, are “multi-targeted” therapies. In this review, we examine two agents that have been around for thousands of years, namely “guggul” from Commiphora and Boswellia. Although we are all familiar with the search engine “google,” this is another type of “guggul” that has been used for centuries and being explored for its various biological activities. The current review summarizes the traditional uses, chemistry, in vitro and in vivo biological activities, molecular targets, and clinical trials performed with these agents.
... Cell viability was determined by the MTT assay as described in Section 2. MTT assay has been widely used to assess doxorubicin-induced toxicity in H9c2 cardiomyoblasts. [25][26][27][28] In contrast to HSA cells, resveratrol did not increase the toxicity of doxorubicin in the cardiac-derived H9c2 cells ( Figure 7). ...
Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti-proliferative and/or pro-apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD-1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth-inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro-apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation.
... Wang et al. [147] 4. Implications for future clinical research and practice ...
Doxorubicin (DOX) is an anthracycline antibiotic, which is effectively used in the treatment of different malignancies, such as leukemias and lymphomas. Its most serious side effect is dose-dependent cardiotoxicity, which occurs through inducing oxidative stress apoptosis. Due to the myelosuppressive effect of dexrazoxane, a commonly-used drug to alleviate DOX-induced cardiotoxicity, researchers investigated the potential of phytochemicals for prophylaxis and treatment of this condition. Phytochemicals are plant chemicals that have protective or disease preventive properties. Preclinical trials have shown antioxidant properties for several plant extracts, such as those of Aerva lanata, Aronia melanocarpa, Astragalus polysaccharide, and Bombyx mori plants. Other plant extracts showed an ability to inhibit apoptosis, such as those of Astragalus polysaccharide, Azadirachta indica, Bombyx mori, and Allium stavium plants. Unlike synthetic agents, phytochemicals do not impair the clinical activity of DOX and they are particularly safe for long-term use. In this review, we summarized the results of preclinical trials that investigated the cardioprotective effects of phytochemicals against DOX-induced cardiotoxicity. Future human trials are required to translate these cardioprotective mechanisms into practical clinical implications.
