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The history of human medicine goes back theoretically to the sheer onset of civilizations and evolved with the corresponding circumstances. Natural ingredients, that are plant based, animal based or mineral based have been incorporated since ages in the management of health and disease. The presently popular and universally accepted modern medicine has developed slowly and methodically, over generations of scientists with their application of scientific studies and an enormous amount of research. The popularity and acceptance of modern medicine may be huge today; however, the base of its research and resources stay put in traditional system of medicine itself. Even today the future of medicine in general has a tremendous scope for natural product-based drug and formulations and hopefully will prove to be more holistic, customized with a wise amalgamation of ancient and modern medicinal fundamentals and skills so as to give maximum benefit to the present and future human generations. Ayurveda, translated as the “Science of Life”, the ancient medicinal system of the Indian subcontinent, remains the oldest of all form of medications. Ayurveda incorporates a holistic approach to medicine and makes it highly personalized. There are around 45,000 species of plants with various medicinal properties attributed to them. This paper aims at understanding the composition, chemical constitution and exact mode of action of Guggulu.
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Aim To investigate the improved effects of Z-guggulsterone on the chemotherapy agents-induced proliferation and apoptosis through regulating PXR(pregnane X receptor)/P-gp(P-glycoprotein)signaling pathway in human hepatocellular carcinoma cells.Methods HepG2 cells were treated with Z-guggulsterone, DDP(cis-platinum)and 5-FU(5-fluorouracil)alone or in combination.CCK-8(Cell Counting Kit-8), Annexin-FITC/PI(Annexin V-fluorescein isothiocyanate isomer/propidium iodide)flow cytometry, RT-qPCR(Real-time quantitively Polymerase Chain Reaction)and Western blot were used to determine cell proliferation, apoptosis, the expression of MDR1 mRNA, PXR and P-gp respectively.Results Compared to DDP or 5-FU treatment alone, Z-guggulsterone(30 μmol·L-1)enhanced the inhibitory effects of DDP or 5-FU on the proliferation and apoptosis of HepG2 cells.Z-guggulsterone(30 μmol·L-1)also significantly reduced the expression levels of PXR,P-gp and MDR1 mRNA in HepG2 cells.Further research demonstrated that rifampicin, one agonist of PXR, increased the expression of PXR and P-gp, while Z-guggulsterone reversed its effects.Meanwhile, the expressions of PXR and P-gp were reduced by ketoconazole, one antagonist of PXR, and further decreased by co-administration with Z-guggulsterone.Conclusion Z-guggulsterone can improve the effects of chemotherapy on the proliferation and apoptosis of hepatocellular carcinoma cell lines by down-regulating the PXR/P-gp signaling pathway.
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OBJECTIVE Chronic kidney disease (CKD) has become a global public health problem with 10％-15％incidence rate, and inhibiting the renal interstitial fibrosis is considered to be a potential strategy to delay the progression of CKD. Z-Guggulsterone (Z-GS), an active compound from derived from Commiphora mukul, has been proved to be effective in various diseases. The present study aimes to determine the protective effect and the molecular mechanism of Z-GS on renal fibrosis. METHODS Unilateral ureteral obstruction (UUO) mice and hypoxia-induced HK-2 cells were used to simulate renal fibrosis in vitro and in vivo, respectively. The mice and cells were treated with different doses of Z-GS to observe the pharmacological action. Renal function, including Scr, BUN, and UA, were detected by commercial kits. H&E and Masson staining were performed to observe histopathological changes of kidney. Cell viability and LDH release of HK-2 cells were detected by commercial kits. Cell cycle distribution and apoptosis rate were analyzed by flow cytometry. Fibrosis markers were detected by immunohistochemistry and immunofluorescence analysis. Cell cycle related proteins and Klotho/p53 signaling were analyzed by Western blotting. RESULTS The results showed that Z-GS decreased the rise of Scr, BUN, and UA and lightened renal histopathological injury, which were induced by UUO. Besides, Z-GS administration alleviated renal fibrosis in mice by inhibiting the expressions of α-SMA, TGF-β and colla?genⅣ, and delayed G2/M cell cycle arrest by promoting the expressions of CDK1 and cyclinD1/B1 rate. Experiments in vitro indicated that Z-GS treatment significantly increased the cell viability while decreased the LDH release in hypoxia-induced HK-2 cells. In addition, hypoxia induced fibrosis and G2/M cycle arrest in HK-2 cells were retarded by Z-GS. The study of its possible mechanism exhibited that Z-GS treatment increased the level of Klotho and inhibited P53 level. Nev?ertheless, the effect of Z-GS on Klotho/P53 signaling was reversed by siRNA-Klotho. Moreover, siRNA-Klotho treatment eliminated the effects of Z-GS on G2/M cell cycle arrest and fibrosis. CONCLUSION This study clarified that Z-GS allevi?ated renal fibrosis and G2/M cycle arrest through Klotho/P53 signaling pathway. People who have suffered CKD may potentially benefit from treatment with Z-GS.
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Objective:To explore natural compounds as potential inhibitors against main protease (Mpro) of SARS-CoV-2. Methods:In the current study, systematic molecular docking analysis was conducted using AutoDock 4.2 to determine the binding affinities and interactions between natural compounds and Mpro. Selected natural compounds were further validated using a combination of molecular dynamic (MD) simulations and molecular mechanic Poisson-Boltzmann surface area (MM/PBSA) free energy calculations. Results:Out of twenty natural compounds, four natural metabolites namely, amentoflavone, guggulsterone, puerarin, and piperine were found to have strong interaction with Mpro of SARS-CoV-2 based on docking analysis. During MD simulations, all four natural compounds bound to Mpro at 50 ns and MM/G/P/BSA free energy calculations showed that all four shortlisted ligands had stable and favorable energies with strong binding to Mpro protein. Conclusions:Guggulsterone is a potential inhibitor of COVID-19 main protease Mpro. Further in vitro and pre-clinical studies are needed.
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OBJECTIVE： To study the improvement effects of Z-guggulsterone （Z-GL） combined with acetyl-11-keto-β- boswellic acid （AKBA） on cerebral ischemia-reperfusion injury model rats. METHODS： Male SD rats were randomly divided into sham operation group， model group， Z-GL+AKBA low-dose and high-dose groups （25， 50 mg/kg）， with 10 rats in each group. Except for sham operation group， middle cerebral artery occlusion/reperfusion injury model was induced by suture method in other groups. Administration groups were given relevant medicine intragastrically after reperfusion； sham operation group and model groups were given constant volume of DMSO intragastrically， every 12 h， for consecutive 7 d. The neurological deficits were evaluated with modified Longa score； HE staining was performed to observe the pathological changes of cerebral tissue in rats； the area of cerebral infarction was measured by TTC， and the percentage of cerebral infarction area； TUNEL staining was performed to detect apoptotic neurons. The expression of CD34， VEGF and DLL4 were detected by immunofluoresence and immunoblotting assay， respectively. RESULTS： Compared with sham operation group， the number of cortical cells in the model group decreased and arranged irregularly， with obvious infarct area and obvious decrease of neovascularization； the neurological deficit score， the percentage of cerebral infarction area and TUNEL positive cells increased significantly， while the expression of CD34， VEGF and DLL4 decreased significantly （P＜0.05 or P＜0.01）. Compared with model group， the above symptoms of the rats in each administration group were significantly improved， the neurological deficit score， the percentage of cerebral infarction area and the number of TUNEL positive cells were significantly reduced； the expression levels of CD34， VEGF and DLL4 were significantly increased； the neurological deficit score， the percentage of cerebral infarction area and the number of TUNEL positive cells in Z-GL+AKBA high-dose group were significantly lower or less than low dose group； the expression of CD34 and DLL4 in high-dose group was significantly higher than low-dose group （P＜0.05 or P＜0.01）. CONCLUSIONS： Z-GL combined with AKBA can relieve neurological deficit and cerebral injury of cerebral ischemia-reperfusion injury model rats， which may be related to promoting angiogenesis and up-regulating the expression of VEGF and DLL4 protein， with a certain dose-dependent effect.
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Aim To investigate the mechanism of the combination of guggulsterone and temozolomide in inhibiting human glioblastoma cells.Methods Glioblastoma U251 cells were treated with guggulsterone and temozolomide alone or in combination.Cell proliferation was determined by CCK-8.The level of apoptosis was evaluated by Hoechst 33342 staining and flow cytometry.PI3K/Akt pathway activity and the level of apoptosis-associated proteins Bcl-2 and Bax expression were analysed by Western blot.Results Guggulsterone(30 μmol·L-1)significantly enhanced the inhibitory effect of temozolomide(1~400 μmol·L-1)on U251 cells, as compared with temozolomide treatment alone.Guggulsterone(30 μmol·L-1)significantly enhanced the effect of temozolomide(400 μmol·L-1)-induced apoptosis on U251 cells, as compared with temozolomide treatment alone(P<0.01).Furthermore, guggulsterone(30 μmol·L-1)significantly down-regulated the expression of PI3K, p-PI3K p110, p-Akt(Ser473)and Bcl-2, as compared with temozolomide treatment alone.Conclusion Guggulsterone enhances the inhibitory effect of temozolomide on human glioblastoma U251 cells through PI3K/Akt pathway.
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OBJECTIVE:To study the improvement effect of Z-Guggulsterone(Z-GL)on blood coagulation and vascular endo-thelial functions of acute blood-stasis model rats and its mechanism. METHODS:40 rats were randomly divided into normal group,model group,positive group(Aspirin tablet,50 mg/kg)and Z-GL low-dose and high-dose groups(25,50 mg/kg),with 8 rats in each group. They were given relevant medicine intragastrically every 12 h,and normal group and model group were given constant volume of normal saline intragastrically for consecutive 7 times. After the fifth administration,except for normal group, those groups were given adrenalin hydrochloride subcutaneously+ice-cold water to induce acute blood-stasis model. Within 30 min after the last administration,aorta abdominalis sample were selected to detect the coagulation parameters [prothrombin time(PT), thrombin time (TT),activated partialthromboplastin time (APTT),fibrinogen (FIB)],and pathological changes of carotid artery were observed. Human umbilical vein endothelial cells (HUEVCs) were divided into blank group (normal saline),model group (normal saline) and Z-GL low-concentration and high-concentration groups (25,50 μmol/L). After culturing for 24 h,the cells were exposed to glucose and oxygen deprivation for 6 h in model group and Z-GL groups. The expression of p-eNOS protein was detected. Other cells were selected,grouped,administrated and treated as above cells,and the NO level of these cells were detect-ed. RESULTS:Compared with normal group,PT,TT and APTT were all shortened in model group,while FIB content was in-creased (P<0.01);vascular endothelium was injured,and endothelial cells fell off from the wall. Compared with model group, PT,TT and APTT were prolonged in administration groups,while FIB content was decreased(P<0.05 or P<0.01);vascular en-dothelium injury was relieved. Results of p-eNOS protein and NO levels determination showed that compared with model group, p-eNOS protein and NO levels were increased in Z-GL groups(P<0.05 or P<0.01). CONCLUSIONS:Z-GL can significantly im-prove coagulation and vascular endothelium functions of blood-stasis model rats,and its mechanism may be associated with the acti-vation of eNOS and the increase of NO level.
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The present study is to investigate the protective actions of guggulsterone against the cytotoxicity produced by exposure to hydrogen peroxide (H2O2) in PC12 cells. It was evaluated by MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide] reduction assay, lactate dehydrogenase (LDH) release assay, and the release of nitric oxide (NO). ROS and Ca2+ in cells were evaluated by DCFH and Fura 2-AM, respectively. Mitochondrial membrane potential (MMP) was assessed by the retention of rhodamine 123 (Rh 123). Apoptosis and morphological alteration in PC12 cells were monitored with flow cytometry and electric microscope. Vitamin E, a potent antioxidant, was employed as a comparative agent. The results showed that preincubation of PC12 cells with guggulsterone (0.1-10 μmol·L-1) prevented cytotoxicity induced by H2O2. Extracellular accumulation of LDH, NO and intracellular accumulation of ROS, Ca2+ resulting from H2O2 were significantly reduced by guggulsterone. Incubation of cells with H2O2 caused a marked decrease in MMP, which was significantly inhibited by guggulsterone. The percentage of H2O2-induced apoptosis in PC12 cells was 24.3%, and decreased in the presence of guggulsterone (0.1-10 μmol·L-1) by .8.4%, 15 .9%, 11.8%, respectively. Guggulsterone exhibited comparable potency against oxidative stress induced by H2O2 in PC12 cells as that of vitamin E. The present findings showed that guggulsterone attenuated H2O2-induced cytotoxicity, extracellular accumulation of LDH and NO, intracellular accumulation of ROS and Ca2+, loss of MMP, and apoptosis, which may represent the cellular mechanisms for its neuroprotective action.
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Modification of low density lipoprotein by nonenzymic glycosylation resulted in decreased receptor-mediated lipoprotein catabolism. Guggulsterone treatment caused significant increase in binding of [125I] low density lipoprotein as well as [125I] glycosylated low density lipoprotein. Scatchard plot analysis of the binding activity revealed that under the influence of guggulsterone, the liver membrane contains increased amounts of a functional lipoprotein receptor that binds more low density lipoprotein particles.