Discussion: (SC = Schizandra Chenisis)
ALD is a major cause of illness and death. Alcoholic fatty liver is characterized by variable deposition of lipids in the hepatocytes. Fatty degeneration of the liver is induced by the deposition of fat in more than 5% of the hepatocytes. This accumulation of fat in the hepatocytes leads to the development of fatty liver (steatosis), which progresses to hepatitis and fibrosis and finally leads to liver cirrhosis.3
In the present study, we investigated whether SC can protect against fatty liver disease in rats chronically fed ethanol. Our results show that chronic ethanol feeding causes hepatic steatosis as evidenced by elevation of serum ALT and AST, accumulation of hepatic TG and TC, and morphologic changes (small lipid droplets and hydropic degeneration of hepatocytes) in the liver. Importantly, we found that SC administration significantly protects against ethanol-induced fatty liver by reducing elevated serum ALT and AST levels, decreasing lipid levels in the serum and hepatic tissue, and alleviating hepatic lipid accumulation.
SC is a popular herb in traditional oriental medicine; its extracts inhibit preadipocyte differentiation and adipogenesis in cultured cells, leading to decreased body weight and fat tissue mass in high-fat diet-induced obese rats.14 Interestingly, Na et al. have isolated dibenzocylooctadiene lignans from SC, which inhibit FA synthetase.20 The lignans from SC also exert hepatoprotective effects against chronic liver injury in rats.21 Moreover, several recent experimental studies reported its beneficial effect against aging-related liver changes and hepatic hypercholesterolemia.22,23
The accumulation of fat in the liver essentially results from alcohol-induced pathogenic processes, which include an increase in uptake of free FAs, synthesis of free FAs, and a decrease in β-oxidation of free FAs.24 These results demonstrate that ethanol administration increases lipid droplet accumulation in hepatocytes, and significantly increases serum and hepatic TG levels. Feeding the animals SC along with ethanol suppresses the increase of fat accumulation in hepatocytes and hepatocellular ballooning degeneration. In addition, the ethanol-induced increase in TG levels in serum and hepatic tissue was significantly suppressed by SC administration.
It is established that AST can be found in the liver, cardiac muscle, skeletal muscle, kidney, pancreas, leukocytes, and erythrocytes, whereas ALT is present only in the liver.25 Therefore, ALT is a reliable marker for detecting liver injury.26 When a hepatocyte is injured, its plasma membrane is disrupted, leading to the leakage of enzymes into the extracellular fluid, which can then be detected in the serum.27 Increased levels of AST and ALT in the serum, therefore, indicate increased damage and/or necrosis of hepatocytes.28 In this study, we demonstrate that ethanol administration elevates serum AST and ALT levels, whereas SC co-administration significantly decreases the level of these enzymes in the serum, suggesting a decrease in liver cell damage. Therefore, our data show that SC has robust hepatoprotective effects.
Cholesterol is a chemical compound that is a combination of lipid and steroid and is naturally produced by the body. About 80% of the body’s cholesterol is produced by and stored in the liver. The liver is able to regulate cholesterol levels in the blood stream and can secrete cholesterol if it is needed by the body.29 In the present study, we show that chronic ethanol consumption significantly increased serum TC and decreased serum HDL cholesterol levels. However, SC administration resulted in decreased total serum cholesterol levels compared with that of the control (ethanol treated) group. In addition, SC-fed rats showed serum HDL cholesterol levels similar to that of the normal group.
Alcoholic fatty liver is characterized by increased concentrations of TG as a result of impaired FA catabolism due to inhibition of PPARα and due to increased lipogenesis in the liver as a result of activation of the AMPK pathway.30,31 We examined the effect of SC on PPARα gene expression in rat liver tissue. Ethanol administration decreased PPARα gene expression, leading to inhibition of FA oxidation. SC treatment increased the expression of PPARα gene but did not alter PPARγ levels. This suggests that the potential mechanism underlying the protection of ethanol-induced fatty liver by SC likely involves the restoration of PPARα function. Ethanol-induced PPARγ-dependent activation of lipogenesis in the liver is not affected by SC. In addition to PPARα, SREBP-1 plays an important role to activate the genes that encode the enzymes involved in FA synthesis, such as ACC, FAS, and SCD1, and drives the formation of TG.32 In this study, the increased expression of SREBP-1 in ethanol-exposed rats was significantly inhibited by SC treatment, indicating that the protective effects of SC might be related with the modulation of SREBP-1.
Next, we investigated whether SC affects the AMPK signaling pathway to inhibit fatty liver formation in ethanol-fed rats. AMPK is known to play a major role in glucose regulation and lipid metabolism and in controlling metabolic disorders such as diabetes, obesity, and liver hepatitis.7 This study shows that SC treatment results in increased AMPK phosphorylation, which occurs at a much lower level in chronic ethanol-induced liver. This is consistent with the observation that dysregulation of hepatic AMPK signaling in response to chronic ethanol exposure is a crucial mechanism for the development of alcoholic fatty liver. Once activated, AMPK stimulates ATP-generating cellular events, such as glucose uptake and lipid oxidation, to produce energy, while turning off energy-consuming processes, such as glucose and lipid production, to restore energy balance.33 The ethanol-mediated inhibition of AMPK was associated with enhanced ACC activity, increased malonyl-CoA concentrations, and the development of liver steatosis. Altogether, our data indicate that ethanol-induced lipid accumulation and development of fatty liver is reversed by SC via activation of AMPK.
In the present study, we demonstrated that ethanol administration results in an increase in intracellular lipid accumulation in hepatocytes along with increased serum TG content. Histopathological examination of the liver from the animals demonstrated that the number of fatty hepatocytes was significantly increased upon chronic alcohol consumption but returned to normal levels in animals that were also administered SC. These results demonstrate that the alcohol-induced hepatic pathological changes were significantly inhibited in SC-fed rats. Taken together, SC treatment suppresses the increase of lipid accumulation in hepatocytes and hepatocellular ballooning degeneration in the liver. Moreover, treatment of rats with SC for 5 weeks reverses fatty liver to the normal condition, as determined biochemically and histologically.
Therefore, the present study strongly indicates that SC has protective effects against alcohol-induced fatty liver in rats. The cellular mechanisms behind ALD involve close associations of PPARα, SREBP-1, and AMPK and the potential development of steatosis in the liver, but this was mitigated by SC. In conclusion, administration of SC diminishes the accumulation of alcohol-derived lipids in the liver. These results suggest that administration of SC may be useful in preventing and improving fatty liver induced by alcohol.
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Shilajit is a resinous blackish-brown sticky tar-like herbomineral exudate that seeps from sedimentary rocks of steep mountainous regions and has reported medicinal properties (1, 2). Although geographic and environmental factors determine the composition of shilajit (1, 3), chemical characterization of shilajit has revealed the presence of three major components as represented by dibenzo-α-pyrones (DBPs, also known as urolithins in free form as well as conjugated with chromoproteins), fulvic acid with DBP core nucleus, and humic acid (2, 3). Shilajit and its active constituents have been reported to possess an array of pharmacological properties including adaptogenic, antioxidant, anti-inflammatory, immunomodulatory, anti-diabetic, and neurological properties (4, 5).
Skin aging is characterized by wrinkles, dryness, laxity, thinning, irregular pigmentation, and loss of elasticity (6). Decrease in dermal thickness and vascularity is a hallmark of cutaneous aging (7). Aging is associated with decreased cutaneous perfusion (8). Dietary supplements show promise in preventing and managing serious health conditions. The present study was aimed at determining the effect of supplementing with a standardized shilajit extract on skin gene expression profile and related function.
The study design comprised six total study visits including a baseline visit (V1) and a final 14-week visit (V6) following oral shilajit supplementation (125 or 250 mg bid). A skin biopsy of the left inner upper arm of each subject was collected at visit 2 and visit 6 for gene expression profiling using Affymetrix Clariom™ D Assay. Skin perfusion was determined by MATLAB processing of dermascopic images. Transcriptome data were normalized and subjected to statistical analysis. The differentially regulated genes were subjected to Ingenuity Pathway Analysis (IPA®). The expression of the differentially regulated genes identified by IPA® were verified using real-time polymerasechain reaction (RT-PCR).
Supplementation with shilajit for 14 weeks was not associated with any reported adverse effect within this period. At a higher dose (250 mg bid), shilajit improved skin perfusion when compared to baseline or the placebo. Pathway analysis identified shilajit-inducible genes relevant to endothelial cell migration, growth of blood vessels, and ECM which were validated by quantitative real-time polymerasechain reaction (RT-PCR) analysis.
This work provides maiden evidence demonstrating that oral shilajit supplementation in adult healthy women induced genes relevant to endothelial cell migration and growth of blood vessels. Shilajit supplementation improved skin microperfusion.
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“Shilajit for Testosterone Given its historical use as an aphrodisiac, it is not a big surprise that two modern studies have demonstrated that shilajit has successfully increased testosterone levels in two different male populations. These studies have also demonstrated ancillary benefits associated with shilajit supplementation. The first study,12 which took place over a period of 90 days, examined the effects of 100 mg shilajit (as PrimaVie purified shilajit, Natreon) twice daily in 28 infertile male patients with oligospermia (a condition with low sperm concentration). This study tested serum levels of testosterone, follicle-stimulating hormone (FSH), and malondialdehyde (MDA). In men, FSH helps control the production of sperm. MDA is a marker for oxidative stress. The results of this study showed that supplementation with shilajit significantly increased serum testosterone by 23.5 percent (P < 0.001), increased FSH by 9.4 percent (P < 0.05), and decreased MDA in semen by 18.7 percent. In addition, there was significant (P < 0.001) improvement in sperm parameters, including 37.6 percent increase in sperm mobility, 61.4 perBy Gene Bruno, MS, MHS, RH(AHG)— Huntington College of Health Sciences SUPPLEMENTSCIENCE An ayurvedic supplement for testosterone, cardiovascular health, energy, physical performance, collagen boosting and more. Shilajit: 42-44_Supplement Science.v1_Layout 1 3/31/17 10:51 AM Page 42 cent increase in total sperm count, 12.4-17.4 percent increase in motility. Liver and kidney tests also verified the safety of supplementation of PrimaVie shilajit. The second study13 also took place over 90 days, and was randomized, double-blind, and placebo-controlled. In this case, 98 healthy male volunteers (45-55 years) participated, and took 250 mg/twice of PrimaVie shilajit daily, or placebo. Total and free testosterones, luteinizing hormone (LH), FSH, and DHEA (as DHEAs) were measured on days 0 (baseline), 30, 60 and 90. In men, LH stimulates the production of testosterone and DHEA can be converted to testosterones in the body. Results showed that the shilajit treated group experienced an increase of testosterone levels on days 30 (6.82 percent), 60 (3.09 percent) and 90 (20.45 percent, P<0.05) compared to baseline. By contrast, there were decreases in testosterone levels in the placebo group (p<0.05). Testosterone levels in the shilajit group were significantly better those of the placebo group at day 90 (P<0.05). Levels of free testosterone in the shilajit group significantly increased by 19.14 percent (p<0.05), which was significantly higher than the placebo group (P<0.05). In addition, FSH levels significantly increased (p<0.004) in the shilajit group, which was significantly better than the placebo group on day 90. Also, DHEAs increased by 31.35 percent on day 90 in the shilajit group, which was significantly higher than baseline or the placebo group (p<0.05). Despite the fact that the two studies summarized above were conducted on oligospermic and healthy male populations using 200 mg and 500 mg shilijit daily, the increase in T levels was markedly similar: 23.5 percent and 20.45 percent, respectively. This similarity suggests the potential for a greater likelihood of efficacy in different populations.”
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“Shilajit is an ayurvedic drug with a long history of human use and has been used in nervous, diabetic, urinary, immune, cardiac, and digestive disorders, and is also used as a performance enhancer.[14–18] Traditionally, it has been recommended for the cure of almost all kinds of human diseases. Ancient works such as the Hindu Materia Medica, Charaka Samhita, and Susruta Samhita also describe the medicinal properties of Shilajit. Hence, it is a highly recommended drug in the ayurvedic and other traditional medicine systems of India. It would certainly be helpful to fight against common high-altitude problems like hypoxia, AMS, HAPO, HACE, dehydration, UV radiation etc when taken as a supplement by people ascending to high altitudes.
In light of Shilajit’s tremendous medicinal potential, it would not be an exaggeration to say that it can be a panacea for all human ailments and Nature’s wonderful gift to mankind.”
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“Shilajit is a potent and very safe dietary supplement, potentially able to prevent several diseases, but its main medical application now appears to come from its actions in benefit of cognition and potentially as a dietary supplement to prevent Alzheimer’s disease. In essence, this is a nutraceutical product. Considering the expected impact of shilajit applications in the medical field, especially in neurological sciences, more investigations at the basic biological level are necessary, and certainly well-developed clinical trials, in order to understand how its active principles act at molecular and cellular levels.”
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“Shilajit treatment significantly reduced the values of AST and ALT, TG, TC, LDL, glucose, liver weight, and steatosis, and instead, increased high-density lipoprotein (HDL) compared with the vehicle group (p < 0.05). Further, Shilajit treatment improved the adverse effects of HFD-induced histopathological changes in the liver as compared with the vehicle group (p < 0.001). MDA level and GPx activity increased but SOD activity decreased in the vehicle group compared with the control group (p < 0.05), while treatment with Shilajit restored the antioxidant/oxidant balance toward a significant increase in the antioxidant system in the Shilajit group (p < 0.05). Conclusions These findings suggest that Shilajit improved the histopathological NAFLD changes in the liver and indicated the potential applicability of Shilajit as a potent agent for NAFLD treatment.”
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