2,3,5,4'- tetrahydroxystilbene-2-O-ß-D- glucopyranoside (TSG)-Driven immune response in the hepatotoxicity of Polygonum multiflorum.

ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside (TSG) as the primary constituent of Polygonum multiflorum Thumb. (PM) possesses anti-oxidative, antihypercholesterolemic, anti-tumor and many more biological activities. The root of PM has been used as a tonic medicine for thousands of years. However, cases of PM-induced liver injury are occasionally reported, and considered to be related to the host immune status. AIM OF THE STUDY: The primary toxic elements and specific mechanisms PM causing liver damage are still not thoroughly clear. Our study aimed to investigate the influences of TSG on the immune response in idiosyncratic hepatotoxicity of PM. MATERIALS AND METHODS: The male C57BL/6 mice were treated with different doses of TSG and the alterations in liver histology, serum liver enzyme levels, proportions of T cells and cytokines secretion were evaluated by hematoxylin and eosin (HE), RNA sequencing, quantitative real time polymerase chain reaction (qRT-PCR), Flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA), respectively. Then, primary spleen cells from drug-naive mice were isolated and cultured with TSG in vitro. T cell subsets proliferation and cytokines secretion after treated with TSG were assessed by CCK8, FCM and ELISA. In addition, mice were pre-treated with anti-CD25 for depleting regulatory T cells (Tregs), and then administered with TSG. Liver functions and immunological alterations were analyzed to evaluate liver injury. RESULTS: Data showed that TSG induced liver damage, and immune cells infiltration in the liver tissues. FCM results showed that TSG could activate CD4+T and CD8+T in the liver. Results further confirmed that TSG notably up-regulated the levels of inflammatory cytokines including TNF-α, IFN-γ, IL-18, perforin and granzyme B in the liver tissues. Furthermore, based on transcriptomics profiles, some immune system-related pathways including leukocyte activation involved in inflammatory response, leukocyte cell-cell adhesion, regulation of interleukin-1 beta production, mononuclear cell migration, antigen processing and presentation were altered in TSG treated mice. CD8+T/CD4+T cells were also stimulated by TSG in vitro. Interestingly, increased proportion of Tregs was observed after TSG treatment in vitro and in vivo. Foxp3 and TGF-ß1 mRNA expressions were up-regulated in the liver tissues. Depletion of Tregs moderately enhanced TSG induced the secretion of inflammatory cytokines in serum. CONCLUSIONS: Our findings showed that TSG could trigger CD4+T and CD8+T cells proliferation, promote cytokines secretion, which revealed that adaptive immune response associated with the mild liver injury cause by TSG administration. Regulatory T cells (Tregs) mainly sustain immunological tolerance, and in this study, the progression of TSG induced liver injury was limited by Tregs. The results of our investigations allow us to preliminarily understand the mechanisms of PM related idiosyncratic hepatotoxicity.

Hepatic Effect of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside, the Signature Component of Traditional Chinese Medicine Heshouwu: Advances and Prospects.

Traditional Chinese medicine Heshouwu, named Polygoni Multiflori Radix in Pharmacopoeia of the People's Republic of China (PPRC, 2020), is derived from the root tuber of Polygonum multiflorum Thunb., Heshouwu or processed Heshouwu is well known for its function in reducing lipids and nourishing the liver. However, increasing cases of Heshouwu-induced hepatotoxicity were reported in recent years. Researchers have begun to study the paradoxical effects of Heshouwu on the liver. 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG), an abundant functional component of Heshouwu, shows various biological activities, among which its effect on the liver is worthy of attention. This paper reviews the current studies of TSG on hepatoprotection and hepatotoxicity, and summarizes the doses, experimental models, effects, and mechanisms of action involved in TSG's hepatoprotection and hepatotoxicity, aiming to provide insight for future study of TSG and understanding the effects of Heshouwu on the liver. Emerging evidence suggests that TSG ameliorates both pathological liver injury and chemical-induced liver injury by modulating lipid metabolism, inhibiting the inflammatory response and oxidative stress in the liver. However, with the reports of clinical cases of Heshouwu induced liver injury, it has been found that long-term exposure to a high dose of TSG cause hepatocyte or hepatic tissue damage. Moreover, TSG may cause hepatotoxicity by affecting the transport and metabolism of other possible hepatoxic compounds in Heshouwu. Studies indicate that trans-TSG can be isomerized into cis-TSG under illumination, and cis-TSG had a less detrimental dose to liver function than trans- TSG in LPS-treated rats. In brief, TSG has protective effects on the liver, but liver injury usually occurs under highdose TSG or is idiosyncratic TSG-induced liver injury.

Biochemical and histopathological analysis after sub-chronic administration of oxyresveratrol in Wistar rats.

Oxyresveratrol (OXY) is a naturally occurring phenolic compound; however, there are no toxicity studies reported on its long term use. The aim of our work was to demonstrate the evaluation of acute and sub-chronic toxicity of oxyresveratrol in rats to assess its safety profile. To evaluate the LD50 value, 2000 mg/kg of oxyresveratrol was administered to Wistar rats by oral gavage. For sub-chronic toxicity assessment, 80 Wistar rats were randomly divided into four groups (10 animal/sex/group) and oxyresveratrol administered at a dose of 50, 100, 150 mg/kg/day by oral gavage. Bodyweight, food, and water consumption were monitored every week. At the end of the experiments, biochemical and hematological parameters were analyzed. Gross and microscopic organ analyses were also carried out. LD50 of oxyresveratrol was greater than 2000 mg/kg sub-chronic administration of oxyresveratrol did not influence any mortality. Doses of 50 and 100 mg/kg of oxyresveratrol did not produce any sign of toxicity. However, the 150 mg/kg oxyresveratrol group depicted changes in multiple biochemical and hematological parameters with changes in the pathology of cardiac, hepatic, and renal tissues when compared with control. Therefore, no observed adverse effect level (NOAEL) of oxyresveratrol was observed to be 100 mg/kg per day for both male and female rats.

Stilbene glucoside: recent advances in pharmacology, bioinformatics investigation, toxicity and future opportunities.

Background: 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) from Polygonum multijiorum Thunb. (PMT), is a major bioactive component. This review is aimed to summarize the present development of TSG regarding pharmaceutics, pharmacology and toxicology, with a focus on the novel mechanism of drug-induced toxicity and provides insight for its potential developments and applications in the future on traditional Chinese medicine. Methods: Studies about TSG's activities and toxicity were searched and summarized. Targets and mechanisms were predicted and analyzed with network pharmacology methods. Affinities and binding modes of key targets with TSG were verified by AutoDock Vina software. Results: TSG plays an essential role among the chemical components of PMT because of multiple pharmacological activities, which suggests a potential application of TSG for a variety of diseases, like atherosclerosis, Alzheimer's disease, Parkinson's disease, cerebral I/R injury, diabetes, osteoporosis, colitis. However, mild liver toxicity of TSG is also pointed out. Conclusions: As a biologically active natural product in PMT, TSG has shown prospective pharmacological activities, particularly as an agent for cardiovascular protection and neuroprotection.

Investigation of toxicity attenuation mechanism of tetrahydroxy stilbene glucoside in Polygonum multiflorum Thunb. by Ganoderma lucidum.

ETHNOPHARMACOLOGICAL RELEVANCE: The idiosyncratic hepatotoxicity of Polygonum multiflorum Thunb. (PM) has attracted great interest, and tetrahydroxy stilbene glucoside (TSG) was the main idiosyncratic hepatotoxicity constituent, but biological detoxification on idiosyncratic hepatotoxicity of PM was not well investigated. AIM OF THE STUDY: This study aimed to illustrate biological detoxification mechanism on PM-induced idiosyncratic hepatotoxicity by Ganoderma lucidum (G. lucidum). MATERIALS AND METHODS: G. lucidum was used for biological detoxification of tetrahydroxy stilbene glucoside (TSG)-induced idiosyncratic hepatotoxicity of PM. The TSG consumption and products formation were dynamically determined during transformation using high-performance liquid chromatography coupled with diode-array detection and electrospray ionization tandem mass spectrometry (HPLC-DAD-MSn). The transformation invertases (ß-D-glucosidase and lignin peroxidase) were evaluated by using intracellular and extracellular distribution and activity assay. The key functions of lignin peroxidase (LiP) were studied by experiments of adding inhibitors and agonists. The entire TSG transformation process was confirmed in vitro simulated test. The cellular toxicity of TSG and the transformation products was detected by MTT. RESULTS: A suitable biotransformation system of TSG was established with G. lucidum, then p-hydroxybenzaldehyde and 2,3,5-trihydroxybenzaldehyde can be found as transformation products of TSG. The transformation mechanism involves two extracellular enzymes, ß-D-glucosidase and LiP. ß-D-glucosidase can remove glycosylation of TSG firstly and then LiP can break the double bond of remaining glycosides. The toxicity of TSG after biotransformation by G. lucidum was attenuated. CONCLUSIONS: This study would reveal a novel biological detoxification method for PM and explain degradation processes of TSG by enzymic methods.

Cytotoxicity studies of a stilbene extract and its main components intended to be used as preservative in the wine industry.

The use of stilbenes has been proposed as an alternative to sulfur dioxide in wine. Provided the feasibility from a technological approach, the cytotoxicity of an extract from grapevine shoots containing a stilbene richness of 99% (ST-99 extract) was assessed in the human cell lines HepG2 and Caco-2. In addition, the effects of the main stilbenes found in ST-99, trans-resveratrol and trans-ε-viniferin were studied, as well as its mixture. Similar cytotoxic effects were obtained in the exposures to trans-ε-viniferin, ST-99 and the mixture; however, trans-resveratrol alone exerted less toxicity. When HepG2 cells were exposed to trans-ε-viniferin, ST-99 and the mixture, the mean effective concentration (EC50) were 28.28 ± 2.15, 31.91 ± 1.55 and 29.47 ± 3.54 µg/mL, respectively. However, in the exposure to trans-resveratrol, the EC50 was higher 50 µg/mL. The morphological study evidenced damage at ultrastructural level in HepG2 cells, highlighting the inhibition of cell proliferation and the induction of apoptosis. The type of interaction produced by trans-ε-viniferin and trans-resveratrol mixtures was assessed by an isobologram analysis using the CalcuSyn software, evidencing an antagonist effect. These data comprise a starting point in the toxicological assessment; further studies are needed in this field to assure the safety of the extract ST-99.

Pterostilbene supplements carry the risk of drug interaction via inhibition of UDP-glucuronosyltransferases (UGT) 1A9 enzymes.

Pterostilbene (PT) is a natural stilbene common in small berries and food supplements, possessing numerous pharmacological activities. However, whether PT can affect the activities of UDP-glucuronosyltransferases (UGT) enzymes remains unclear. The aim of the present study was to investigate the effect of PT on UGT activities and to quantitatively evaluate the food-drug interaction potential due to UGT inhibition. Our data indicated that PT exhibited potent inhibition against HLM, UGT1A6, UGT1A9, UGT2B7, and UGT2B15, moderate inhibition against UGT1A1, UGT1A3, UGT1A8, and UGT2B4, negligible inhibition against UGT1A4, UGT1A7, UGT1A10, and UGT2B17. Further kinetic investigation demonstrated that PT exerted potent noncompetitive inhibition 4-MU glucuronidation by UGT1A9, with IC50 and Ki values of 0.92 µM and 0.52 ± 0.04 µM, respectively. Quantitative prediction study suggested that coadministration of PT supplements at 100 mg/day or higher doses may result in at least a 50% increase in the AUC of drugs predominantly cleared by UGT1A9. Thus, the coadministration of PT supplements and drugs primarily cleared by UGT1A9 may result in potential drug interaction, and precautions should be taken when coadministration of PT supplements and drugs metabolized by UGT1A9.

Components synergy between stilbenes and emodin derivatives contributes to hepatotoxicity induced by Polygonum multiflorum.

Polygonum multiflorum Thunb. (PM) is a famous traditional Chinese medicine with liver tonic effect, but arousing great concerns for hepatotoxicity issue. In this study, we elucidated the contribution of the two major compounds, emodin-8-O-ß-D-glucoside (EG) and 2,3,5,4´-tetrahydroxyl diphenylethylene-2-O-glucoside (TSG), in PM-induced liver injury.Based on LC-MS, the two concerned compounds were detected simultaneously in the sera of patients with PM-induced liver injury. In the lipopolysaccharide (LPS)-mediated inflammatory stress rat model, by the analysis of plasma biochemistry and liver histopathology, we observed that the solo treatment of EG, not TSG, could induce significant liver injury; and the combined administration of EG and TSG caused more severe liver injury than that of EG.Metabolomics analysis revealed that the EG-triggered liver injury was associated with significant disturbances of sphingolipids and primary bile acids metabolism pathways. In the combined administration group, much more disturbances in EG-triggered metabolic pathways, as well as alterations of several additional pathways such as retinol metabolism and vitamin B6 metabolism, were observed.Taken together, we considered EG was involved in the idiosyncratic liver injury of PM, and TSG played a synergetic role with EG, which contributed to the understanding of the hepatotoxic basis of PM.

Prenylated stilbenes and flavonoids from the leaves of Cajanus cajan.

Three new prenylated stilbenes, named as cajanusins A-C (1-3), and one new natural product cajanusin D (4), along with six known derivatives (5-10) were isolated from the leaves of Cajanus cajan. Their structures were fully elucidated by means of extensive spectroscopic methods and comparison with data in the reported literatures. The new compounds of 1 and 2 were evaluated for in vitro cytotoxic activities against a panel of human cancer cell lines.

Attributes of Polygonum multiflorum to transfigure red biotechnology.

A vast array of plant-based compounds has enriched red biotechnology to serve the human health and food. A peculiar medicinal plant which was an element of traditional Chinese medicine for centuries as a liver and kidney tonic, for life longevity and hair blackening, is Polygonum multiflorum Thunb. (PM) which is popularly known as "He shou wu" or "Fo-ti" and is rich in chemical components like stilbenes, quinones, and flavonoids which have been used as anti-aging, anti-alopecia, anti-cancer, anti-oxidative, anti-bacterial, anti-hyperlipidemia, anti-atherosclerosis, and immunomodulating and hepatoprotective agents in the modern medicine. The health benefits from PM are attained since long through commercial products such as PM root powder, extract, capsules, tincture, shampoo, and body sprays in the market. Currently, the production of these pharmaceuticals and functional foods possessing stilbenes, quinones, and flavonoids is through cell and organ cultures to meet the commercial demand. However, hepatotoxic effects of PM-based products are the stumbling blocks for its long-term usage. The current review encompasses a comprehensive account of bioactive compounds of PM roots, their biological activities as well as efficacy and toxicity issues of PM ingredients and future perspectives.

Pharmacokinetic studies unveiled the drug-drug interaction between trans-2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucopyranoside and emodin that may contribute to the idiosyncratic hepatotoxicity of Polygoni Multiflori Radix.

Polygoni Multiflori Radix (PMR) has been a reputable tonifying traditional Chinese medicine for a long history. However, clinical side effects regarding its idiosyncratic hepatotoxicity are occasionally reported. The containing anthraquinones, particularly emodin, could cause liver injury in both in vitro and in vivo experiments. It is well-known that some compounds could influence other compounds' pharmacokinetic parameters significantly. In this work, the influence of trans-2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucopyranoside (TSG) on the pharmacokinetic behavior of emodin in rats was evaluated by an ultra-high performance liquid chromatography/triple quadrupole mass spectrometry (UHPLC/MS-MS) approach. Pharmacokinetic parameters of emodin, PMR extract, and TSG-free PMR extract (prepared by a component "knock-out" strategy with TSG eliminated), in rats after one-day and seven-day administration were determined and compared. We found that, after seven-day administration of the whole PMR extract (rather than TSG-free extract), emodin in rats was accumulated. And accordingly, the exposure of emodin in rats pre-treated with single TSG for seven days could be significantly enhanced. The results indicate that TSG was able to accelerate the exposure and metabolism of emodin. The effect of TSG on the metabolic activities of cytochrome P450 enzymes was further assessed by an LC-MS cocktail method. The accelerated exposure and metabolism of emodin could result from the up-regulation activity of CYP450s, in particular CYP1A2 isozyme. The findings obtained in this work firstly unveiled DDI between TSG and emodin in the administration of PMR, thus may provide a basis for unveiling the underlying mechanism of PMR-induced liver injury.

Two new stilbenoids from aerial parts of Flickingeria fimbriata.

Two new stilbenoids, named 2,3 -dimethoxyl-7-hydroxyl-1,4-phenanthrenedione (1) and 2-methoxyl-3-methyl-7-hydroxyl-9,10-dihydro-1,4-phenanthrenedione (2), together with two known stilbenoids including densiflorol B (3) and ephemeranthoquinone (4), were isolated from aerial parts of Flickingeria fimbriata (Bl.) Hawkes. The structures of two new compounds were elucidated by extensive spectroscopic analysis, including HRESIMS, 1H and 13C NMR, DEPT, HMBC, COSY, HMQC, NOESY. All the compounds were obtained from this genus for the first time. In addition, they all exhibited moderate cytotoxic activities against HepG2 cell lines.

Deciphering molecular mechanisms of arginine deiminase-based therapy - Comparative response analysis in paired human primary and recurrent glioblastomas.

Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (» cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Our results suggest an alternative treatment regimen for this fatal cancer type which circumvents many of the traditional barriers. Using the metabolic defect in GBM thus warrants further (pre-) clinical evaluation.

Structural Modification of Stilbenoids from Acanthopanax leucorrhizus and Their Cytotoxic Activity.

A new cis-stilbenoid, 1,9-dihydroxy-10-methoxy-6H-dibenzo[b,f]oxocin-6-one (2) was isolated from the AcOEt extract of the stem barks of Acanthopanax leucorrhizus, along with three known stilbenoids, 9-hydroxy-10-methoxy-6H-dibenzo[b,f]oxocin-6-one (1), 5-O-methyl-(E)-resveratrol 3-O-ß-d-glucopyranoside (3), and (E)-resveratrol 3-O-ß-d-xylopyranoside (4). Two derivatives (2a and 2b) were synthesized by the structural modification of compound 2, which exhibited certain cytotoxic activities against HT-29 and HeLa cell lines in vitro. All compounds were structurally characterized by comprehensive analysis of their spectroscopic data and comparison with literature information, and evaluated for their cytotoxic activities against three human tumor cell lines (HL-60, HT-29, and HeLa) by the standard MTT assay in vitro. The results showed that derivatives 2a and 2b exhibited strong activities than compounds 2 against HT-29 and HeLa cell lines.

Enhanced absorption and inhibited metabolism of emodin by 2, 3, 5, 4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside: Possible mechanisms for Polygoni Multiflori Radix-induced liver injury.

Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. However, PMR-associated hepatotoxicity is becoming a safety issue. In our previous in vivo study, an interaction between stilbenes and anthraquinones has been discovered and a hypothesis is proposed that the interaction between stilbene glucoside-enriching fraction and emodin may contribute to the side effects of PMR. To further support our previous in vivo results in rats, the present in vitro study was designed to evaluate the effects of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside (TSG) on the cellular absorption and human liver microsome metabolism of emodin. The obtained results indicated that the absorption of emodin in Caco-2 cells was enhanced and the metabolism of emodin in human liver microsomes was inhibited after TSG treatment. The effects of the transport inhibitors on the cellular emodin accumulation were also examined. Western blot assay suggested that the depressed metabolism of emodin could be attributed to the down-regulation of UDP-glucuronosyltransferases (UGTs) 1A8, 1A10, and 2B7. These findings definitively demonstrated the existence of interaction between TSG and emodin, which provide a basis for a better understanding of the underlying mechanism for PMR-induced liver injury.

Effects of dietary resveratrol supplementation on hepatic and serum pro-/anti-inflammatory activity in juvenile GIFT tilapia, Oreochromis niloticus.

Dietary resveratrol (RES) supplementation may have some pharmacological effects including anti-inflammation. Previous studies have shown that Kupffer cell activation and apoptosis induction increases the transcription of pro- and anti-inflammatory cytokines. The main purpose of this study was to investigate the pro- and anti-inflammatory activities of 0.1 or 0.3 g/kg RES as a dietary supplement in juvenile freshwater tilapia (Oreochromis niloticus). The results showed that hepatic and serum immunoglobulin M (IgM) significantly decreased and increased while anti- and pro-inflammatory cytokines significantly increased and decreased, respectively, in the RES-treated groups. The expression of serum and hepatic IgM and anti-inflammatory cytokines [interleukin (IL)-10] and its inverse inhibitor interferon (IFN)-γ significantly increased while pro-inflammatory cytokine transcription significantly decreased. Hematoxylin-eosin staining and scanning electron microscopy revealed intestinal deformation, irregular goblet cells, and apoptotic cells in the 0.3 g/kg RES groups. RES (0.3 g/kg) also induced necrosis, apoptosis, reduction in Kupffer cell number, compressed sinusoids, and deformation of epidermal cells in the liver of the treated groups. In conclusion, the results of the present study show that high doses of RES were absorbed in the gut and then damaged the liver and intestinal tissue.

Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum.

The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent "knock-out" and "knock-in" strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-ß-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

A Combination of Resveratrol and Curcumin is Effective Against Aluminum Chloride-Induced Neuroinflammation in Rats.

BACKGROUND: Experimental studies have demonstrated that aluminum is an environmental toxin that induces neuroinflammation and the development of Alzheimer's disease. OBJECTIVE: In this report, we investigated the beneficial effect of a combination of resveratrol and curcumin to reduce aluminum-induced neuroinflammation. METHOD: We employed both an in vivo model of aluminum-induced neuroinflammation and an in vitro aluminum stimulated cultured PC-12 cells. Neuroinflammation in rats was assessed by measuring the expression of ß-secretase, amyloid-ß protein precursor, and γ-subunits (PS-1 and PS-2), along with the inflammatory COX-2, Il-1ß, Il-1α, and TNF-α. Furthermore, we measured the expression profiles of neuro-protective Apurinic/apyrimidinic endonuclease 1 (APE1) protein and let-7c microRNA. In parallel, PC-12 cells were treated with 0.5 mM aluminum to induce a neuroinflammation-like state. In addition, curcumin effect, as a selective COX-2 expression inhibitor, was detected in a time course manner. RESULTS: An overall significant attenuation of the inflammatory markers, as well as a decrease in the amyloidogenic mediators, was observed in resveratrol-curcumin treated rats. The therapeutic effect was also confirmed by transmission electron microscopic analysis of the brain cortexes. APE1 was significantly induced by resveratrol-curcumin combination. Both in vivo and in vitro studies indicated that Let-7c expression is significantly reduced after aluminum stimulation, an effect that was partially suppressed by co-addition of either resveratrol or curcumin and totally restored to the normal level by their combination. CONCLUSIONS: The present study clearly indicates the synergistic and therapeutic effect of a  resveratrol-curcumin combination. We also show that both compounds exert beneficial effect either cooperatively or through differential molecular mechanisms in counteracting aluminum-induced neuroinflammation.

Amphiphilic nanoparticles of resveratrol-norcantharidin to enhance the toxicity in zebrafish embryo.

Direct coupling of a hydrophobic drug and a hydrophilic natural product via an ester bond produced an amphiphilic adduct that formed liposomes. Liposomes of resveratrol-norcantharidin adduct are capable of forming a tadpole-like nanoparticle and exhibited high toxicity in zebrafish embryos to give the better transportation and the effective concentration into cells. Using fluorescent chromophore showed the liposome in the stomach and intestinal villi rather than in the skin and muscle. This result may provide an insight into the mechanism of action of traditional Chinese medicines, which often contain a significant amount of flavonoids and polyphenol analogs.

Resveratrol Derivative-Rich Melinjo Seed Extract Attenuates Skin Atrophy in Sod1-Deficient Mice.

The oxidative damages induced by a redox imbalance cause age-related changes in cells and tissues. Superoxide dismutase (SOD) enzymes play a pivotal role in the antioxidant system and they also catalyze superoxide radicals. Since the loss of cytoplasmic SOD (SOD1) resulted in aging-like phenotypes in several types of murine tissue, SOD1 is essential for the maintenance of tissue homeostasis. Melinjo (Gnetum gnemon Linn) seed extract (MSE) contains trans-resveratrol (RSV) and resveratrol derivatives, including gnetin C, gnemonoside A, and gnemonoside D. MSE intake also exerts no adverse events in human study. In the present studies, we investigated protective effects of MSE on age-related skin pathologies in mice. Orally MSE and RSV treatment reversed the skin thinning associated with increased oxidative damage in the Sod1 (-/-) mice. Furthermore, MSE and RSV normalized gene expression of Col1a1 and p53 and upregulated gene expression of Sirt1 in skin tissues. In vitro experiments revealed that RSV significantly promoted the viability of Sod1 (-/-) fibroblasts. These finding demonstrated that RSV in MSE stably suppressed an intrinsic superoxide generation in vivo and in vitro leading to protecting skin damages. RSV derivative-rich MSE may be a powerful food of treatment for age-related skin diseases caused by oxidative damages.