Ginsenosides from Panax ginseng as potential therapeutic candidates for the treatment of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the intestine, which significantly affects patients' quality of life. As a perennial plant with the homology of medicine and food, Panax ginseng is known for its substantial anti-inflammatory effects in various inflammatory disorders. Ginsenosides, the main bioactive compounds of P. ginseng, are recognized for their efficacy in ameliorating inflammation. PURPOSE: Over the past decade, approximately 150 studies have investigated the effects of P. ginseng and ginsenosides on IBD treatment and new issues have arisen. However, there has yet to be a comprehensive review assessing the potential roles of ginsenosides in IBD therapy. METHOD: This manuscript strictly adheres to the PRISMA guidelines, thereby guaranteeing systematic synthesis of data. The research articles referenced were sourced from major scientific databases, including Google Scholar, PubMed, and Web of Science. The search strategy employed keywords such as "ginsenoside", "IBD", "colitis", "UC", "inflammation", "gut microbiota", and "intestinal barrier". For image creation, Figdraw 2.0 was methodically employed. RESULTS: Treatment with various ginsenosides markedly alleviated clinical IBD symptoms. These compounds have been observed to restore intestinal epithelia, modulate cellular immunity, regulate gut microbiota, and suppress inflammatory signaling pathways. CONCLUSION: An increasing body of research supports the potential of ginsenosides in treating IBD. Ginsenosides have emerged as promising therapeutic agents for IBD, attributed to their remarkable efficacy, safety, and absence of side effects. Nevertheless, their limited bioavailability presents a substantial challenge. Thus, efforts to enhance the bioavailability of ginsenosides represent a crucial and promising direction for future IBD research.

Protopanaxatriol activates EGFR and HER2 to strengthen the molecules of skin protection in human keratinocytes.

BACKGROUND: Protopanaxatriol (PPT) is an important ginsenoside produced by ginseng, a tonic plant used in many areas. PPT has beneficial effects against many disease states including inflammation, diabetes, and cancer. However, PPT's protective effects on skin integrity have been rarely studied. Previously, we reported that PPT can maintain skin moisture through activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) pathways. However, the cellular targets for enhancing skin moisturizing effects via PPT are still unknown. PURPOSE: We wanted to identify the upstream targets of PPT on upregulating moisturizing factor (HAS-2) expression. STUDY DESIGN: We investigated which upstream proteins can be directly stimulated by PPT to modulate NF-κB, MAPKs and other signaling cascades. Then, the targeted proteins were overexpressed to check the relationship with HAS-2. Next, the cellular thermal shift assay (CETSA) was conducted to check the relationship between targeted proteins and PPT. METHODS: A human keratinocyte HaCaT were employed to measure the levels of moisturizing factors and the signaling proteins activated by PPT. Transfection conditions were established with DNA constructs expressing epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) and their mutants prepared by site-directed mutagenesis. Further investigation on molecular mechanisms was conducted by RT-PCR, luciferase reporter gene assay, CETSA, or Western blot. RESULTS: We found that PPT can activate the phosphorylation of EGFR and HER2. These stimulations caused Src phosphorylation, which resulted in the activation of phosphoinositide 3-kinases (PI3K)/pyruvate dehydrogenase kinase 1 (PDK1)/protein kinase B (AKT)/NF-κB and MAPKs signaling cascades. Additionally, EGFR and HER2 activation resulted in phosphorylation of signal transducer and activator of transcription 3 (STAT3) and calcium/calmodulin-dependent protein kinase II (CaMKII). This induced the AMP-activated protein kinase alpha (AMPKα) signaling pathway. Additionally, PPT blocked peroxisome proliferator activated receptor gamma (PPARγ), which also contributed to the phosphorylation of Src. CONCLUSION: Overall, we first found that PPT offers excellent protection of the skin barrier and hydrogen supply in keratinocytes. Moreover, growth factor receptors such as EGFR and HER2 were revealed to be central enzymes to be directly targeted by PPT. These results suggest a potentially valuable role as a cosmetic ingredient.

Jinyinqingre Oral Liquid alleviates LPS-induced acute lung injury by inhibiting the NF-κB/NLRP3/GSDMD pathway.

Acute lung injury (ALI) is a prevalent and severe clinical condition characterized by inflammatory damage to the lung endothelial and epithelial barriers, resulting in high incidence and mortality rates. Currently, there is a lack of safe and effective drugs for the treatment of ALI. In a previous clinical study, we observed that Jinyinqingre oral liquid (JYQR), a Traditional Chinese Medicine formulation prepared by the Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, exhibited notable efficacy in treating inflammation-related hepatitis and cholecystitis in clinical settings. However, the potential role of JYQR in ALI/acute respiratory distress syndrome (ARDS) and its anti-inflammatory mechanism remains unexplored. Thus, the present study aimed to investigate the therapeutic effects and underlying molecular mechanisms of JYQR in ALI using a mouse model of lipopolysaccharide (LPS)-induced ALI and an in vitro RAW264.7 cell model. JYQR yielded substantial improvements in LPS-induced histological alterations in lung tissues. Additionally, JYQR administration led to a noteworthy reduction in total protein levels within the BALF, a decrease in MPAP, and attenuation of pleural thickness. These findings collectively highlight the remarkable efficacy of JYQR in mitigating the deleterious effects of LPS-induced ALI. Mechanistic investigations revealed that JYQR pretreatment significantly inhibited NF-κB activation and downregulated the expressions of the downstream proteins, namely NLRP3 and GSDMD, as well as proinflammatory cytokine levels in mice and RAW2647 cells. Consequently, JYQR alleviated LPS-induced ALI by inhibiting the NF-κB/NLRP3/GSDMD pathway. JYQR exerts a protective effect against LPS-induced ALI in mice, and its mechanism of action involves the downregulation of the NF-κB/NLRP3/GSDMD inflammatory pathway.

20(S)-Protopanaxadiol from Panax ginseng Induces Apoptosis and Autophagy in Gastric Cancer Cells by Inhibiting Src.

20(S)-protopanaxadiol (PPD), a metabolite of Panax ginseng, has multiple pharmacological properties. However, the effects of PPD against human gastric cancer have not been elucidated. Our purpose in this study was to investigate if PPD has anticancer effects against human gastric cancer in vitro. Cell viability, migration, clone formation, and invasion were assessed to explore the effects of PPD on cancer cells. PI and annexin V staining as well as immunoblotting were employed to determine if PPD-induced apoptosis and autophagy of MKN1 and MKN45 cells. The target of PPD was identified using immunoblotting, overexpression analysis, and flow cytometric analysis. PPD exhibited significantly suppressed cell viability, migration, colony formation, and invasion. Phosphorylation of Src and its down-stream effectors were inhibited by PPD. PPD-enhanced apoptosis and autophagy in a dose- and time-dependent manner by inhibiting Src. Collectively, our results demonstrate that PPD induces apoptosis and autophagy in gastric cancer cells in vitro by inhibiting Src.

Atherosclerosis amelioration by allicin in raw garlic through gut microbiota and trimethylamine-N-oxide modulation.

Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE-/-) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation.

Global Microbiota-Dependent Histone Acetylation Patterns Are Irreversible and Independent of Short Chain Fatty Acids.

BACKGROUND AND AIMS: Although germ-free mice are an indispensable tool in studying the gut microbiome and its effects on host physiology, they are phenotypically different than their conventional counterparts. While antibiotic-mediated microbiota depletion in conventional mice leads to physiologic alterations that often mimic the germ-free state, the degree to which the effects of microbial colonization on the host are reversible is unclear. The gut microbiota produce abundant short chain fatty acids (SCFAs), and previous studies have demonstrated a link between microbial-derived SCFAs and global hepatic histone acetylation in germ-free mice. APPROACH AND RESULTS: We demonstrate that global hepatic histone acetylation states measured by mass spectrometry remained largely unchanged despite loss of luminal and portal vein SCFAs after antibiotic-mediated microbiota depletion. In contrast to stable hepatic histone acetylation states, we see robust hepatic transcriptomic alterations after microbiota depletion. Additionally, neither dietary supplementation with supraphysiologic levels of SCFA nor the induction of hepatocyte proliferation in the absence of microbiota-derived SCFAs led to alterations in global hepatic histone acetylation. CONCLUSIONS: These results suggest that microbiota-dependent landscaping of the hepatic epigenome through global histone acetylation is static in nature, while the hepatic transcriptome is responsive to alterations in the gut microbiota.

Vina-Ginsenoside R4 from Panax ginseng Leaves Alleviates 6-OHDA-Induced Neurotoxicity in PC12 Cells Via the PI3K/Akt/GSK-3ß Signaling Pathway.

Vina-ginsenoside R4 (VGN4) is the first example of protopanaxatriol saponin possessing sugar chains located at C-3 and C-20 of aglycone. However, to the best of our knowledge, no report has been published on the neuroprotective effect of VGN4. In the present work, we investigated the neuroprotective effect of VGN4 against 6-hydroxydopamine (6-OHDA)-induced toxicity and its potential mechanism. Pretreatment of PC12 cells with VGN4 attenuated 6-OHDA-induced cell damage and cell apoptosis, which was correlated with the decrease of reactive oxygen species and the increase of antioxidant enzyme activities including superoxide dismutase and catalase. In addition, VGN4 markedly decreased nuclear translation of the nuclear factor-κB and PI3K/Akt/GSK/3ß signaling pathway including p85, PDK1, Akt, and GSK-3ß. Further studies revealed that PI3K siRNA attenuated the neuroprotective effect of VGN4 on caspase-3 activity. These data indicate that VGN4 might have the potential to be developed as a new neuroprotective functional food.

Evolving geographic diversity in SARS-CoV2 and in silico analysis of replicating enzyme 3CLpro targeting repurposed drug candidates.

BACKGROUND: Severe acute respiratory syndrome (SARS) has been initiating pandemics since the beginning of the century. In December 2019, the world was hit again by a devastating SARS episode that has so far infected almost four million individuals worldwide, with over 200,000 fatalities having already occurred by mid-April 2020, and the infection rate continues to grow exponentially. SARS coronavirus 2 (SARS-CoV-2) is a single stranded RNA pathogen which is characterised by a high mutation rate. It is vital to explore the mutagenic capability of the viral genome that enables SARS-CoV-2 to rapidly jump from one host immunity to another and adapt to the genetic pool of local populations. METHODS: For this study, we analysed 2301 complete viral sequences reported from SARS-CoV-2 infected patients. SARS-CoV-2 host genomes were collected from The Global Initiative on Sharing All Influenza Data (GISAID) database containing 9 genomes from pangolin-CoV origin and 3 genomes from bat-CoV origin, Wuhan SARS-CoV2 reference genome was collected from GeneBank database. The Multiple sequence alignment tool, Clustal Omega was used for genomic sequence alignment. The viral replicating enzyme, 3-chymotrypsin-like cysteine protease (3CLpro) that plays a key role in its pathogenicity was used to assess its affinity with pharmacological inhibitors and repurposed drugs such as anti-viral flavones, biflavanoids, anti-malarial drugs and vitamin supplements. RESULTS: Our results demonstrate that bat-CoV shares > 96% similar identity, while pangolin-CoV shares 85.98% identity with Wuhan SARS-CoV-2 genome. This in-depth analysis has identified 12 novel recurrent mutations in South American and African viral genomes out of which 3 were unique in South America, 4 unique in Africa and 5 were present in-patient isolates from both populations. Using state of the art in silico approaches, this study further investigates the interaction of repurposed drugs with the SARS-CoV-2 3CLpro enzyme, which regulates viral replication machinery. CONCLUSIONS: Overall, this study provides insights into the evolving mutations, with implications to understand viral pathogenicity and possible new strategies for repurposing compounds to combat the nCovid-19 pandemic.

Anti-neuroinflammatory effect of 3,4-dihydroxybenzaldehyde in ischemic stroke.

BACKGROUND: Increasing evidence from human and animal studies suggests that cerebral ischemic diseases are associated with nerve dysfunction and neuroinflammation. Therefore, alleviating neuroinflammation is a potential way to treat ischemic stroke. Gastrodia elata Blume (GEB) is a traditional Chinese medicine used to treat central nervous system diseases and related conditions, such as vertigo, headache, epilepsy. We have previously shown that GEB has a protective effect in ischemic stroke, and that the underlying mechanism is related to anti-neuroinflammation. 3,4-Dihydroxybenzaldehyde (DBD) is a phenolic component of GEB and may be responsible for the neuroprotective effect of GEB; however, the detailed molecular mechanisms underlying the effects of DBD are unknown. METHODS: The anti-neuroinflammatory effect of DBD and the potential mechanisms underlying it were assessed. We using a rat model of middle cerebral artery occlusion/reperfusion and lipopolysaccharide-treated BV2 microglial cells. RESULTS: DBD (10 mg/kg) significantly decreased infarct volume. Additionally, it alleviated neurological deficits in the rats by inhibiting microglia activation. DBD (0.01, 0.1, and 1 µM) also significantly decreased the levels of inflammatory mediators and cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, prostaglandin E2. Furthermore, phenotypic analysis of the BV2 cells showed that DBD significantly down-regulated the expression of M1 marker but significantly up-regulated the expression of M2 marker. Moreover, it suppressed nuclear factor (NF)-κB activation and inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase, and extracellular signal-regulated protein kinases 1/2. CONCLUSIONS: The neuroprotective and anti-inflammatory effects of DBD are associated with selective modulation of microglia polarization and reduction in the production of inflammatory mediators and cytokines through inhibition of MAPK and NF-κB activation. These findings suggest that DBD may be a potential treatment for ischemic stroke and other neuroinflammatory diseases.

Phenolic compounds present in fruit extracts of Malus spp. show antioxidative and pro-apoptotic effects on human gastric cancer cell lines.

The study aims to analyze the phenolic compounds in Malus spp. and evaluate their antioxidant and pro-apoptotic effects in BGC-803 gastric cancer cells. The results showed that cyanidin-3-galactoside was the main polyphenol in Malus "Royalty" (MR), while catechin, epicatechin, and proanthocyanidin B1 and B2 contents were higher in Malus "Cinnabar" (MC) and Malus micromalus (MM) than in MR fruits. The total polyphenol content, total flavonoid content, and antioxidative properties of Malus spp. fruits followed an order of MR > MC > MM. Fruit extracts could inhibit BGC-803 cells growth and induce apoptosis, with IC50 values of 0.47, 0.36, and 0.31 mg/ml for MR, MC, and MM, respectively. Furthermore, fruit extracts induced cell apoptosis through increasing Bcl-2 and Bcl-xl (pro-apoptosis) expression and inhibiting Bax and Bak (anti-apoptosis) expression, thereby accelerating cell apoptosis. Taken together, these results demonstrate that red fruits (i.e., MR and MC) were more effective against cancer cells than green fruits (i.e., MM). PRACTICAL APPLICATIONS: Fruits of Malus spp. are ≤5 cm in size, considerably smaller than apples. They are rich in various natural bioactive compounds that are often consumed as a dietary supplement or used as natural raw materials for function food. In the current study, it is comprehensively characterized profile and bioactivity of phenolic metabolites in Malus spp. fruits of different colors, and found that red fruits are more effective in reducing the free radicals and inducing cancer cells apoptosis than green fruits. These findings are valuable for food technologists and food manufacturers, especially those who produce crabapple supplement. The study investigated the molecular mechanism of how Malus spp. fruits exert anti-cancer functions. This lays a theoretical foundation for future research on developing anti-cancer function food and provides helpful guidance for fruit market management and fruit processing industry.

Target-Guided Isolation of Three Main Antioxidants from Mahonia bealei (Fort.) Carr. Leaves Using HSCCC.

Mahonia bealei (Fort.) Carr. is an economically important plant that is widely cultivated in Southwest China. Its leaves are commonly used for tea and contain an abundance of antioxidant compounds. However, methods of the systematic purification of antioxidants from M. bealei are lacking. In this study, antioxidants from this plant were effectively and rapidly enriched. First, antioxidants were screened using online 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH)-high performance liquid chromatography (HPLC), followed by separation using high-speed countercurrent chromatography with an optical solvent system composed of n-hexane/ethyl acetate/methanol/water (1:5:1:5, v/v/v/v). Three phenolics-chlorogenic acid (1, 8.3 mg), quercetin-3-O-ß-d-glucopyranoside (2, 20.5 mg), and isorhamnetin-3-O-ß-d-glucopyranoside (3, 28.4 mg)-were obtained from the ethyl acetate-soluble fraction (240 mg) by one-step separation. The chemical structures of the phenolics were characterized by MS and NMR techniques, and the purity of each compound was >92.0% as determined by HPLC. The isolated compounds were assessed by scavenging activities on DPPH and superoxide radicals as well as cytoprotective assays, all of which showed similar trends regarding the antioxidant capacities of the compounds. Moreover, compounds 1-3 significantly attenuated the lipid peroxidation and antioxidant enzyme activities in H2O2-treated RAW264.7 cells. Our study demonstrated the efficiency of a newly developed integrative system for the comprehensive characterization of pure compounds from M. bealei, which will allow their use as reference substances.

A Network-Based Method for Mechanistic Investigation and Neuroprotective Effect on Post-treatment of Senkyunolid-H Against Cerebral Ischemic Stroke in Mouse.

Senkyunolide-H (SEH), a major bioactive compound extracted from Ligusticum chuanxiong, has been reported to be effective in preventing cerebral ischemic stroke (CIS). In this study, we employed network pharmacology to reveal potential mechanism of SEH against CIS on a system level and confirmed the therapeutic effects of SEH on CIS by models of cerebral ischemia-reperfusion in vivo and in vitro. Through protein-protein interaction networks construction of SEH- and CIS-related targets, a total of 62 key targets were obtained by screening topological indices and analyzed for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Gene Ontology analysis indicated that SEH might have a role in treating CIS via regulating some biological processes including regulation of transcription from RNA polymerase II promoter, epidermal growth factor receptor signaling pathway, phosphatidylinositol-mediated signaling, and some molecular function, such as transcription factor and protein phosphatase binding and nitric oxide synthase regulator activity. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes analysis showed that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was significantly enriched. In addition, our result showed that SEH posttreatment significantly decreased the neurological scores, infarct volume, and neuronal death in the middle cerebral artery occlusion mice. Moreover, the PI3K/Akt/nuclear factor kappa B signaling pathway was activated by intragastric administration of 40 mg/kg SEH, as verified by Western blot. In vitro, treatment of PC12 cells with 100 µM SEH markedly reduced cell death induced by oxygen-glucose deprivation through the activation of PI3K/Akt/nuclear factor kappa B pathway, and the therapeutic effect of SEH was obviously inhibited by 10 µM LY294002. In summary, these results suggested that SEH carries a therapeutic potential in CIS involving multiple targets and pathways, and the most crucial mechanism might be through the activation of PI3K/Akt/nuclear factor kappa B (NF-κB) signaling pathway to inhibit inflammatory factor releases and increase the antiapoptosis capacity. Our study furnishes the future traditional Chinese medicine research with a network pharmacology framework.

Anti-Inflammatory Effects of Chloranthalactone B in LPS-Stimulated RAW264.7 Cells.

Chloranthalactone B (CTB), a lindenane-type sesquiterpenoid, was obtained from the Chinese medicinal herb Sarcandra glabra, which is frequently used as a remedy for inflammatory diseases. However, the anti-inflammatory mechanisms of CTB have not been fully elucidated. In this study, we investigated the molecular mechanisms underlying these effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. CTB strongly inhibited the production of nitric oxide and pro-inflammatory mediators such as prostaglandin E2, tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 in RAW264.7 cells stimulated with LPS. A reverse-transcription polymerase chain reaction assay and Western blot further confirmed that CTB inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1ß at the transcriptional level, and decreased the luciferase activities of activator protein (AP)-1 reporter promoters. These data suggest that inhibition occurred at the transcriptional level. In addition, CTB blocked the activation of p38 mitogen-activated protein kinase (MAPK) but not c-Jun N-terminal kinase or extracellular signal-regulated kinase 1/2. Furthermore, CTB suppressed the phosphorylation of MKK3/6 by targeting the binding sites via formation of hydrogen bonds. Our findings clearly show that CTB inhibits the production of inflammatory mediators by inhibiting the AP-1 and p38 MAPK pathways. Therefore, CTB could potentially be used as an anti-inflammatory agent.

The dichloromethane fraction from Mahonia bealei (Fort.) Carr. leaves exerts an anti-inflammatory effect both in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Mahonia bealei has a long history of medical use in traditional Chinese medicine for the treatment of inflammatory-associated diseases. Despite numerous phytochemical and pharmacological studies, there is a lack of systematic studies to understand the cellular and molecular mechanisms of the anti-inflammatory activity of this plant. AIM OF STUDY: This study aimed to evaluate the anti-inflammatory activity of the dichloromethane fraction from M. bealei leaves (MBL-CH). MATERIALS AND METHODS: RAW 264.7 cells were pretreated with different concentrations of MBL-CH for 30min prior to treatment with 1µg/ml of lipopolysaccharide (LPS). The nuclear factor κB (NF-κB) pathway and subsequent production of inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), and tumour necrosis factor (TNF)-α were investigated. Furthermore, the in vivo mouse model of LPS-induced acute lung injury (ALI) was employed to study the anti-inflammatory effects of MBL-CH. RESULTS: Pre-treatment with MBL-CH significantly inhibited the LPS-stimulated secretion of NO, PGE2, and TNF-α into the culture medium, as well as the mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α, which were associated with a reduction in the phosphorylation of IκBα, Akt, and PI3K and inhibition of the transcriptional activity of NF-κB. Furthermore, in vivo experiments revealed that MBL-CH attenuated LPS-stimulated lung inflammation in mice. CONCLUSION: Taken together, our findings indicate that MBL-CH attenuates LPS-stimulated inflammatory responses in macrophages by blocking NF-κB activation through interference with activation of the PI3K/Akt pathway, providing scientific evidence that the plant can be employed in traditional remedies.

NIR light/H2O2-triggered nanocomposites for a highly efficient and selective synergistic photodynamic and photothermal therapy against hypoxic tumor cells.

In this work, smart near-infrared (NIR) light/H2O2-triggered and O2-evolving nanocomposites were designed and applied for efficient production of (1)O2 by converting a deeply penetrating NIR light into a visible light to excite the photosensitizers and achieve a self-sufficiency of the O2 generation in the photodynamic therapy process to overcome the hypoxia-induced drug resistance.

Apigenin-7-O-ß-D-glucuronide inhibits LPS-induced inflammation through the inactivation of AP-1 and MAPK signaling pathways in RAW 264.7 macrophages and protects mice against endotoxin shock.

Apigenin-7-O-ß-D-glucuronide (AG), an active flavonoid derivative isolated from the agricultural residue of Juglans sigillata fruit husks, possesses multiple pharmacological activities, including anti-oxidant, anti-complement, and aldose reductase inhibitory activities. To date, no report has identified the anti-inflammatory mechanisms of AG. This study was therefore designed to characterize the molecular mechanisms of AG on lipopolysaccharide (LPS)-induced inflammatory cytokines in RAW 264.7 cells and on endotoxin-induced shock in mice. AG suppressed the release of nitric oxide (NO), prostaglandin E2 (PGE2), and tumour necrosis factor-α (TNF-α) in LPS-stimulated RAW 264.7 macrophages in a dose-dependent manner without affecting cell viability. Additionally, AG suppressed LPS-induced mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α. AG treatment decreased the translocation of c-Jun into the nucleus, and decreased activator protein-1 (AP-1)-mediated luciferase activity through the inhibition of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) phosphorylation. Consistent with the in vitro observations, AG protected mice from LPS-induced endotoxin shock by inhibiting proinflammatory cytokine production. Taken together, these results suggest that AG may be used as a source of anti-inflammatory agents as well as a dietary complement for health promotion.

Combined therapy of Di-Huang-Yi-Zhi with Donepezil in patients with Parkinson's disease dementia.

Here we conducted a randomized and double-blind study attempting to explore the safety and efficacy of combined therapy of Di-Huang-Yi-Zhi (DHYZ) with donepezil in treating Parkinson's disease dementia (PDD). Sixty PDD patients were included and randomly divided into control group and DHYZ group. All patients were given donepezil (5 mg last for a month, then 10 mg for the rest months, once daily), while patients in DHYZ group were additionally administrated with DHYZ (150 ml, twice daily). The measurement subjects included mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Barthel Index for activities of daily living (ADL) and Traditional Chinese medical (TCM) symptoms before and after treatment in this study. The whole study lasted for six months. Significant differences were observed on MMSE, MoCA, ADAS-Cog, ADL and TCM in both control and DHYZ group (P<0.05 or P<0.01) before and after drug treatment. Furthermore, there were more obvious changes of MMSE, MoCA, ADAS-Cog, ADL and TCM scores compared the DHYZ group with the control group (P<0.01) which suggested the DHYZ group showed a more effective improvement on cognition, behavior as well global function. In conclusion, the combined therapy of DHYZ with donepezil showed a more effective improvement in PDD and the underlying mechanism may be related to the synergic amelioration of cholinergic system between them.

Engineering the gut microbiota to treat hyperammonemia.

Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here, we engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility.

Antioxidant effects of lipophilic tea polyphenols on diethylnitrosamine/phenobarbital-induced hepatocarcinogenesis in rats.

BACKGROUND: The purpose of the present study was to compare the antioxidant potential of lipophilic tea polyphenols (LTP) against the one of naturally-occurring water-soluble green tea polyphenols (GTP) in a two-stage model of diethylnitrosamine (DEN)/phenobarbital (PB)-induced hepatocarcinogenesis in Sprague-Dawley rats. MATERIALS AND METHODS: GTP/LTP was given 5-times weekly by oral gavage with tea polyphenols equivalent to 0-, 40- and 400-mg/kg of body weight/day. GTP/LTP treatment was started 2 weeks prior to the initiation of DEN and continued for 30 weeks. RESULTS: Histopathological and electron microscopic examination of liver tissue confirmed the protective effect of LTP on DEN/PB-induced liver damage and pre-carcinogenesis. LTP treatment significantly increased total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) activity in liver tissues. Immunohistochemical detection of cellular nuclear factor erythroid-2-related factor-2 (Nrf2) and peroxiredoxin-6 (P6) indicated a down-regulation in Nrf2 and up-regulation of P6 expression in the liver of LTP-supplemented rats. CONCLUSION: The present study provides evidence for the first time, that LTP exerts significant antioxidant effects on DEN/PB-induced liver damage and hepatocarcinogenesis through elevating T-AOC levels, enhancing GSH-Px activity and inducing P6 expression in rat liver tissues.

Chemoprevention by lipid-soluble tea polyphenols in diethylnitrosamine/phenobarbital-induced hepatic pre-cancerous lesions.

BACKGROUND: Green tea polyphenols (GTPs) have been proposed as promising candidates for chemoprevention. However, GTPs levels are maintained relatively low in the blood and are chemically-unstable. Lipid-soluble tea polyphenols (LTPs) are products of modified GTPs with ester linkage with fatty acids. LTPs are lipophilic and expected to provide improved absorption and utilization in the body compared with water-soluble polyphenols. The current study was designed to investigate the chemo-preventive property and the possible mechanisms of LTP action against diethylnitrosamine (DEN)-induced liver cancer in rats. MATERIALS AND METHODS: Oral administration of LTPs at doses of 0, 40, and 400 mg/kg/day was initiated 2 weeks prior to DEN injection and was continued for 30 weeks. At that time point samples were collected and liver histopathological analyses were performed. RESULTS: LTPs decreased the area and number of placental glutathione S-transferase-positive foci in liver samples of DEN-treated rats. Furthermore, LTPs counteracted DEN-induced fibrosis formation in liver. Immunohistochemical staining of rat liver showed that LTPs inhibited DEN-mediated elevations in numbers of cells positive for PCNA and 8-OHdG. CONCLUSION: For the first time, the present study demonstrated, that LTPs exert a chemo-preventive effect against precancerous lesions through inhibition of cellular proliferation and DNA damage in a rat liver model.