A novel flavonol-polysaccharide from Tamarix chinensis alleviates influenza A virus-induced acute lung injury. Evidences for its mechanism of action.

BACKGROUND: Tamarix chinensis Lour. is a Chinese medicine used for treating inflammation-related diseases and its crude polysaccharides (MBAP90) exhibited significant anticomplement activities in vitro. PURPOSE: To obtain anticomplement homogenous polysaccharides from MBAP90 and explore its therapeutic effects and potential mechanism on influenza A virus (IAV)-induced acute lung injury (ALI). METHODS: Anticomplement activity-guided fractionation of the water-soluble crude polysaccharides from the leaves and twigs of T. chinensis were performed by diethylaminoethyl-52 (DEAE-52) cellulose and gel permeation columns to yield a homogeneous polysaccharide MBAP-5, which was further characterized using ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MS) and nuclear magnetic resonance (NMR) analysis. In vitro, the anticomplement activity of MBAP-5 through classical pathway was measured using a hemolytic test. The therapeutic effects of MBAP-5 on ALI were evaluated in H1N1-infected mice. H&E staining, enzyme linked immunosorbent assay (ELISA), immunohistochemistry, and western blot were used to systematically access lung histomorphology, inflammatory cytokines, degree of complement component 3c, 5aR, and 5b-9 (C3c, C5aR, and C5b-9) deposition, and inflammasome signaling pathway protein expressions in lung tissues. RESULTS: MBAP-5 was a novel flavonol-polysaccharide with the molecular weight (Mw) of 153.6 kDa. Its structure was characterized to process a backbone of →4)-α-D-GlcpA-(1→, →6)-α-D-Glcp-(1→, →3,4)-α-D-Glcp-(1→, →3,4,6)-α-D-Glcp-(1→, and →4,6)-ß-D-Glcp-(1→, as well as branches of α-L-Araf-(1→ and ß-D-Galp-(1→. Particularly, O-3 of →3,4,6)-α-D-Glcp-(1→ was substituted by quercetin. In vitro assay showed that MBAP-5 had a potent anticomplement activity with a CH50 value of 102 ± 4 µg/ml. Oral administration of MBAP-5 (50 and 100 mg/kg) effectively attenuated the H1N1-induced pulmonary injury in vivo by reducing pulmonary edema, virus replication, and inflammatory responses. Mechanistically, MBAP-5 inhibited the striking deposition and contents of complement activation products (C3c, C5aR, and C5b-9) in the lung. Toll-like receptor 4 (TLR4) /transcription factor nuclear factor κB (NF-κB) signaling pathway was constrained by MBAP-5 treatment. In addition, MBAP-5 could suppress activation of the inflammasome pathways, including Nod-like receptor pyrin domain 3 (NLRP3), cysteinyl aspartate specific proteinase-1/12 (caspase-1/12), apoptosis­associated speck­like protein (ASC), gasdermin D (GSDMD), interleukin (IL)-1ß, and IL-18 expressions. CONCLUSIONS: A novel flavonol-polysaccharide MBAP-5 isolated from T. chinensis demonstrated a therapeutic effect against ALI induced by IAV attack. The mechanism might be associated with inhibition of complement system and inflammasome pathways activation.

Network pharmacology identifies fisetin as a treatment for osteoporosis that activates the Wnt/ß-catenin signaling pathway in BMSCs.

BACKGROUND: Although fisetin may exist widely in many natural herbs, its anti-OP mechanism is still unclear. The aim of this study is to explore the molecular anti-osteoporosis (OP) mechanism of fisetin based on network pharmacology and cell experiments. METHODS: The target of fisetin was extracted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The targets of OP were obtained by DisGeNET, GeneCards and the Comparative Toxicogenomics Database, and the targets of fisetin in OP were screened by cross-analysis. The protein-protein interaction (PPI) network was constructed by STRING, and the core targets were obtained. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses on common targets via the Database for Annotation, Visualization and Integrated Discovery. Finally, an in vitro cell experiment was used to verify the anti-OP effect and mechanism of fisetin. RESULTS: There are 44 targets of fisetin related to the treatment of OP. The PPI results suggest that CTNNB1, CCND1, TP53, JUN, and AKT1 are the core targets. A total of 259 biological process, 57 molecular function and 26 cell component terms were obtained from GO enrichment analysis. The results of KEGG pathway enrichment analysis suggested that fisetin treatment of OP may be related to the Wnt signaling pathway, estrogen signaling pathway, PI3K-Akt signaling pathway and other signaling pathways. In vitro cell experiments showed that fisetin significantly increased the expression levels of ALP, collagen I, osteopontin and RUNX2 in bone marrow mesenchymal stem cells (BMSCs) (p < 0.05). Fisetin also increased the gene expression levels of Wnt3 and ß-catenin (CTNNB1) in BMSCs, which indicates that fisetin can regulate the Wnt/ß-catenin signaling pathway and promote the osteogenic differentiation of BMSCs. CONCLUSIONS: Fisetin acts on multiple targets and pathways in the treatment of OP; mechanistically, it regulates the Wnt/ß-catenin signaling pathway, which promotes the osteogenic differentiation of BMSCs and maintains bone homeostasis. The results of this study provide a theoretical basis for further study on the complex anti-OP mechanism of fisetin.

Molecular mechanisms and promising role of dihydromyricetin in cardiovascular diseases.

Vine tea, a Chinese herbal medicine, is widely used in traditional Asian medicine to treat common health problems. Dihydromyricetin (DMY) is the main functional flavonoid compound extracted from vine tea. In recent years, preclinical studies have focused on the potential beneficial effects of dihydromyricetin, including glucose metabolism regulation, lipid metabolism regulation, neuroprotection, and anti-tumor effects. In addition, DMY may play a role in cardiovascular disease by resisting oxidative stress and participating in the regulation of inflammation. This review is the first review that summaries the applications of dihydromyricetin in cardiovascular diseases, including atherosclerosis, myocardial infarction, myocardial hypertrophy, and diabetic cardiomyopathy. We also clarified the underlying mechanisms and signaling pathways involved in the above process. The aim of this review is to provide a better understanding and quick overview for future researches of dihydromyricetin in the field of cardiovascular diseases, and more detailed and robust researches are needed for evaluation and reference.

Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review.

Diet plays a crucial role in homeostasis maintenance. Plants and spices containing flavonoids have been widely used in traditional medicine for thousands of years. Flavonols present in our diet may prevent cancer initiation, promotion and progression by modulating important enzymes and receptors in signal transduction pathways related to proliferation, differentiation, apoptosis, inflammation, angiogenesis, metastasis and reversal of multidrug resistance. The anticancer activity of fisetin has been widely documented in numerous in vitro and in vivo studies. This review summarizes the worldwide, evidence-based research on the activity of fisetin toward various types of cancerous conditions, while describing the chemopreventive and therapeutic effects, molecular targets and mechanisms that contribute to the observed anticancer activity of fisetin. In addition, this review synthesized the results from preclinical studies on the use of fisetin as an anticancer agent. Based on the available literature, it might be suggested that fisetin has a bioactive potential to become a complementary drug in the prevention and treatment of cancerous conditions. However, more in-depth research is required to validate current data, so that this compound or its derivatives can enter the clinical trial phase.

O-methylated flavonol as a multi-kinase inhibitor of leukemogenic kinases exhibits a potential treatment for acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications. PURPOSE: In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells. METHODS: The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively. RESULTS: In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC50 values of 1 - 2 µM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G0/G1 phase and followed by the cells undergoing apoptosis. CONCLUSION: O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization.

Targeting Cardiovascular Diseases by Flavonols: An Update.

Flavonols are one of the most plentiful flavonoid subclasses found in natural products and are extensively used as dietary supplements. Numerous in vitro and in vivo studies have shown the cardioprotective properties of flavonols, especially quercetin. This group of substances exerts positive impacts primarily due to their antiatherogenic, antithrombotic, and antioxidant activities. The potential of flavonols to promote vasodilation and regulation of apoptotic processes in the endothelium are other beneficial effects on the cardiovascular system. Despite promising experimental findings, randomized controlled trials and meta-analyses have yielded inconsistent results on the influence of these substances on human cardiovascular parameters. Thus, this review aims to summarize the most recent clinical data on the intake of these substances and their effects on the cardiovascular system. The present study will help clinicians and other healthcare workers understand the value of flavonol supplementation in both subjects at risk for cardiovascular disease and patients with cardiovascular diseases.

Rhamnazin suppresses melanosome transport by promoting the ubiquitin-mediated proteasomal degradation of melanophilin.

BACKGROUND: Melanosomes are intracellularly transported from the perinuclear region to the cell periphery and then to neighboring keratinocytes. We recently reported that the flavonoid rhamnazin suppresses melanosomal transport within pigment cells, yet the action mechanism remained unclear. OBJECTIVE: Our aim was to elucidate how rhamnazin influences the intracellular transport of melanosomes. METHODS: A melanosome distribution assay and immunostaining were performed using B16F10 mouse melanoma cells and normal human epidermal melanocytes, respectively. Expression levels of melanosome transport-related proteins, including melanophilin (MLPH), RAB27A, and myosin VA (MYO5A), were analyzed by immunoblotting. Ubiquitinated MLPH was detected using a commercial ubiquitin detection kit. To investigate the interaction between rhamnazin and MLPH, we prepared rhamnazin conjugated with magnetic FG beads. RESULTS: Immunoblotting analysis revealed that rhamnazin specifically reduces the expression of MLPH but not RAB27A or MYO5A proteins. The ubiquitin detection assay, which made use of a proteasome inhibitor, showed that MLPH accumulated as a polyubiquitinated protein after treatment with rhamnazin. We speculated that the affinity of rhamnazin for the components of the melanosome transport-related tripartite complex may alter the stability of the formation of the tripartite assembly. By using affinity-based techniques with B16F10 whole cell lysates or recombinant MLPH and RAB27A proteins, we revealed the interaction of rhamnazin with the components of the tripartite complex. CONCLUSION: We found that rhamnazin inhibits intracellular transport of melanosomes through proteasomal degradation of MLPH. Our results suggest that topical application of rhamnazin may provide a new approach for treating skin pigmentation disorders.

Cocoa Flavanols Adjuvant to an Oral Nutritional Supplement Acutely Enhances Nutritive Flow in Skeletal Muscle without Altering Leg Glucose Uptake Kinetics in Older Adults.

Ageing is associated with postprandial muscle vascular and metabolic dysfunction, suggesting vascular modifying interventions may be of benefit. Reflecting this, we investigated the impact of acute cocoa flavanol (450-500 mg) intake (versus placebo control) on vascular (via ultrasound) and glucose/insulin metabolic responses (via arterialised/venous blood samples and ELISA) to an oral nutritional supplement (ONS) in twelve healthy older adults (50% male, 72 ± 4 years), in a crossover design study. The cocoa condition displayed significant increases in m. vastus lateralis microvascular blood volume (MBV) in response to feeding at 180 and 240-min after ONS consumption (baseline: 1.00 vs. 180 min: 1.09 ± 0.03, p = 0.05; 240 min: 1.13 ± 0.04, p = 0.002), with MBV at these timepoints significantly higher than in the control condition (p < 0.05). In addition, there was a trend (p = 0.058) for MBV in m. tibialis anterior to increase in response to ONS in the cocoa condition only. Leg blood flow and vascular conductance increased, and vascular resistance decreased in response to ONS (p < 0.05), but these responses were not different between conditions (p > 0.05). Similarly, glucose uptake and insulin increased in response to ONS (p < 0.05) comparably between conditions (p > 0.05). Thus, acute cocoa flavanol supplementation can potentiate oral feeding-induced increases in MBV in older adults, but this improvement does not relay to muscle glucose uptake.

Natural flavonol fisetin attenuated hyperuricemic nephropathy via inhibiting IL-6/JAK2/STAT3 and TGF-ß/SMAD3 signaling.

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.

Effect of dihydromyricetin on hepatic encephalopathy associated with acute hepatic failure in mice.

CONTEXT: Hepatic encephalopathy (HE) is a complex neuropsychiatric disease caused by liver failure. Dihydromyricetin (DMY) is a traditional medicine used to treat liver injury. OBJECTIVE: To investigate the effects of dihydromyricetin (DMY) on hepatic encephalopathy associated with acute hepatic failure mice models established by thioacetamide (TAA) exposure. MATERIALS AND METHODS: Female BALB/c mouse were randomly divided into control, DMY, TAA, and TAA + DMY groups (n = 8). The first two groups were intraperitoneally injected with saline or 5 mg/kg DMY, respectively. The last two groups were injected with 600 mg/kg TAA to establish HE models, and then the mice in the last group were treated with 5 mg/kg DMY. Neurological and cognition functions were evaluated 24 and 48 h after injection. Mice were sacrificed after which livers and brains were obtained for immunoblot and histopathological analysis, while blood was collected for the analysis of liver enzymes. RESULTS: In the TAA + DMY group, ALT and AST decreased to 145.31 ± 12.88 U/L and 309.51 ± 25.92 U/L, respectively, whereas ammonia and TBIL decreased to 415.67 ± 41.91 µmol/L and 3.31 ± 0.35 µmol/L, respectively. Moreover, MDA decreased to 10.74 ± 3.97 nmol/g, while SOD and GST increased to 398.69 ± 231.30 U/g and 41.37 ± 21.84 U/g, respectively. The neurological score decreased to 2.87 ± 0.63, and the number of GFAP-positive cells decreased to 41.10 ± 1.66. Furthermore, the protein levels of TNF-α, IL-6, and GABAA in the cortex decreased. CONCLUSIONS: We speculate that DMY can serve as a novel treatment for HE.

Effectiveness of supplementation with quercetin-type flavonols for treatment of viral lower respiratory tract infections: Systematic review and meta-analysis of preclinical studies.

Viral infections of the lower respiratory tract are considered a public health problem. They affect millions of people worldwide, causing thousands of deaths, and are treated with expensive medicines, such as antivirals or palliative measures. In this study, we conducted a systematic review to describe the use of quercetin-type flavonols against lower respiratory tract viruses and discussed the preclinical impact of this approach on different signs and clinical mechanisms of infection. The systematic review was performed in PubMed/MEDLINE, Scopus, Scielo, and Biblioteca Virtual de Saúde (BVS). After the database search, 11 relevant studies were identified as eligible. The analysis of these studies showed evidence of antiviral activity of quercetin-type flavonols with significantly reduced mortality rate (M-H = 0.19, 95% CI: 0.05 to 0.65, p-value = 0.008) of infected animals and a reduction in the average viral load (IV = -1.93, 95% CI: -3.54 to -0.31, p-value = 0.02). Additionally, quercetin and its derivatives reduced the amount of proinflammatory cytokines, chemokines, reactive oxygen species, mucus production, and airway resistance in animals infected with a respiratory virus. Overall, supplementation with quercetin-type flavonols is a promising strategy for treating viral-induced lower respiratory tract infections.

Ameliorative effects and molecular mechanisms of vine tea on western diet-induced NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a disease that is prevalent worldwide, and its prevention by dietary administration has recently been considered as an important strategy. In this study, we administered mice with vine tea polyphenol (VTP) extracted from Ampelopsis grossedentata, a Chinese herb, to investigate the preventive effect on western diet (WD)-induced NAFLD. Male C57BL/6N mice were fed either a normal diet (ND) or WD with or without VTP for 12 weeks. The results revealed that VTP supplementation decreased the serum levels of cholesterol and triglycerides, and reduced the accumulation of hepatic lipid droplets caused by WD. Molecular data revealed that VTP enhanced fatty acid oxidation by reactivating the WD-suppressed phosphorylation of AMP-activated protein kinaseα (AMPKα) and the expressions of peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmitoyl transferase IA (CPT1A) and cytochrome P450, family 4, subfamily a1 (CYP4A1). VTP inhibited hepatic lipogenesis by reducing the WD-enhanced level of mature sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS). Moreover, VTP activated nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated expressions of hemeoxygenase-1 (HO-1) and quinone oxidoreductase (NQO1), and reduced hepatic TBARS levels to prevent hepatic oxidative stress. On the other hand, VTP also increased intestinal zonula occludens-1 (ZO-1) expression and the relative abundance of gut Akkermansia, and reduced the ratio of Firmicutes/Bacteroidetes. Thus, VTP might prevent WD-induced NAFLD by balancing fatty acid oxidation and lipogenesis, hepatic oxidative stress, and gut microbiome, at least. These results suggest that vine tea, containing a high content of the bioactive compound dihydromyricetin, is a potential food resource for preventing NAFLD.

ASTILBIN: A PROMISING UNEXPLORED COMPOUND WITH MULTIDIMENSIONAL MEDICINAL AND HEALTH BENEFITS.

BACKGROUND: Many flavonoids have various beneficial actions like anti-inflammatory, anti-carcinogenic properties and many other clinical conditions. Astilbin is one such flavanoid compound having many physiological as well as pharmacological actions. PURPOSE: To summarize the important findings from the research conducted using astilbin having significance to its physiological and pharmacological activities as well as the patents filed using astilbin. STUDY DESIGN: Systematic review and compilation of the collected literature. METHOD: An extensive investigation of literature was done using several worldwide electronic scientific databases like PUBMED, SCOPUS, Science Direct and Google Scholar etc. All the article available in the English language that used our compound of interest i.e. astilbin, on the basis of inclusion criteria decided were retrieved from these databases, thoroughly reviewed and were summarized. RESULT: It has been established that astilbin can play a vital in the management of diseases associated with immune system. It also possesses antibacterial, anti-oxidative and hepatoprotective activity. CONCLUSION: These researches provide evidence that astilbin possesses great potential and thus can be utilized in the management of various disorders, thus establishing itself as a potential candidate for novel drug development. Also, there is still room for research on astilbin like it can be evaluated for anticancer potential, protective effect in various diabetic complications and many more. Overall observations from data suggested that astilbin is a promising compound and proved its efficacy in every preclinical study which is conducted till date. Some of the pharmacological activity is still unexplored. After successful preclinical trials, astilbin can go for further clinical trials.

Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice.

Natural products were extracted from traditional Chinese herbal emerging as potential therapeutic drugs for treating cardiovascular diseases. This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted from Ampelopsis grossedentata, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4-positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E-deficient (Apoe-/- ) mice. Yet, those protective effects are abrogated by using NOS inhibitor L-NAME in Apoe-/- mice received DMY. Mechanistically, DMY decreases microRNA-21 (miR-21) and increases its target gene dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression, an effect that reduces asymmetric aimethlarginine (ADMA) levels, and increases endothelial NO synthase (eNOS) phosphorylation and NO production in cultured HUVECs, vascular endothelium of atherosclerotic lesions and liver. In contrast, systemic delivery of miR-21 in Apoe-/- mice or miR-21 overexpression in cultured HUVECs abrogates those DMY-mediated protective effects. These data demonstrate that endothelial miR-21-inhibited DDAH1-ADMA-eNOS-NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management.

The Roles of Flavonols/Flavonoids in Neurodegeneration and Neuroinflammation.

The inflammatory process in the human body is a physiological response involving many cellular types and mediators. It results in scar formation to separate the damaged area from the surrounding healthy tissue. Because of increased blood-brain barrier permeability following inflammation, leukocytes infiltrate the CNS and are also supplemented by proinflammatory mediators. However, an acute inflammatory process after cerebral trauma or stroke may also result in a prolonged lesion formation, leading to a severe neuronal loss. The prolonged inflammatory process in the CNS may cause serious damage to the neuronal system. It may lead to CNS damage in such a way that endangers functional integration and proinflammatory system balance. Effects of different flavonoid species on ischemia-reperfusion injury and cognition and function have also been shown in experimental studies. Flavonoids are presented broadly in plants and diets. They are believed to have various bioactive effects including anti-viral, anti-inflammatory, cardioprotective, anti-diabetic, anti-cancer, anti-aging, etc. Quercetine is the predominant dietary flavonoid. Main sources are tea, onion, and apple. It is demonstrated that the frequently consumed food like soybean, peanut, mustard, rice, sesame, olive, potatoes, onion, and oats contain flavonoids. Catechin and its derivates which are isolated from tea leaves have antioxidant activity but in low doses, their prooxidant effects are also reported. Ipriflavone which is a synthetic flavonoid may increase total calcium in bone. In this review, the effects of flavonoids species on the inflammatory process in the neurodegenerative process were examined as general.

Dihydromyricetin alleviates acetaminophen-induced liver injury via the regulation of transformation, lipid homeostasis, cell death and regeneration.

AIMS: We previously reported that Hovenia dulcis Thunb. extract, a traditional Chinese medicine rich in dihydromyricetin (DHM), exhibited a significant hepatoprotective effect against acetaminophen (APAP)-induced liver injury. However, whether DHM plays a protective role in APAP hepatotoxicity and what mechanisms are involved remain unclear. In this study, we evaluated the hepatoprotective effects of DHM against APAP-induced liver injury. MAIN METHODS: Male C57BL/6 mice were used for the experiment. LC-MS, q-PCR, immunochemistry and western blot analysis were employed to mechanism analysis. KEY FINDINGS: DHM exhibited a protective effect against APAP-induced liver injury. Further mechanistic investigations revealed that the protective effect of DHM against APAP hepatotoxicity had multi-target and multi-pathway characteristics involving APAP metabolism, lipid regulation, and hepatocyte death and regeneration. DHM pretreatment resulted in cytochrome P450 2E1 inhibition and UDP-glucuronosyltransferase 1A1 activation, affecting APAP biotransformation. Moreover, DHM pretreatment significantly ameliorated lipid dysregulation via peroxisome proliferator-activated receptor and sterol regulatory element-binding protein-1c (SREBP-1c) signalling pathways. Furthermore, DHM regulated the expression of cell death- and liver regeneration-associated proteins. SIGNIFICANCE: These results suggested that DHM alleviated APAP-induced liver injury in mice by inhibiting hepatocyte death, promoting p53-related regeneration, and regulating lipid homeostatic imbalance and APAP transformation. Based on these findings, DHM provides a potential and novel approach for preventing and treating APAP-induced liver damage, and SREBP-1c signalling might be a new therapeutic target for APAP hepatotoxicity.

Protective effects of Rhizoma smilacis glabrae extracts on potassium oxonate- and monosodium urate-induced hyperuricemia and gout in mice.

BACKGROUND: Rhizoma smilacis glabrae (RSG, tufuling) has been widely used in traditional Chinese medicine for deoxidation, dampness relief, and easing joint movement. The chemical composition of RSG has been systematically confirmed, and some of its compounds have been revealed to possess antioxidant, anti-inflammatory, immunomodulatory, hypouricemic, and hepatoprotective effects. PURPOSE: We aimed to clarify whether a RSG extract attenuates hyperuricemia, paw edema, and renal injury in mice with potassium oxonate (PO)- and monosodium urate (MSU)-induced chronic hyperuricemia and gout. METHODS: RSG water extract was obtained and analyzed by HPLC-DAD-MS/MS. To establish a murine model with chronic hyperuricemia and gout, PO was orally administered daily from day 0 to day 24, whereas MSU was injected into the tibiotarsal joint on day 21. The mice in the drug intervention groups were treated once daily with doses of allopurinol or RSG extract from day 21 to day 24. The diameter of the ankle joints was measured with calipers. Serum TNF-α and IL-1ß concentrations, hepatic XOD activity, and uric acid, creatinine, and blood urea nitrogen (BUN) levels were also determined. The right kidney and articular cavities were fixed, cut into sections, and stained with hematoxylin and eosin. RESULTS: Nine compounds in the RSG water extract were unambiguously identified as 5-O-caffeoylshikimic acid, neoastilbin, astilbin, taxifolin, neoisoastilbin, isoastilbin, engeletin, isoengeletin, and trans-resveratrol. The RSGE treatment dose-dependently reduced PO- and MSU-induced paw edema, serum TNF-α, IL-1ß, IL-6, IL-12, uric acid, and BUN, while significantly elevated serum IL-10, urinary uric acid and creatinine levels as compared with the respective values in the hyperuricemic and gouty mice group (vehicle group). Moreover, the hepatic XOD activity was dose-dependently reduced by the RSGE treatment. In addition, RSGE treatment not only ameliorated the infiltration of inflammatory cells, tubular dilation and vacuole formation in renal tubular, but also improved the synovial hyperplasia, reduced inflammatory cells infiltration into the synovium, and diminished the erosive damage in the cartilage. CONCLUSION: The murine model with chronic hyperuricemia and gout be built in present study is consistent with the clinical symptoms of patients with long-standing hyperuricemia and acute gouty arthritis. RSG water extract has potent efficacy in ameliorating murine hyperuricemia and gout induced by PO and MSU.

The anti-hyperuricemic effect of four astilbin stereoisomers in Smilax glabra on hyperuricemic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Smilax glabra Roxb. (SG), a Chinese medicinal herb which called "tufuling", is believed to be effective in treating hyperuricemia and gout symptoms. But the active substance and pharmacological mechanism of reducing uric acid remain unknown. This study aimed to obtain the total flavonoids including four astilbin stereoisomers and to examine their effects on reducing uric acid content in hyperuricemic mice. MATERIALS AND METHODS: The total flavonoids of S. glabra (TFSG) were purified and then analysed by HPLC-PDA-MS. The effect of TFSG on the content of serum uric acid (SUA), Serum creatinine (SCr), blood urea nitrogen (BUN) and the activities of xanthine oxidase (XOD) in hyperuricemic mouse model induced by potassium oxonate were examined. Western blot and PCR method were also used to investigate whether TFSG have effect on renal transport protein organic anion transporter 1 (OAT1), organic cation/carnitine transporter 2 (OCTN2) and their mRNA in hypeuricemic mice. RESULT: Total flavonoids were obtained from EtOAc soluble portion of S. glabra. Four compounds were identified as neoastilbin, astilbin, neoisoastilbin and isoastilbin, which accounted for 55.6% of total flavonoids. TFSG could significantly reduce the serum uric acid content in hyperuricemic mouse (p < 0.01 or p < 0.05). The activities of hepatic XOD have been reduced in hyperuricemic mouse administered with 125 mg/kg TFSG (p < 0.05). The expressions of renal OAT1, OCTN2 and their mRNA have been up-regulated in hyperuricemic mice administered with TFSG (250, 125 mg/kg) (p < 0.01or p < 0.05). TFSG (62.5 mg/kg) could also elevated the expression of renal OCTN2 (p < 0.05). CONCLUSION: A novel and simple method for preparative separation of astilbin stereoisomers from S. glabra was developed. It was the first time to obtain total flavonoids (including four marker compounds) of S. glabra, and the total content was up to 55.6%. The results suggested TFSG has significant effect on reducing uric acid in hyperuricemic mice by inhibiting the XOD activities and up-regulating the expression of OAT1, OCTN2 and their mRNA in kidney tissue.

Dihydromyricetin from ampelopsis grossedentata protects against vascular neointimal formation via induction of TR3.

Vine tea has been used as a medicinal herb in traditional Chinese medicine for hundreds of years. As the most abundant ingredient in vine tea, Dihydromyricetin (DHM) has been reported to exert anti-inflammatory, antioxidant, and anti-cardiovascular disease. However, the role of DHM in injury-induced neointimal formation remains poorly characterized. We determined the effects of DHM on ligation-induced carotid artery neointimal formation. We found that ligation-induced carotid artery neointimal formation could be significantly attenuated by DHM treatment. We provide evidence that DHM increases orphan nuclear receptor TR3 expression in smooth muscle cell (SMC) and carotid artery. Moreover, overexpression and loss-of-function strategies of TR3 were done to overexpression and knockdown of TR3, and demonstrate that DHM promotes SMC differentiation, however, inhibits SMC proliferation and migration, via regulating expression of TR3. Collectively, we reveal that DHM may be a therapeutic agent for the treatment of injury-induced vascular diseases.

Improvement of glucocorticoid-impaired thymus function by dihydromyricetin via up-regulation of PPARγ-associated fatty acid metabolism.

T lymphocytes produced by the thymus are essential mediators of immunity. Accelerated thymic atrophy appears in the patients with administration of glucocorticoids (GCs) which are commonly-used drugs to treat autoimmune and infectious diseases, leading to dysregulation of immunity with manifestation of progressive diminution of new T cell production. However, there is no ideal method to overcome such side effects of GCs. In the current study, we proposed a composition of dexamethasone (DEX) and dihydromyricetin (DMY) derived from a medicinal plant, which could protect from DEX-induced thymus damage and simultaneously enhance the anti-inflammatory effect of DEX. In the current study, we found that DEX-damaged thymic cellularity and architecture, reduced thymocyte numbers, induced thymocyte apoptosis and dropped CD4+ and CD8+ double positive T cell numbers in thymus which was effectively improved by co-treatment with DMY. Quantification of signal joint TCR delta excision circles (TRECs) and Vß TCR spectratyping analysis were employed to determine the thymus function with indicated treatments. The results showed that DEX-impaired thymus output and decreased TCR cell diversity which was ameliorated by co-treatment with DMY. iTRAQ 2D LC-MS/MS was applied to analyze the proteomic profiling of thymus of mice treated with or without indicated agents, followed by informatics analysis to identify the correlated signaling pathway. After validated by Western blotting and Real-time PCR, we found that PPARγ-associated fatty acid metabolism was increased in the thymic tissues of the animals treated with DMY plus DEX than the animals treated with DEX alone. The agonist and antagonist of PPARγ were further employed to verify the role of PPARγ in the present study. Furthermore, DMY demonstrated a synergistic effect with co-administration of DEX on suppressing inflammation in vivo. Collectively, DMY relieved thymus function damaged by DEX via regulation of PPARγ-associated fatty acid metabolism. Our findings may provide a new strategy on protection of thymus from damage caused by GCs by using appropriate adjuvant natural agents through up-regulation of PPARγ-associated fatty acid metabolism.