Air-Assisted Electrospinning of Dihydromyricetin-Loaded Dextran/Zein/Xylose Nanofibers and Effects of the Maillard Reaction on Fiber Properties.

Dihydromyricetin (DMY) has been encapsulated in delivery systems to address the solubility limitations of DMY in water and improve its bioavailability. Air-assisted electrospinning has been used as a novel technology to load DMY. To evaluate the impact of adding DMY to dextran/zein nanofibers and understand the effects of the Maillard reaction (MR) on the physical and functional properties of DMY-loaded nanofibers, dextran/zein/xylose nanofibers with 0%, 1%, 2%, 3%, and 4% DMY were fabricated, followed by MR crosslinking. Scanning electron microscopy (SEM) observations indicated that the addition of DMY and the MR did not affect the morphology of the nanofibers. X-ray diffraction (XRD) results indicated amorphous dispersion of DMY within the nanofibers and a decreased crystalline structure within the nanofibers following the MR, which might improve their molecular flexibility. The nanofibrous film formed after the MR exhibited both increased tensile strength and elastic modulus due to hydrogen bonding within the nanofibers and increased elongation at break attributed to the increased amorphization of the structure after crosslinking. The nanofibers were also found to exhibit improved heat stability after the MR. The antioxidant activity of the nanofibers indicated a dose-dependent effect of DMY on radical scavenging activity and reducing power. The maintenance of antioxidant activity of the nanofibers after the MR suggested heat stability of DMY during heat treatment. Overall, dextran/zein nanofibers with various DMY contents exhibited tunable physical properties and effective antioxidant activities, indicating that dextran/zein nanofibers offer a successful DMY delivery system, which can be further applied as an active package.

Modulation of keap-1/Nrf2/HO-1 and NF-ĸb/caspase-3 signaling pathways by dihydromyricetin ameliorates sodium valproate-induced liver injury.

Nuclear factor erythroid factor 2 (Nrf2) is the key regulatory of the antioxidant response elements. Also, Nrf2 interacts with nuclear factor kappa B (NF-ĸB) to inhibit subsequent inflammatory cascade. Activation of Nrf2 signaling ameliorates drug-induced liver injury. Sodium valproate (SVP) is an anti-epilepsy drug with a hepatotoxic adverse effect that restricts its clinical use. In this study, coadministration of Dihydromyricetin (DHM), a natural flavonoid, with SVP to rats upregulated gene expression of Nrf2 and its downstream gene, heme oxygenase 1 (HO-1), while suppressed the Nrf2 repressor, Keap-1. Additionally, DHM led to downregulation of proinflammatory factors in liver tissues, including NF-ĸB, interleukin 1 beta (IL-1ß), and tumor necrosis factor alpha (TNF-α). This was accompanied by a decrease in the proapoptotic protein (cleaved caspase-3) expression level. Furthermore, biochemical and histopathological studies showed that DHM treatment improved liver function and lipid profile while decreased inflammatory cell infiltration, congestion, and hepatocellular damage. According to our knowledge, prior research has not examined the protective effect of DHM on the liver injury induced by SVP. Consequently, this study provides DHM as a promising herbal medication that, when used with SVP, can prevent its induced hepatotoxicity owing to its potential anti-oxidative, anti-inflammatory, and anti-apoptotic properties.

Dihydromyricetin ameliorates experimental ulcerative colitis by inhibiting neutrophil extracellular traps formation via the HIF-1α/VEGFA signaling pathway.

Dihydromyricetin (DHM), which has various biological functions, possesses therapeutic potential for ulcerative colitis (UC). Neutrophil extracellular traps (NETs) and their components play a crucial role in several pathological processes in UC. However, whether DHM alleviates UC by regulating NETs remains unclear. Mice with dextran sulfate sodium (DSS)-induced acute colitis were treated with DHM at different concentrations, and the severity of colitis was evaluated by assessing body weight, colon length, histological scores, cytokine production, and epithelial barrier integrity. To quantify and visualize NETs, the expression of cell free-DNA (cf-DNA) in serum and Cit-H3 in colonic tissue was analyzed via western blotting and immunofluorescence analysis. HL-60 cells and mouse bone marrow-derived neutrophils (BMDNs) were used to evaluate the effects of DHM on NETs in vitro. NETs were treated with DHM at varying concentrations or DNase I and used to repair the intestinal epithelial barrier in a Caco-2/HIEC-6 cell monolayer model. Furthermore, the genes targeted by DHM through neutrophils for alleviating UC were identified by screening online databases, and the results of network pharmacological analysis were verified via western blotting and quantitative real-time polymerase chain reaction. DHM alleviated DSS-induced colitis in mice by reversing weight loss, increased DAI score, colon length shortening, enhanced spleen index, colonic pathological damage, cytokine production, and epithelial barrier loss in a dose-dependent manner. In addition, it inhibited the formation of NETs both in vivo and in vitro. Based on the results of network pharmacological analysis, DHM may target HIF-1α and VEGFA through neutrophils to alleviate UC. Treatment with PMA increased the expression of HIF-1α and VEGFA in D-HL-60 cells and BMDNs, whereas treatment with DHM or DNase I reversed this effect. Treatment with DMOG, an inhibitor of HIF prolyl hydroxylase (HIF-PH), counteracted the suppressive effects of DHM on NETs formation in D-HL-60 cells and BMDNs. Accordingly, it partially counteracted the protective effects of DHM on the intestinal epithelial barrier in Caco-2 and HIEC-6 cells. These results indicated that DHM alleviated DSS-induced UC by regulating NETs formation via the HIF-1α/VEGFA signaling pathway, suggesting that DHM is a promising therapeutic candidate for UC.

Dihydromyricetin ameliorates diabetic renal fibrosis via regulating SphK1 to suppress the activation of NF-κB pathway.

Dihydromyricetin (DHM) is a flavonoid from vine tea with broad pharmacological benefits, which improve inflammation by blocking the NF-κB pathway. A growing body of research indicates that chronic kidney inflammation is vital to the pathogenesis of diabetic renal fibrosis. Sphingosine kinase-1 (SphK1) is a key regulator of diabetic renal inflammation, which triggers the NF-κB pathway. Hence, we evaluated whether DHM regulates diabetic renal inflammatory fibrosis by acting on SphK1. Here, we demonstrated that DHM effectively suppressed the synthesis of fibrotic and inflammatory adhesion factors like ICAM-1, and VCAM-1 in streptozotocin-treated high-fat diet-induced diabetic mice and HG-induced glomerular mesangial cells (GMCs). Moreover, DHM significantly suppressed NF-κB pathway activation and reduced SphK1 activity and protein expression under diabetic conditions. Mechanistically, the results of molecular docking, molecular dynamics simulation, and cellular thermal shift assay revealed that DHM stably bound to the binding pocket of SphK1, thereby reducing sphingosine-1-phosphate content and SphK1 enzymatic activity, which ultimately inhibited NF-κB DNA binding, transcriptional activity, and nuclear translocation. In conclusion, our data suggested that DHM inhibited SphK1 phosphorylation to prevent NF-κB activation thus ameliorating diabetic renal fibrosis. This supported the clinical use and further drug development of DHM as a potential candidate for treating diabetic renal fibrosis.

Chitosan-modified dihydromyricetin liposomes promote the repair of liver injury in mice suffering from diabetes mellitus.

Liver injury caused by type-II diabetes mellitus (DM) is a significant public-health concern worldwide. We used chitosan (CS) to modify dihydromyricetin (DHM)-loaded liposomes (DL) through charge interaction. The effect of CS-modified DL (CDL) on liver injury in mice suffering from DM was investigated in vivo and in vitro. CDL exhibited superior antioxidant capacity and stability. Pharmacokinetic analyses revealed a 3.23- and 1.92-fold increase in the drug concentration-time curve (953.60 ± 122.55 ng/mL/h) in the CDL-treated group as opposed to the DHM-treated group (295.15 ± 25.53 ng/mL/h) and DL-treated group (495.31 ± 65.21 ng/mL/h). The maximum drug concentration in blood (Tmax) of the CDL group saw a 2.26- and 1.21-fold increase compared with that in DHM and DL groups. We observed a 1.49- and 1.31-fold increase in the maximum drug concentration in blood (Cmax) in the CDL group compared with that in DHM and DL groups. Western blotting suggested that CDL could alleviate liver injury in mice suffering from DM by modulating inflammatory factors and the transforming growth factor-ß1/Smad2/Smad3 signaling pathway. In conclusion, modification of liposomes using CS is a viable approach to address the limitations of conventional liposomes and insoluble drugs.

Dihydromyricetin regulates KEAP1-Nrf2 pathways to enhance the survival of ischemic flap.

In clinical flap practice, there are a lot of studies being done on how to promote the survival of distal random flap necrosis in the hypoxic and ischemic state. As a traditional Chinese medicine, dihydromyricetin (DHM) is crucial in preventing oxidative stress and apoptosis in a number of disorders. In this work, we examined the impact of DHM on the ability to survive of ischemia flaps and looked into its fundamental mechanism. Our results showed that DHM significantly increased the ischemic flaps' survival area, encouraged angiogenesis and blood flow, reduced oxidative stress and apoptosis, and stimulated KEAP1-Nrf2 (Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor) signaling pathways. Adeno-associated virus (AAV) upregulation of KEAP1 expression also negated the favorable effects of DHM on flap survival. By activating KEAP1-Nrf2 signaling pathways, DHM therapy promotes angiogenesis while reducing oxidative stress and apoptosis.

Study on the stability of molecular chirality and the configuration protection of dihydromyricetin in vine tea.

This study aims to investigate the impact of four key factors, namely, temperature, water source, metal ion, and pH, on the stability of molecular chirality of dihydromyricetin (DMY) and proposed effective strategies for configuration protection. The findings reveal that temperatures exceeding 80°C could accelerate the racemization process of DMY, with a significant increase in racemization observed at 100°C. In addition, DMY exhibited heightened stability in ultrapure water as compared to various water sources, including pure water-1, pure water-2, mineral water, and running water. Notably, the presence of Fe2+ displayed an inhibitory effect on the racemization of DMY, whereas Mg2+, Ca2+, and Mn2+ showed a substantial promotional effect. Additionally, acidic conditions (pH < 5.0) were found to be protective for maintaining the stability of DMY, whereas alkaline conditions (pH > 9.0) were observed to be detrimental. Meanwhile, we first identified the presence of another pair of DMY isomers in this work.

The structural, antioxidant and emulsifying properties of cellulose nanofiber-dihydromyricetin mixtures: Effects of composite ratio.

In this work, effects of cellulose nanofiber/dihydromyricetin (CNF/DMY) ratio on the structural, antioxidant and emulsifying properties of the CNF/DMY mixtures were investigated. CNF integrated with DMY via hydrogen bonding and the antioxidant capacity of mixtures increased with decreasing CNF/DMY ratio (k). The oxidative stability of emulsions enhanced as the DMY content increased. Emulsions formed at Φ = 0.5 displayed larger size (about 25 µm), better viscoelasticity and centrifugal stability than those at Φ = 0.3 (about 23 µm). The emulsions at k = 17:3 and Φ = 0.5 exhibited the most excellent viscoelasticity. In conclusion, the DMY content in mixtures and the oil phase fraction exhibited distinct synergistic effects on the formation and characteristics of emulsions, and the emulsions could demonstrate superior oxidative and storage stability. These findings could provide a novel strategy to extend the shelf life of cellulose-based emulsions and related products.

Electrospun medicated gelatin/polycaprolactone Janus fibers for photothermal-chem combined therapy of liver cancer.

Liver cancer is a common cancer in the world, and core-shell nanoparticles as a commonly used combination therapy for local tumor ablation, have many shortcomings. In this study, photothermal Janus nanofibers were prepared using a electrospinning technology for tumor treatment, and the products were characterized and in vitro photothermal performance investigated. The micromorphology analysis showed that the photothermic agent CuS and electrospun fibers (loaded with CuS and anticancer drug dihydromyricetin) were successfully prepared, with diameters of 11.58 ± 0.27 µm and 1.19 ± 0.01 µm, respectively. Water contact angle and tensile test indicated that the fiber membranes has a certain hydrophilic adhesion and excellent mechanical strength. The fiber membranes has 808 nm near-infrared laser photothermal heating performance and photothermal stability, and it also has a strong response to the laser that penetrates biological tissue. In addition, in vitro cell culture and in vivo implantation study showed that the fiber membranes could kill HepG2 hepatocellular carcinoma cells combined with photothermal-chem and could be enriched in the implantation area, respectively. Hence, the Janus membranes may be a potential cancer treatment material.

Dihydromyricetin regulates RIPK3-CaMKII to prevent necroptosis in high glucose-stimulated cardiomyocytes.

Background: Diabetic cardiomyopathy is one common cardiovascular complication without effective treatments. Dihydromyricetin (DHY), a natural dihydroflavonol compound extracted from Ampelopsis grossedentata, possesses versatile pharmacologically important effects. In our current research, we planned to evaluate the impact and probable DHY mechanisms in high glucose (HG)-induced cardiomyocytes. Methods: Primary cardiomyocytes were pretreated with different concentrations of DHY (0, 20, 40, 80, 160, and 320 µM) for various time (0, 1, 2, 4, 12, and 24 h). They were then stimulated for 48 h with 5.5 mmol/L normal glucose (NG) and 33.3 mmol/L high glucose (HG). Cell viability, adenosine-triphosphate (ATP) levels, and lactate dehydrogenase (LDH) release of cardiomyocytes were detected. JC-1 staining was employed to measure the mitochondrial membrane potential. MitoSOX staining and dihydroethidium (DHE) staining were applied to evaluate the oxidative stress levels. TDT mediated dUTP nick end labeling (TUNEL) was used to measure apoptotic levels. Expressions of calcium/calmodulin-dependent protein kinase II (CaMKII), phospholamban (PLB), optic atrophy 1 (OPA1), dynamin-related protein 1 (DRP1), caspase 3, mixed kinase lineage domain like protein (MLKL), receptor interacting protein kinase 3 (RIPK3), and receptor interacting protein kinase 1 (RIPK1) were detected by immunofluorescence and/or Western blot. Results: DHY improved cell viability, enhanced ATP level, and decreased LDH content in HG-stimulated cardiomyocytes, suggesting DHY attenuating cell injury. DHY reduced number of TUNEL positive cells, inhibited RIPK3 and cleaved-caspase 3 expression, implying DHY alleviated necroptosis in HG-stimulated cardiomyocytes. DHY diminished JC-1 monomers, DHE and MitoSOX fluorescence intensity as well as DRP1 expression but increased JC-1 aggregates intensity and OPA1 expression, indicating that DHY attenuated oxidative stress in HG-stimulated cardiomyocytes. DHY also attenuated CaMKII activity by suppressed PLB phosphorylation and inhibited CaMKII oxidation in HG-stimulated cardiomyocytes. Conclusions: HG-induced cardiomyocytes injury was alleviated wherein DHY attenuated necroptosis, repressed ROS production, and inhibited CaMKII oxidation, suggesting that DHY may serve as potential agent to prevent and treat diabetic cardiomyopathy.

Multiple molecular and cellular mechanisms of the antitumour effect of dihydromyricetin (Review).

Dihydromyricetin (DHM) is a natural flavonoid compound with multiple antitumour effects, including inhibition of proliferation, promotion of apoptosis, inhibition of invasion and migration, clearance of reactive oxygen species (ROS) and induction of autophagy. For example, DHM can effectively block the progression of the tumour cell cycle and inhibit cell proliferation. In different types of cancer cells, DHM can regulate the PI3K/Akt pathway, mTOR, and NF-κB pathway components, such as p53, and endoplasmic reticulum stress can alter the accumulation of ROS or induce autophagy to promote the apoptosis of tumour cells. In addition, when DHM is used in combination with various known chemotherapy drugs, such as paclitaxel, nedaplatin, doxorubicin, oxaliplatin and vinblastine, it can increase the sensitivity of tumour cells to DHM and increase the therapeutic effect of chemotherapy drugs. In the present review, the multiple molecular and cellular mechanisms underlying the antitumour effect of DHM, as well as its ability to increase the effects of various traditional antitumour drugs were summarized. Through the present review, it is expected by the authors to draw attention to the potential of DHM as an antitumour drug and provide valuable references for the clinical translation of DHM research and the development of related treatment strategies.

Mechanism of Dihydromyricetin-Induced Reduction of Furfural Derived from the Amadori Compound: Formation of Adducts between Dihydromyricetin and Furfural or Its Precursors.

Dihydromyricetin (DMY) was employed to reduce the yield of furfural derived from the Amadori rearrangement product of l-threonine and d-xylose (Thr-ARP) by trapping Thr-ARP, 3-deoxyxyosone (3-DX), and furfural to form adducts. The effect of different concentrations of DMY at different pH values and temperatures on the reduction of furfural production was studied, and the results showed that DMY could significantly reduce furfural production at higher pH (pH 5-7) and lower temperature (110 °C). Through the surface electrostatic potential analysis by Gaussian, a significant enhancement of the C6 nucleophilic ability at higher pH (pH ≥ 5) was observed on DMY with hydrogen-dissociated phenol hydroxyl. The nucleophilic ability of DMY led to its trapping of Thr-ARP, 3-DX, and furfural with the generation of the adducts DMY-Thr-ARP, DMY-3-DX, and DMY-furfural. The formation of the DMY-Thr-ARP adduct slowed the degradation of Thr-ARP, caused the decrease of the 3-DX yield, and thereby inhibited the conversion of 3-DX to furfural. Therefore, DMY-Thr-ARP was purified, and the structure was identified by nuclear magnetic resonance (NMR). The results confirmed that C6 or C8 of DMY and carbonyl carbon in Thr-ARP underwent a nucleophilic addition reaction to form the DMY-Thr-ARP adduct. In combination with the analysis results of Gaussian, most of the DMY-Thr-ARP adducts were calculated to be C6-DMY-Thr-ARP. Furthermore, the formation of DMY-furfural caused furfural consumption. The formation of the adducts also shunted the pathway of both Thr-ARP and 3-DX conversion to furfural, resulting in a decrease in the level of furfural production.

Dihydromyricetin ameliorates hepatic steatosis and insulin resistance via AMPK/PGC-1α and PPARα-mediated autophagy pathway.

BACKGROUND: Dihydromyricetin (DHM), a flavonoid compound of natural origin, has been identified in high concentrations in ampelopsis grossedentata and has a broad spectrum of biological and pharmacological functions, particularly in regulating glucose and lipid metabolism. The objective of this research was to examine how DHM affected nonalcoholic fatty liver disease (NAFLD) and its underlying mechanisms involved in the progression of NAFLD in a rat model subjected to a high-fat diet (HFD). Additionally, the study examines the underlying mechanisms in a cellular model of steatohepatitis using palmitic acid (PA)-treated HepG2 cells, with a focus on the potential correlation between autophagy and hepatic insulin resistance (IR) in the progress of NAFLD. METHODS: SD rats were exposed to a HFD for a period of eight weeks, followed by a treatment with DHM (at doses of 50, 100, and 200 mg·kg-1·d-1) for additional six weeks. The HepG2 cells received a 0.5 mM PA treatment for 24 h, either alone or in conjunction with DHM (10 µM). The histopathological alterations were assessed by the use of Hematoxylin-eosin (H&E) staining. The quantification of glycogen content and lipid buildup in the liver was conducted by the use of PAS and Oil Red O staining techniques. Serum lipid and liver enzyme levels were also measured. Autophagic vesicle and autolysosome morphology was studied using electron microscopy. RT-qPCR and/or western blotting techniques were used to measure IR- and autophagy-related factors levels. RESULTS: The administration of DHM demonstrated efficacy in ameliorating hepatic steatosis, as seen in both in vivo and in vitro experimental models. Moreover, DHM administration significantly increased GLUT2 expression, decreased G6Pase and PEPCK expression, and improved IR in the hepatic tissue of rats fed a HFD and in cells exhibiting steatosis. DHM treatment elevated Beclin 1, ATG 5, and LC3-II levels in hepatic steatosis models, correlating with autolysosome formation. The expression of AMPK levels and its downstream target PGC-1α, and PPARα were decreased in HFD-fed rats and PA-treated hepatocytes, which were reversed through DHM treatment. AMPK/ PGC-1α and PPARα knockdown reduced the impact of DHM on hepatic autophagy, IR and accumulation of hepatic lipid. CONCLUSIONS: Our findings revealed that AMPK/ PGC-1α, PPARα-dependent autophagy pathways in the pathophysiology of IR and hepatic steatosis has been shown, suggesting that DHM might potentially serve as a promising treatment option for addressing this disease.

Protective Effect of Dihydromyricetin Against Exercise-Induced Muscle Damage and Its Mechanism.

Objective To investigate the protective effect of dihydromyricetin (DHM) against exercise-induced muscle damage (EIMD) in mice and its potential mechanism.Methods Adult male C57BL/6J mice were randomly divided into control group (CG), exercise group (EG), and exercise + 100 mg/kg weight ·d DHM (DHM) group. The intervention lasted for four weeks, during which the animals in the EG and DHM groups were subjected to exercise training for 1 h per day. The day after the training, a 90-min treadmill exercise (slope: 0 and speed: 18 m/min) was conducted in both EG and DHM groups. Samples of blood and gastrocnemius muscles were harvested from the three groups 24 h after the exercise, followed by the measurement of serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities, total superoxide dismutase (T-SOD) activity, malondialdehyde (MDA), and skeletal muscle mitochondrial enzyme complex I and II activities. Histological changes in the skeletal muscle were observed by transmission electron microscopy, and the protein expressions of mitochondrial function-related pathways were detected by Western blotting.Results Skeletal muscle morphological changes and mitochondrial damage were alleviated in the DHM group compared to those in the EG. The activities of EIMD markers CK and LDH and the level of lipid peroxidation were notably repressed and the serum T-SOD activity was enhanced after DHM intervention. Western blotting demonstrated that the expressions of sirtuin type 3 (SIRT3), estrogen-related receptor alpha, and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha in the skeletal muscle of mice increased after the DHM intervention.Conclusion DHM can relieve EIMD in mice, possibly by promoting the recovery of the mitochondrial structure and function in the skeletal muscle of mice after high-intensity exercise via the activation of the SIRT3 signaling pathway.

A Poloxamer 407/chitosan-based thermosensitive hydrogel dressing for diabetic wound healing via oxygen production and dihydromyricetin release.

The current clinical treatment of diabetic wounds is still based on oxygen therapy, and the slow healing of skin wounds due to hypoxia has always been a key problem in the repair of chronic skin injuries. To overcome this problem, the oxygen-producing matrix CaO2NPS based on the temperature-sensitive dihydromyricetin-loaded hydrogel was prepared. In vitro activity showed that the dihydromyricetin (DHM) oxygen-releasing temperature-sensitive hydrogel composite (DHM-OTH) not only provided a suitable oxygen environment for cells around the wound to survive but also had good biocompatibility and various biological activities. By constructing a T2D wound model, we further investigated the repairing effect of DHM-OTH on chronic diabetic skin wounds and the mechanisms involved. DHM-OTH was able to reduce inflammatory cells and collagen deposition and promote angiogenesis and cell proliferation for diabetic wound healing. These in vitro and in vivo data suggest that DHM-OTH accelerates diabetic wound repair as a novel method to efficiently deliver oxygen to wound tissue, providing a promising strategy to improve diabetic wound healing.

Effects of Nanoparticle-Mediated Dihydromyricetin to Diabetic Wounds: An In Vivo Study.

Diabetic wound is one of the serious complications of diabetes, and the wound is persistent and easily recurring, which seriously endangers the health and life of patients. How to effectively promote the healing of diabetic wounds has been a hot spot and difficult area of clinical research. Some previous studies have shown that dihydromyricetin has the effects of regulating blood glucose, controlling the severity, and inhibiting scarring. In the present study, we used polylactic-co-glycolic acid nanoparticles as a carrier to load dihydromyricetin to make drug-loaded nanoparticles and applied them dropwise (200 µL) to diabetic mice wounds by topical application to observe the healing and scar formation of diabetic wounds. We found that the healing rate of the diabetic mice was faster and the scar formation was less obvious. In addition, the elevated blood glucose level and weight loss of the mice in the treatment group were also reduced. Therefore, nanoparticle-mediated dihydromyricetin may be an effective treatment for diabetic wounds.

Study on the molecular mechanism of dihydromyricetin in alleviating liver cirrhosis based on network pharmacology.

Dihydromyricetin (DHM) is a bioactive flavonoid extracted from Hovenia dulcis, which has various activities. In the present study, the molecular mechanism of dihydromyricetin (DHM) in relieving liver cirrhosis was investigated through network pharmacology and experimental verification. The cell model was induced by TGF-ß1 activating the human hepatic stellate cell line (HSC; LX-2). The protein levels of α-SMA, collagen I, and collagen III and pathway-related proteins within LX-2 cells were detected using Western blot. EdU staining was conducted to detect cell proliferation. Immunofluorescence staining was performed to detect the expression levels of α-SMA and collagen I. Next, the drug targets of DHM were screened from the PubChem database. The differentially expressed genes in the liver cirrhosis dataset GSE14323 were identified. The expression of the identified drug targets in LX-2 cells was verified using qRT-PCR. The results showed that TGF-ß1 treatment notably increased LX-2 cell viability, promoted cell proliferation, and elevated α-SMA, collagen I, and collagen III protein contents. DHM treatment could partially eliminate TGF-ß1 effects, as evidenced by the inhibited cell viability and proliferation and reduced α-SMA, collagen I, and collagen III contents. After network pharmacology analysis, nine differentially expressed target genes (MMP2, PDGFRB, PARP1, BCL2L2, ABCB1, TYR, CYP2E1, SQSTM1, and IL6) in liver cirrhosis were identified. According to qRT-PCR verification, DHM could inhibit the expression of MMP2, PDGFRB, PARP1, CYP2E1, SQSTM1, and IL6, and enhance ABCB1 expression levels within LX-2 cells. Moreover, DHM inhibited mTOR and MAPK signaling pathways in TGF-ß1-induced HSCs. In conclusion, DHM could inhibit HSC activation, which may be achieved via acting on MMP2, PDGFRB, PARP1, CYP2E1, SQSTM1, IL6, and ABCB1 genes and their downstream signaling pathways, including mTOR and MAPK signaling pathway.

Dietary Dihydromyricetin Zinc Chelate Supplementation Improves the Intestinal Health of Magang Geese.

To fulfill the nutritional requirements of poultry, effective Zn supplementation is required due to Zn deficiency in basic feed. In this study, we investigated the effects of DMY-Zn (dihydromyricetin zinc chelate) on the growth performance, morphology, and biochemical indices; the expression of intestinal barrier-related genes; the intestinal microflora; and the cecum metabolome of Magang geese. A total of 300 14-day-old Magang geese (equal number of males and females) with an average body weight of 0.82 ± 0.08 kg were randomly divided into five groups and fed a basal diet; these groups were given DMY-Zn (low, medium, or high level of DMY-Zn with 30, 55, or 80 mg/kg Zn added to the basal diet) or ZnSO4 (80 mg/kg Zn added) for 4 weeks. Our results revealed that DMY-Zn significantly impacts growth and biochemical indices and plays a significant role in regulating the intestinal barrier and microflora. DMY-Zn is involved in the upregulation of intestinal barrier gene (ZO1 and MUC2) expression, as well as upregulated Zn-related gene expression (ZIP5). On the other hand, a low concentration of DMY-Zn increased the ɑ diversity index and the abundance of Lactobacillus and Faecalibacterium. Additionally, a cecal metabolomics study showed that the main metabolic pathways affected by DMY-Zn were the pentose phosphate pathway, the biosynthesis of different alkaloids, and the metabolism of sphingolipids. In conclusion, DMY-Zn can reduce feed intake, increase the expression of intestinal barrier-related genes, help maintain the intestinal microflora balance, and increase the abundance of beneficial bacteria in the intestine to improve intestinal immunity.

The Molecular Mechanism Underlying the Therapeutic Effect of Dihydromyricetin on Type 2 Diabetes Mellitus Based on Network Pharmacology, Molecular Docking, and Transcriptomics.

Type 2 diabetes mellitus (T2DM) is a chronic and complex disease, and traditional drugs have many side effects. The active compound dihydromyricetin (DHM), derived from natural plants, has been shown in our previous study to possess the potential for reducing blood glucose levels; however, its precise molecular mechanism remains unclear. In the present study, network pharmacology and transcriptomics were performed to screen the molecular targets and signaling pathways of DHM disturbed associated with T2DM, and the results were partially verified by molecular docking, RT-PCR, and Western blotting at in vivo levels. Firstly, the effect of DHM on blood glucose, lipid profile, and liver oxidative stress in db/db mice was explored and the results showed that DHM could reduce blood glucose and improve oxidative stress in the liver. Secondly, GO analysis based on network pharmacology and transcriptomics results showed that DHM mainly played a significant role in anti-inflammatory, antioxidant, and fatty acid metabolism in biological processes, on lipoprotein and respiratory chain on cell components, and on redox-related enzyme activity, iron ion binding, and glutathione transferase on molecular functional processes. KEGG system analysis results showed that the PI3K-Akt signaling pathway, IL17 signaling pathway, HIF signaling pathway, MAPK signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and TNF signaling pathway were typical signaling pathways disturbed by DHM in T2DM. Thirdly, molecular docking results showed that VEGFA, SRC, HIF1A, ESR1, KDR, MMP9, PPARG, and MAPK14 are key target genes, five genes of which were verified by RT-PCR in a dose-dependent manner. Finally, Western blotting results revealed that DHM effectively upregulated the expression of AKT protein and downregulated the expression of MEK protein in the liver of db/db mice. Therefore, our study found that DHM played a therapeutic effect partially by activation of the PI3K/AKT/MAPK signaling pathway. This study establishes the foundation for DHM as a novel therapeutic agent for T2DM. Additionally, it presents a fresh approach to utilizing natural plant extracts for chemoprevention and treatment of T2DM.

A dihydromyricetin-loaded phellinus igniarius polysaccharide/l-arginine modified chitosan-based hydrogel for promoting wound recovery in diabetic mice via JNK and TGF-ß/Smad signaling pathway.

The wound of diabetes has long-term excessive inflammation leading to wound fibrosis and scar formation. In the process of diabetic wound healing, good wound dressing is required for intervention. In this study, we designed a dihydromyricetin-loaded hydrogel (PCD) based on phellinus igniarius polysaccharide and l-arginine modified chitosan as an alternative material to promote diabetes wound healing. PCD had a uniform porous structure, good thermal stability, excellent mechanical properties, high water absorption, excellent antioxidant and anti-inflammatory activities and good biocompatibility and biodegradability. In addition, in the full-thickness skin trauma model of diabetes, PCD significantly inhibited the JNK signaling pathway to reduce inflammatory response, and significantly down-regulated the expression of TGF-ß1, Smad2, Smad3 and Smad4 to directly inhibit the TGF-ß/Smad signaling pathway to accelerate wound healing and slow down scar formation in diabetes mice. Therefore, PCD has a broad application prospect in promoting diabetes wound healing.