ETHNOPHARMACOLOGICAL RELEVANCE:Ban-xia-xie-xin-tang (BXXXT) is a classic traditional Chinese medicine formula used for treating gastrointestinal and metabolic disorders. It has demonstrated definite ameliorative effects on blood glucose and lipid dysregulation. However, the molecular mechanisms underlying the actions of its active components remain to be elucidated. AIM OF THE STUDY:The global rise in obesity has escalated the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM), driven by lipid metabolism disorders and aberrant inter-organ crosstalk, particularly between liver and adipose tissue. This study aimed to identify baicalein as a novel natural peroxisome proliferator-activated receptor-α (PPARα) agonist. We further sought to elucidate its mechanism in alleviating MAFLD-associated lipid disorders by activating the fibroblast growth factor 21 (FGF21)-adiponectin axis. MATERIALS AND METHODS:Active components of BXXXT targeting PPARα were screened using molecular docking and validated by surface plasmon resonance (SPR). The therapeutic effects of baicalein were evaluated in high-fat diet (HFD)-induced obese mice through metabolic phenotyping, histopathology, and biomarker analysis. Mechanistically, a hepatocyte-adipocyte transwell co-culture model was established to investigate the intercellular communication mediated by the PPARα-FGF21-adiponectin axis. RESULTS:The active component of BXXXT, baicalein, was identified as a high-affinity PPARα ligand. In vivo, baicalein treatment significantly reduced hepatic steatosis, body weight, and insulin resistance in HFD-fed mice. It promoted energy expenditure and fatty acid oxidation while inhibiting hepatic lipid synthesis. Crucially, baicalein upregulated hepatic FGF21 expression and increased circulating adiponectin levels. In the co-culture system, baicalein stimulated FGF21 secretion from hepatocytes, which subsequently triggered adiponectin release from adipocytes. This feedback loop suppressed lipid synthesis and enhanced fatty acid oxidation in hepatocytes. CONCLUSIONS:By bridging traditional pharmacology with molecular endocrinology, this study demonstrates that baicalein restores liver-adipose crosstalk via the PPARα-FGF21-adiponectin axis. These findings position baicalein as a promising therapeutic candidate for managing metabolic disorders.

To investigate the therapeutic effects and molecular mechanisms of berberine (BBR) for non-alcoholic fatty liver disease (NAFLD) concomitant with type 2 diabetes mellitus (T2DM). In vivo, 16 db/db mice were randomly assigned to the model group and the BBR group by a random number table method (n=8), with db/m mice serving as the control group. Mice were given BBR [100 mg/(kg·d)] or distilled water via gavage for 4 weeks. In vitro, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and compound C were introduced as a AMP-activated protein kinase (AMPK) agonist and an inhibitor, respectively. HepG2 cells were induced with palmitic acid (PA) and high glucose, and the treatment cells received BBR (5 µmol/L), AICAR (0.8 mmol/L) or compound C (10 µmol/L) or a combination of BBR and compound C for 24 h additionally. Biochemical assays and pathological staining were performed to assess lipid and glucose metabolism. qPCR and Western blot analysis were used to evaluate the mRNA and protein expressions related to fatty acids (FA) translation [including FA transport proteins (FATP) 2, FATP5, CD36], FA synthesis [including stearoyl-CoA desaturase 1 (SCD1), sterol regulatory element-binding proteins-1c (SREBP-1c), fatty acid synthase (FASN)], and FA β-oxidation [acyl-CoA synthetase long-chain family member 1 (ACSL1), carnitine palmitoyltransferase (CPT)1A, CPT1B, CPT2, short-chain-acyl-CoA dehydrogenase(SCAD), medium-chain-acyl-CoA dehydrogenase (MCAD), long-chain-acyl-CoA dehydrogenase (LCAD), and very-long-chain-acyl-CoA dehydrogenase (VLCAD), as well as AMPK/Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway. In vivo, compared with the model group, the mice in the BBR group showed lower TG, TC, LDL-C, fasting blood glucose levels and improved insulin sensitivity, as well as reduced lipid accumulation in liver tissues (P<0.05 or P<0.01). In the molecules related to fatty acid metabolism, the mice in the BBR group showed decreased protein expression of FASN and increased expressions of ACSL1 and CPT1A (P<0.05). Additionally, the mRNA expressions of fatp5 and CD36 were decreased, and CPT1A, CPT2, SCAD, LCAD, and VLCAD were increased (P<0.05). AMPK/SIRT1/PGC-1α pathway was activated in the liver of BBR-treated mice (P<0.05 or P<0.01). In vitro, BBR reduced lipid accumulation in HepG2 cells and activated the AMPK/SIRT1/PGC-1α pathway, and these effects were blocked by compound C (P<0.05 or P<0.01). Berberine activates AMPK/SIRT1/PGC-1α pathway, thereby improving fatty acid metabolism, and ultimately exerts therapeutic effects on NAFLD accompanied by T2DM.

BACKGROUND Diabetic kidney disease (DKD) is one of the most severe microvascular complications of diabetes, characterized by pathological changes such as glomerulosclerosis and renal interstitial fibrosis. Recent studies indicate that abnormal renal lipid metabolism and lipotoxicity are key drivers of DKD progression, where dysfunctional coupling between lipid droplets and mitochondria leads to insufficient fatty acid (FA) oxidation, exacerbating lipid deposition and fibrosis. Although ginsenoside Rd, a primary active component of Panax ginseng, has shown potential in alleviating DKD, its specific mechanism particularly whether it acts by regulating lipid droplet-mitochondria interactions and related signaling pathways remains unclear. AIM To investigate the protective effect of ginsenoside Rd against DKD and its underlying mechanism via the protein kinase A/perilipin (Plin) 1/mitofusin (Mfn) 2-mediated lipid droplet-mitochondria interaction. METHODS Db/db mouse DKD model was used and treated with different doses of ginsenoside Rd. Renal function and lipid levels were assessed biochemically; fibrosis was evaluated via histochemical staining; lipid droplet-mitochondria interaction was examined by electron microscopy and immunofluorescence. Using Plin1 deficient models, we examined the Plin1/Mfn2 signaling pathway and related molecules by polymerase chain reaction and western blotting. RESULTS Ginsenoside Rd significantly improved glycemic control, renal function, and attenuated renal fibrosis in db/db mice. This was associated with reduced renal lipid deposition and enhanced FA oxidation. Further studies showed that ginsenoside Rd promoted lipid droplet-mitochondria contact and activated the Plin1/Mfn2 pathway. These protective effects were abolished in Plin1 knockout or knockdown models. CONCLUSION This study demonstrates that ginsenoside Rd alleviates DKD by activating protein kinase A, which enhances Plin1/Mfn2-mediated lipid droplet-mitochondria contact, thereby accelerating FA oxidation, reducing lipotoxicity and renal fibrosis.

Abstract:Ginsenoside Rd shows positive effects on T2DM, but its mechanism remains unclear. In this study, we explored its mechanism focusing on inflammation levels in the pancreas and intestine, and provided evidence that this is related to modulation of the GLP-1/MAPK/NF-κB signaling pathway. We recorded and compared changes in metabolic indicators of T2DM, and tested levels of GLP-1 and GLP-1R through immunohistochemistry, Western blotting, and PCR after the mice were euthanized. Additionally, we detected the effects of ginsenoside Rd on inflammatory related molecules such as AMPK, Sirt1, MAPK, and NF-κB by ELISA, transcriptomics, Western blot, and PCR, while also conducting in vitro experiments to investigate the GLP-1 signaling pathway. After treatment with ginsenoside Rd, blood glucose decreased and insulin resistance weakened in db/db mice, and the results showed an increase in the expression of GLP-1 and GLP-1R. Transcriptome analysis revealed differences in inflammatory response-related signaling pathways after treatment, and Western blot results showed increased AMPK phosphorylation and decreased MAPK phosphorylation. Consistent experimental results were also obtained in vitro. In conclusion, our data suggest that ginsenoside Rd may ameliorate T2DM in db/db mice, potentially through the inhibition of inflammatory responses in the intestine and pancreas, an effect that might be mediated by the promotion of GLP-1 secretion.

Diabetic kidney disease (DKD) is one of the most common microvascular complications among individuals with diabetes and has become a leading cause of end-stage renal disease (ESRD). The mechanisms underlying DKD are complex, and effective therapeutic strategies remain limited. Mitochondrial dysfunction occurs earlier than proteinuria and renal morphological changes, and is considered a key event in the progression of DKD. Mitochondrial dysfunction in diabetic kidneys involves several processes, including excessive production of mitochondrial reactive oxygen species, reduced mitochondrial biogenesis, impaired mitophagy, and disturbances in mitochondrial dynamics. Recently, mitochondria-targeted drugs, including antioxidants, CD38 inhibitors, glucose-linked transport 2 sodium inhibitor (SGLT2i), and compounds derived from traditional Chinese medicine, have shown positive effects in animal experiments or clinical trials. This review aims to highlight the role of mitochondrial quality control and dysfunction in DKD, the specific mitochondrial regulators of different renal cell types, as well as the therapeutic potential of some emerging drugs and the limitations of existing preclinical evidence, thereby identifying promising therapeutic targets and strategies for the disease.

Ferroptosis, an iron-dependent form of programmed cell death, is closely associated with tubular damage in diabetic nephropathy (DN). Glutathione peroxidase 4 (GPX4) is an important anti-oxidant enzyme, and plays a crucial role in protecting against ferroptosis. However, the regulatory mechanism of GPX4 expression levels in renal tubular epithelial cells (RTECs) remains elusive. This study reveals that ferroptosis occurs in the late-stage of DN, and the GPX4 level is significantly downregulated in DN patients, animal models and cell models. By applying database predictions, luciferase reporter assays and chromatin immunoprecipitation, we find that vitamin D receptor (VDR) transcription factor promotes GPX4 expression and plays a key role in inhibiting ferroptosis of RTECs. VDR knockout exacerbates ferroptosis in RTECs and worsens renal function, while intraperitoneal injection of VDR agonist paricalcitol significantly improves renal injury. Proteomics analysis suggests that E3 ligase PRPF19 mediates ubiquitination degradation of VDR and is an important therapeutic target for DN. Therefore, through molecular docking, targeted fishing technology using high-performance affinity beads, and surface plasmon resonance (SPR), we screen and identify berberine (BBR) as a novel inhibitor of PRPF19, which offers renal protection by inhibiting VDR degradation and tubular ferroptosis. These findings elucidate the role of ferroptosis in DN renal tubular injury, and suggest that PRPF19 is a promising therapeutic target.

To identify the underlying molecular mechanism of Modified Hu-Lu-Ba-Wan (MHW) in alleviating renal lesions in mice with diabetic kidney disease (DKD). The db/db mice were divided into model group and MHW group according to a random number table, while db/m mice were settled as the control group (n=8 per group). The control and model groups were gavaged daily with distilled water [10 mL/(kg·d)], and the MHW group was treated with MHW [17.8 g/(kg·d)] for 6 weeks. After MHW administration for 6 weeks, indicators associated with glucolipid metabolism and urinary albumin were tested. Podocytes were observed by transmission electron microscopy. Kidney transcriptomics was performed after confirming therapeutic effects of MHW on DKD mice. The relevant target of MHW’ effect in DKD was further determined by enzyme-linked immunosorbent assay, Western blot analysis, immunohistochemistry, and immunofluorescence staining. Compared with the model group, MHW improved glucose and lipid metabolism (P<0.05), and reduced lipid deposition in the kidney. Meanwhile, MHW reduced the excretion of urinary albumin (P<0.05) and ameliorated renal damage. Transcriptomic analysis revealed that the inflammation response, particularly the interleukin-17 (IL-17) signaling pathway, may be responsible for the effect of MHW on DKD. Furtherly, our results found that MHW inhibited IL-17A and alleviated early fibrosis in the diabetic kidney. MHW ameliorated renal damage in DKD via inhibiting IL-17A, suggesting a potential strategy for DKD therapy.

Abstract Background This research aims to explore the anti-obesity potential of Wu-Mei-Wan (WMW), particularly its effects on adipose tissue regulation in obese mice induced by a high-fat diet (HFD). The study focuses on understanding the role of heat shock factor 1 (HSF1) in mediating these effects. Methods HFD-induced obese mice were treated with WMW. Body weight, food intake, and histopathological analysis of adipose tissue were conducted. Brown adipose tissue (BAT) activity was evaluated using Positron Emission Tomography, and ultrastructural changes were examined via transmission electron microscopy. Proteomic analysis identified targets of WMW in obesity treatment. HSF1 expression was inhibited to confirm its role. Molecular docking studied interactions between WMW and HSF1. Short-chain fatty acids (SCFAs) in the intestines were measured to determine if WMW’s effects on HSF1 are mediated through SCFAs. Protein expression was assessed using western blot, immunohistochemistry, immunofluorescence and RT-qPCR were employed to detect the mRNA levels. Statistical analyses included t-tests, ANOVA, and non-parametric tests like the Mann–Whitney U test or Kruskal–Wallis test. Results WMW significantly mitigates the adverse effects of a HFD on body weight and glucose metabolism in obese mice. Both low-dose WMW and high-dose WMW treatments led to reduced weight gain and improved glucose tolerance, with low-dose WMW showing more pronounced effects. WMW also reversed structural damage in BAT, enhancing mitochondrial integrity and thermogenic function, particularly at the low dose. Additionally, WMW treatment promoted the browning of WAT, evidenced by increased expression of key thermogenic proteins such as UCP1 and PGC-1α. The increase in HSF1 expression in both BAT and WAT, observed with WMW treatment, was crucial for these beneficial effects, as inhibition of HSF1 negated the positive outcomes. Furthermore, WMW treatment led to elevated levels of short-chain fatty acids SCFAs in the intestines, which are associated with increased HSF1 expression. Conclusions WMW represents a potent therapeutic strategy for obesity, promoting metabolic health and beneficial modulation of adipose tissue through an HSF1-dependent pathway.

Oxyberberine (OBB), a natural metabolite of berberine, has been shown to exhibit inhibitory effects on gluconeogenesis in our previous work. This work was designed to investigate the potential effects and underlying mechanisms of OBB on hepatic gluconeogenesis. Our work found that OBB significantly inhibited the expressions of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), and decreased the glucose production in palmitic acid-induced HepG2 cells. Then, AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways were confirmed by transcriptomics and network pharmacology analyses. It was shown that AMPK activation may phosphorylate and promote nuclear exclusion of FoxO1 and CRTC2, two key regulators of hepatic gluconeogenesis transcriptional pathways, resulting in the inhibition of gluconeogenesis under OBB administration. Afterwards, AMPK/Akt/FoxO1, AMPK/CRTC2 signaling pathways were evidenced by western blot, immunoprecipitation and confocal immunofluorescence, and the targeted inhibitor (Compound C) and siRNA of AMPK were applied for further mechanism verification. Moreover, it was found that OBB treatment activated AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways to decrease hepatic gluconeogenesis in db/db mice. Similarly, the in vivo inhibitory effects of OBB on gluconeogenesis were also diminished by AMPK inhibition. Our work demonstrated that OBB can inhibit hepatic gluconeogenesis in vitro and in vivo, and its underlying mechanisms were associated with AMPK-mediated suppression of FoxO1 and CRTC2 signaling axes.

OBJECTIVE:Diminished ovarian reserve (DOR) is a disorder characterized by impaired ovarian function. Sleep disorders are disruptions of the circadian rhythm, which appears to be closely linked to reproductive systems. This study aimed to investigate the impact of poor sleep quality on the ovarian reserve of childbearing-age women.METHODS:A cross-sectional study was conducted in China from June 2021 to March 2023. In total, 102 participants diagnosed with chronic insomnia disorder were included in the study. Questionnaires were administered to assess participants' menstrual patterns, insomnia severity, anxiety, and depression. The anti-Müllerian hormone level and the basal antral follicle count were measured for ovarian reserve evaluation. Correlation analysis and ordinal logistic regression analysis were conducted.RESULTS:The women with insomnia presented high percentages of hypomenorrhea, premenstrual syndrome, and dysmenorrhea (78.4%, 74.5%, and 46.1%, respectively). Severe sleep disorder in the past month was identified as an independent risk factor for hypomenorrhea and premenstrual syndrome (odds ratio [OR], 2.64 and OR, 2.688; p<0.05). The prevalence of DOR among women with insomnia (33.3%) was significantly higher than the average reported in previous studies for young women. Insomnia duration exceeding 1 year was determined to be an independent risk factor for DOR in women aged 36 to 40 years (OR, 4.5; p=0.033).CONCLUSION:This study highlights the association between sleep disorders and menstrual problems. Prolonged poor sleep quality in women aged 36 to 40 years was identified as a significant risk factor for DOR. We should pay more attention to improving sleep quality in order to maintain normal ovarian function.

To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine. The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively. HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01). HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.

Depression is a major global health issue that urgently requires innovative and precise treatment options. In this context, saikosaponin has emerged as a promising candidate, offering a variety of therapeutic benefits that may be effective in combating depression. This review delves into the multifaceted potential of saikosaponins in alleviating depressive symptoms. We summarized the effects of saikosaponins on structural and functional neuroplasticity, elaborated the regulatory mechanism of saikosaponins in modulating key factors that affect neuroplasticity, such as inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, and the brain-gut axis. Moreover, this paper highlights existing gaps in current researches and outlines directions for future studies. A detailed plan is provided for the future clinical application of saikosaponins, advocating for more targeted researches to speed up its transition from preclinical trials to clinical practice.

Objectives: Diabetic kidney disease (DKD) is a prevalent microvascular complication of diabetes. Inhibiting the epithelial-mesenchymal transition (EMT) of proximal tubule epithelial cells (PTCs) can slow down renal fibrosis. Trigonelline (TRL), an alkaloid isolated from the fenugreek, has demonstrated therapeutic effects on diabetes and its complications. Nevertheless, the underlying mechanisms for the effects of TRL are still obscure. The present study was aimed to evaluate the treatment of TRL against DKD and explore the potential mechanisms. Methods: The db/db mice were used as a spontaneous model of DKD and TRL solution was administered by daily gavage for 8 weeks. Indicators associated with glucose metabolism, renal function and urinary albumin were tested. Renal fibrosis in diabetic mice was evaluated by histopathological staining. Kidney transcriptomics was performed after confirming therapeutic effects of TRL on DKD mice. Molecular biology techniques and in vitro experiments were utilized for final mechanism verification. Results: Biochemical tests revealed that TRL ameliorated renal damage and reduced microalbuminuria in DKD mice. TRL exhibited a protective effect on PTCs, effectively mitigating tubular EMT and renal fibrosis in diabetic kidneys. Transcriptomics analysis indicated that TRL may target Smad7, an inhibitor of TGF-β1 signaling, to alleviate fibrosis. Furthermore, in vitro experiments validated that silencing Smad7 abolished the therapeutic effect of TRL. Conclusion: Our findings indicate that TRL can alleviate tubular epithelial-mesenchymal transition and renal fibrosis in db/db mice by upregulating Smad7 in PTCs, suggesting that TRL is a promising medicine against DKD.

The global prevalence of diabetes is steadily increasing, with a high percentage of patients unaware of their disease status. Screening for diabetes is of great significance in preventive medicine and may benefit from deep learning technology. In traditional Chinese medicine, specific features on the ocular surface have been explored as diagnostic indicators for systemic diseases. Here we explore the feasibility of using features from the entire ocular surface to construct deep learning models for risk assessment and detection of type 2 diabetes (T2DM). We performed an observational, multicenter study using ophthalmic images of the ocular surface to develop a deep convolutional network, OcularSurfaceNet. The deep learning system was trained and validated with a multicenter dataset of 416580 images from 67151 participants and tested independently using an additional 91422 images from 12544 participants, and can be used to identify individuals at high risk of T2DM with areas under the receiver operating characteristic curve (AUROC) of 0.89–0.92 and T2DM with AUROC of 0.70–0.82. Our study demonstrated a qualitative relationship between ocular surface images and T2DM risk level, which provided new insights for the potential utility of ocular surface images in T2DM screening. Overall, our findings suggest that the deep learning framework using ocular surface images can serve as an opportunistic screening toolkit for noninvasive and low-cost large-scale screening of the general population in risk assessment and early identification of T2DM patients.

Background: More than 70% of patients with type 2 diabetes (T2DM) concomitantly suffer from Non-alcoholic fatty liver disease (NAFLD), and the coexistence and interaction of them increases the intractability of NAFLD. With the protective effect against hepatic steatosis and liver fibrosis, SIRT6 is becoming a notable target of NAFLD. Diosgenin, an active monomer from Chinese herbs, has been reported to protect against NAFLD. Purpose: This study aims to figure out the mechanism how diosgenin alleviate NAFLD in T2DM and the rela-tionship with SIRT6. Methods: In vivo studies used spontaneous diabetic db/db mice and divided them into two parts. The first part included four groups consisting of control (Con) group, model (Mod) group, low dose of diosgenin (DL) group and high dose of diosgenin (DH) group. The second part included four groups consisting of Con group, Mod group, DH+OSS (OSS_128167, inhibitor of SIRT6) group, MDL (MDL800, agonist of SIRT6) group. HepG2 cell line was selected in study in vitro, which was mainly composed of six groups including Con group, palmitic acid (PA) group, PA+DL group, PA+DH group, PA+DH+OSS group, PA+MDL group. OGTT, Biochemical biomarker (including TG, TC, AST, ALT), inflammatory biomarker (including IL-6 and TNF-alpha) were measured. HE, Oil Red O, and DHE staining were conducted. Immunohistochemistry, immunofluorescence, mRNA-seq, and qPCR were used to explore the mechanism. Results: Results in the first part of study in vivo indicated that diosgenin protected against lipid accumulation, oxidative stress, cell injury, and light inflammatory of liver in db/db mice and regulated the expression of SIRT6 and fatty acid transporter including CD36, FATP2, FABP1. The effect of diosgenin could be reversed in DH+OSS group and the same effect was observed in MDL group in the second part of study in vivo. The same results were also noted in followed study in vitro. Diosgenin inhibited the fatty acids uptake and regulated the expression of SIRT6 and fatty acid transporter including CD36, FATP2, and FABP1 in PA-induced hepG2 cells, and which was reversed in DH+OSS group and resembled in MDL group. Conclusions: Diosgenin could attenuate non-alcoholic fatty liver disease in type 2 diabetes through regulating SIRT6-related fatty acid uptake.

Background: Depression, a global neuropsychiatric disorder, brings a serious burden to patients and society as its incidence continues to rise. Berberine is one of the main compounds of a variety of Chinese herbal medicines and has been shown to have multiple pharmacological effects. However, whether berberine can exert antidepressant effects in vivo and in vitro and its related mechanisms remain to be explored. Methods: The chronic restraint stress (CRS) method and corticosterone (CORT) were applied to simulate depression-like behavior in vivo and neuronal apoptosis in vitro, respectively. The antidepressant effects of berberine were evaluated by behavioral tests and changes in the content of monoamine neurotransmitters. Inflammatory cytokines were detected and immunofluorescence staining was used to observe the expression levels of apoptosis-related proteins. RT-qPCR and Western blot were used to examine the mRNA and protein expression (or phosphorylation) levels of biomarkers of the PI3K/AKT/CREB/BDNF signaling pathways. Results: Behavioral tests and levels of neurotransmitters proved that berberine could effectively ameliorate depression-like symptoms in CRS mice. Meanwhile, the results of ELISA and immunofluorescence staining showed that berberine could alleviate inflammatory status and reduce cell apoptosis in vivo and in vitro. Moreover, the changes of the PI3K/AKT/CREB/BDNF signaling pathway induced by CRS or CORT in mouse hippocampus or HT-22 cells were significantly reversed by berberine. Conclusion: Our current study suggested that berberine could exert antidepressant effects in vitro and in vivo, which may be associated with the PI3K/AKT/CREB/BDNF signaling pathway.

Background: Mitochondrial dysfunction is implicated in the progression of diabetic kidney disease (DKD). Damaged mitochondria produce excessive reactive oxygen species (ROS) that can cause apoptosis. Mitochondrial dynamics control the quality and function of mitochondria. Targeting mitochondrial dynamics may reduce ROS-induced apoptosis and improve renal injury in DKD. Modified Hu-lu-ba-wan (MHLBW) shows distinct clinical effects on DKD patients, which are related to its role in antioxidant stress modulation. However, the relevant mechanisms of MHLBW have not been clearly explored. Purpose: This study was aimed to evaluate the therapeutic effects of MHLBW on spontaneous DKD mice and clarify the potential mechanisms. Methods: The main components of MHLBW were identified by HPLC. Using db/db mice as DKD models, we evaluated the therapeutic effects of MHLBW on mice after an 8-week administration. We investigated the mo-lecular mechanism of MHLBW in regulating mitochondrial dynamic homeostasis, podocyte apoptosis, and glomerular damage. After that, computational docking analysis and in vitro experiments were conducted for further mechanism verification. Results: Intragastric administration of MHLBW for 8 weeks in db/db mice significantly improved glucose metabolism, basement membrane thickening, mesangial expansion, glomerular fibrosis, and podocyte injury. MHLBW can reverse podocyte apoptosis via promoting mitochondrial dynamic homeostasis, which was related to regulating the PKM2/ PGC-1 alpha/Opa1 pathway. Berberine (BBR), one of the components of MHLBW, exhibited preeminent affinity with PKM2 as reflected by computational docking analysis. In cultured podocytes, BBR can also prevent apoptosis by promoting PKM2-mediated mitochondrial dynamic homeostasis. Conclusion: Our study demonstrates that MHLBW can treat DKD by inhibiting glomerular damage and podocyte apoptosis through positive regulation of PKM2-mediated mitochondrial dynamic homeostasis. These results may provide a potential strategy against DKD.

Background: The evidence on berberine stimulating the secretion of GLP-1 in intestinal L cell has been studied. However, few research has explored its role on generating GLP-1 of islet α cell. Our experiment aims to clarify the mechanism of berberine promoting the secretion of GLP-1 in intestinal L cell and islet α cell, activating GLP-1R and its downstream molecules through endocrine and paracrine ways, thus improving the function of islet β cell and treating T2DM. Methods: After confirming that berberine can lower blood glucose and improve insulin resistance in db/db mice, the identity maintenance, proliferation and apoptosis of islet cells were detected by immunohistochemistry and immunofluorescence. Then, the activation of berberine on GLP-1/GLP-1R/PKA signaling pathway was evaluated by Elisa, Western blot and PCR. Finally, this mechanism was verified by in vitro experiments on Min6 cells, STC-1 cells and aTC1/6 cells. Results: Berberine ameliorates glucose metabolism in db/db mice. Additionally, it also increases the number and enhances the function of islet β cell. This process is closely related to improve the secretion of intestinal L cell and islet α cell, activate GLP-1R/PKA signaling pathway through autocrine and paracrine, and increase the expression of its related molecule such as GLP-1, GLP-1R, PC1/3, PC2, PKA, Pdx1. In vitro , the phenomenon that berberine enhanced the GLP-1/GLP-1R/PKA signal pathway had also been observed, which confirmed the results of animal experiments. Conclusion: Berberine can maintain the identity and normal function of islet β cell, and its mechanism is related to the activation of GLP-1/GLP-1R/PKA signal pathway in intestinal L cell and islet α cell.