Diabetic liver injury (DLI) is one of the complications of diabetes mellitus, which seriously jeopardizes human health. Punicalagin (PU), a polyphenolic compound mainly found in pomegranate peel, has been shown to ameliorate metabolic diseases such as DLI, and the mechanism needs to be further explored. In this study, a HFD/STZ-induced diabetic mouse model is established to investigate the effect and mechanism of PU on DLI. The results show that PU intervention significantly improves liver histology and serum biochemical abnormalities in diabetic mice, significantly inhibits the expression of pyroptosis-related proteins such as NLRP3, Caspase1, IL-1β, and GSDMD in the liver of diabetic mice, and up-regulated the expression of autophagy-related proteins. Meanwhile, PU treatment significantly increases FoxO1 protein expression and inhibits TXNIP protein expression in the liver of diabetic mice. The above results are further verified in the HepG2 cell injury model induced by high glucose. AS1842856 is a FoxO1 specific inhibitor. The intervention of AS1842856 combined with PU reverses the regulatory effects of PU on pyroptosis and autophagy in HepG2 cells. In conclusion, this study demonstrates that PU may inhibit pyroptosis and upregulate autophagy by regulating FoxO1/TXNIP signaling, thereby alleviating DLI.

OBJECTIVE: In diabetes, chronic hyperglycemia increases the overactivation of oxidative phosphorylation of mitochondria in the liver, resulting in oxidative stress (OS) damage. The Nrf2 signaling pathway plays a key role in preventing hepatic oxidative injury and inflammation. This study aims to investigate the therapeutic effect and mechanism of Modified Buyang Huanwu Decoction (mBYHWD) on diabetic liver injury (DLI) by regulating oxidative stress mediated by Nrf2 signaling pathway.
METHODS: The experiment was divided into three groups: a control group (db/m mice, Con), a diabetes model group (db/db mice, Mod), and a traditional Chinese medicine group (db/m mice, mBYHWD). Post-treatment, serum from each group was analyzed to assess changes of blood glucose, blood lipid, and liver function. These results were combined with data mining to explore the possible pathogenesis of DLI. Liver tissues were collected to observe the pathological morphology and detect related proteins.
RESULTS: The results demonstrated that mBYHWD significantly reduced blood lipids and improved liver function following diabetic liver injury. The histopathological results demonstrated that mBYHWD could significantly ameliorate damage of diabetic hepatocytes. Protein analysis revealed that mBYHWD treatment significantly increased the expression of antioxidant proteins in diabetic liver tissue and inhibited inflammation.
CONCLUSIONS: The therapeutic mechanism of mBYHWD on DLI may involve activating the Nrf2 signaling pathway to improve oxidative stress, inhibit inflammation, and reduce liver tissue fibrosis.

BACKGROUND: Huang-Qi-Ge-Gen decoction (HGD) is a traditional Chinese medicine prescription that has been used for centuries to treat \"Xiaoke\" (the name of diabetes mellitus in ancient China). However, the ameliorating effects of HGD on diabetic liver injury (DLI) and its mechanisms are not yet fully understood.
OBJECTIVE: To elucidate the ameliorative effect of HGD on DLI and explore its material basis and potential hepatoprotective mechanism.
METHODS: A diabetic mice model was induced by feeding a high-fat diet and injecting intraperitoneally with streptozotocin (40 mg kg-1) for five days. After the animals were in confirmed diabetic condition, they were given HGD (3 or 12 g kg-1, i. g.) for 14 weeks. The effectiveness of HGD in treating DLI mice was evaluated by monitoring blood glucose and blood lipid levels, liver function, and pathological conditions. Furthermore, UPLC-MS/MS was used to identify the chemical component profile in HGD and absorption components in HGD-treated plasma. Network pharmacology and molecular docking were performed to predict the potential pathway of HGD intervention in DLI. Then, the results of network pharmacology were validated by examining biochemical parameters and using western blotting. Lastly, urine metabolites were analyzed by metabolomics strategy to explore the effect of HGD on the metabolic profile of DLI mice.
RESULTS: HGD exerted therapeutic potential against the disorders of glucose metabolism and lipid metabolism, liver dysfunction, liver steatosis, and fibrosis in a DLI model mice induced by HFD/STZ. A total of 108 chemical components in HGD and 18 absorption components in HGD-treated plasma were preliminarily identified. Network pharmacology and molecular docking results of the absorbed components in plasma indicated PI3K/AKT as a potential pathway for HGD to intervene in DLI mice. Further experiments verified that HGD markedly reduced liver oxidative stress in DLI mice by modulating the PI3K/AKT/Nrf2 signaling pathway. Moreover, 19 differential metabolites between normal and DLI mice were detected in urine, and seven metabolites could be significantly modulated back by HGD.
CONCLUSIONS: HGD could ameliorate diabetic liver injury by modulating the PI3K/AKT/Nrf2 signaling pathway and urinary metabolic profile.

Solanesol is a tetra sesquiterpene enol with various biological activities. Modern medical studies have confirmed that solanesol has the function of lipid antioxidation and scavenges free radicals. This study aimed to investigate the protective effect of solanesol against oxidative damage induced by high glucose on human normal hepatocytes (L-02 cells) and its possible mechanism. The results showed that solanesol could effectively improve the decrease of cell viability induced by high glucose, decrease the contents of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in the extracellular medium, increased the enzyme activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), balanced the level of reactive oxygen species (ROS) in cells, inhibited lipid peroxidation of all kinds of biological membranes, and restored mitochondrial membrane potential (MMP). In addition, Solanesol also inhibited the expression of Keap1, promoted the nuclear translocation of Nrf2 by hydrogen bonding with Nrf2, and activated the expression of downstream antioxidant factors NQO1 and HO-1. Altogether, these findings suggest that solanesol may be a potential protectant against diabetic liver injury.

OBJECTIVE: To investigate the effect of α-lipoic acid in ameliorating liver injury in rats with type 2 diabetes mellitus via activating adenosine 5\'-monophosphate-activate protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway.
METHODS: The T2DM rat models were established by feeding with high-fat, high-sucrose diet and intraperitoneal injection of 27.5 mg/(kg·d) streptozotocin. The 32 rats with T2DM were randomly divided into 4 groups: T2DM group, α-lipoic acid group (LA), Compound C group (Comp C, an inhibitor of AMPK) and LA+Comp C group, with 8 rats in each group. Additionally, 8 Sprague-Dawlay (SD) rats without diabetes were set as normal control. The rats received α-lipoic acid at a dosage of 100 mg/(kg·d) or Compound C at a dosage of 20 mg/(kg·d) by intraperitoneal injection for 8 weeks as needed. The levels of relevant biochemical indexes were detected. The weight of liver was recorded to calculate liver weight index (LWI), and the pathological changes of liver tissues were detected by light and electron microscopy. The levels of AMPK, p-AMPK, mTOR, p-mTOR in rat liver were detected by Western blot.
RESULTS: Compared with control group, the levels of LWI, homeostasis model assessment of insulin resistance, fasting blood glucose, alanine transaminase, aspartate transaminase, gamma glutamyl transferase and triglyceride in T2DM group were increased significantly (all P＜0.05). The liver tissue lesions were more serious and hepatic steatosis grade was higher. The expression of p-AMPK was decreased (P＜0.05) and the expression of p-mTOR was increased significantly(P＜0.05). α-lipoic acid could reverse the above-mentioned changes, ameliorate insulin resistance (all P＜0.05), protect the structure and function of liver, and activate the AMPK/mTOR pathway (P＜0.05). The protection of α-lipoic acid was weakened by the inhibition of AMPK with Compound C (P＜0.05).
CONCLUSIONS: α-lipoic acid could protect the liver of rats with T2DM by activating AMPK/mTOR pathway.
目的: 探讨α-硫辛酸是否通过激活腺苷酸活化蛋白激酶(AMPK)/雷帕霉素靶蛋白(mTOR)通路改善2型糖尿病(T2DM)大鼠肝损伤。方法: 应用高糖高脂饮食联合链脲佐菌素27.5 mg/(kg·d)腹腔注射法制备T2DM大鼠模型。将32只成模大鼠随机分为4组:T2DM组、α-硫辛酸组、Compound C(AMPK抑制剂)组和α-硫辛酸+ Compound C组,每组各8只。另8只健康Sprague-Dawlay(SD)大鼠作为正常对照组。α-硫辛酸注射液 100 mg/(kg·d) 腹腔注射,Compound C 20 mg/(kg·d) 腹腔注射,药物干预共持续8周。检测相关生化指标;计算肝脏质量指数;进行光镜、电镜观察;采用Western blot方法检测大鼠肝脏中AMPK、p-AMPK、mTOR、p-mTOR蛋白的表达水平。结果: 与正常对照组相比,T2DM组大鼠肝脏质量指数、胰岛素抵抗指数、空腹血糖、谷丙转氨酶、谷草转氨酶、γ –谷氨酰转肽酶、甘油三酯水平均升高(P均＜0.05);肝组织结构损伤,脂肪变明显;肝脏组织中p-AMPK表达显著减少(P＜0.05),p-mTOR表达显著增多(P＜0.05)。α-硫辛酸可逆转上述改变,改善大鼠的胰岛素抵抗(P＜0.05),保护肝脏的结构和功能,同时激活肝细胞内的AMPK/mTOR通路(P均＜0.05)。应用Compound C抑制AMPK活性后,α-硫辛酸的上述保护作用受到抑制(P＜0.05)。结论: α-硫辛酸可通过激活AMPK/mTOR信号通路发挥对T2DM大鼠的肝脏保护作用。.

OBJECTIVE: The study aims to find a new functional additive for diabetic liver injury.
BACKGROUND: It is well-established that type 2 diabetes mellitus (T2DM) is a metabolic disease with multiple complications and places a significant health and economic burden on modern society. Linarin is a natural flavonoid isolated from Asteraceae and Lamiaceae, which has beneficial effects in preventing and treating metabolic diseases such as nonalcoholic steatohepatitis and diabetes.
OBJECTIVE: We aimed to investigate the pharmacological effect and underlying mechanism of linarin on T2DM-associated liver injury in vivo and in vitro.
METHODS: Using a high-glucose and high-palmitic acid-induced hepatocyte injury model and a type 2 diabetic rat model. Following linarin treatment, serum biochemical parameters, liver histology, and lipid profiles of rats were examined. Oxidative stress index and inflammatory response were detected in vivo and in vitro. The expression level of AKR1B1 in rat liver tissues and in vitro cells was detected by western blot and by real-time fluorescent quantitative PCR.
RESULTS: The present study found that linarin could prevent oxidative stress and inflammation. In high-fat-fed diabetic rats, linarin administration (15, 30, and 60 mg/kg/day) reduced hepatic lipid accumulation, oxidative stress, and inflammation. Linarin (20 μM) significantly alleviated oxidative stress, inflammation, and apoptosis induced by high glucose combined with palmitic acid in LX-2 cells. Western blotting and overexpression experiments showed that these effects were related to AKR1B1 inhibition in vivo and in vitro.
CONCLUSIONS: This study indicated that linarin could protect against liver injury in T2DM by alleviating oxidative stress and inflammation mediated by AKR1B1 and may be a promising additive for diabetic liver injury therapy.

UNASSIGNED: Chronic hyperglycaemia of diabetes causes long-term damage and impaired function of multiple organs. However, the pathological changes in the liver following long-term diabetes remain unclear. This study aimed to determine the pathological complications of long-term diabetes in the rat liver.
UNASSIGNED: Intraperitoneal injection of streptozotocin (STZ) was used to induce diabetes in rats at a single dose (60 mg/kg body weight [BW]). Rats were euthanised at 1 month (DM1 group), 2 months (DM2 group) and 4 months (DM4 group) following diabetes induction with six rats in each group. Immunohistochemistry was performed against SOD1, CD68, p53 and p16 antibodies. Messenger RNA (mRNA) expressions of SOD1, SOD2, GPx, CD68, p53, p21 and caspase-3 genes were measured by reverse transcription-polymerase chain reaction.
UNASSIGNED: Hepatic p53 mRNA expression was significantly higher in DM1, DM2 and DM4 groups compared to the control group. The p21 and caspase-3 mRNA expressions were significantly upregulated in the DM2 and DM4 groups. The p16-positive cells were obviously increased, particularly in the DM4 group. Bivariate correlation analysis showed mRNA expressions of p21 and caspase-3 genes were positively correlated with the p53 gene.
UNASSIGNED: Diabetic rats exhibited increased apoptosis and senescence in the liver following a longer period of hyperglycaemia.

Type 2 diabetes mellitus is a complex multifactorial disease characterized by poor glucose tolerance and insulin resistance. Rice-husk silica liquid (RHSL) derived from rice husk has the ability to improve the dysfunction of pancreatic β-cells. This study aimed to confirm the potential protective effects of RHSL in streptozotocin (STZ)-induced diabetic mice. Diabetes was induced in male C57BL/6J mice by intraperitoneal administration of STZ (200 mg/kg BW). RHSL, food-grade silica liquid (FDSL), and rosiglitazone (RSG) were administered to diabetic mice for 12 weeks after successful induction of diabetes. During the experiment, fasting blood glucose, serum insulin, and organ weights were measured. The histopathology of liver tissue was evaluated by H&E staining. Western blotting was performed to assess protein expression levels. The results showed that RHSL significantly reversed the serum insulin levels and improved oral glucose tolerance test (OGTT) results (p < 0.05). In addition, liver sections of STZ-induced diabetic mice after RHSL treatment showed neatly arranged and intact hepatocytes. Furthermore, RHSL was more effective than FDSL in increasing the expression of SIRT1 and decreasing the expression of the PPAR-γ and p-NF-κB proteins. Taken together, this study demonstrated that RHSL ameliorated STZ-induced insulin resistance and liver tissue damage in C57BL/6J mice.

Diabetic liver injury has received increasing attention as a serious complication of type 2 diabetes. Punicalagin (PU), a major component of pomegranate polyphenols, has various biological activities such as antioxidant, anti-inflammatory, and lipid metabolism regulation. In this study, we observed the protective effect of punicalagin on a high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic liver injury in mice and revealed the underlying mechanism. The results showed that fasting blood glucose (FBG), fasting serum insulin (FINS), and homeostasis model assessment for insulin resistance (HOMA-IR) in diabetic liver injury mice were significantly decreased after punicalagin intervention. Simultaneously, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFA), malondialdehyde (MDA), and total superoxide dismutase (T-SOD) in the serum and liver were significantly decreased, with reductions in fat lesions and inflammatory cells. Mitophagy is a selective autophagy that maintains a balance between the quality and quantity of intracellular mitochondria. Studies have shown that mitophagy is closely related to the occurrence and development of diabetic liver injury. In our study, the mitochondrial membrane potential (MMP) was significantly increased in mice with diabetic liver injury after punicalagin intervention; the protein expression of Pink1, Parkin, Bnip3, LC3b, P62, manganese superoxide dismutase (MnSOD), and catalase (CAT) was significantly increased in the liver; and the activities of MnSOD and CAT in the serum and liver were significantly increased, which is consistent with the results of in vitro experiments. In summary, our study provided evidence that punicalagin could reduce the level of oxidative stress in the liver by upregulating mitophagy and the activities of antioxidant enzymes, thus having a certain protective effect against diabetic liver injury.

Huang Qin Decoction (HQD), is used for the treatment of diabetic liver injury (DLI) and in this study, its mechanisms were evaluated by metabonomics and system pharmacology. To study the anti-DLI effects of HQD. The 48 male db/db mice were fed adaptively for one week, and a random blood glucose test was performed twice. The db/db mice with a blood glucose level of more than 11.1mol/l were separated into four groups: the model group, the active control group, the high-dose HQD group the low-dose HQD group, the control group consisted of db/m mice. Using the UHPLC/Q-TOF-MS metabolomics approach, 18 metabolites were found to be profoundly altered in the model group, and the levels of these biomarkers were significantly recovered after treatment with HQD. 8 signaling pathways related to HQD, including the Sphingolipid metabolism, Taurine and hypotaurine metabolism, Phenylalanine metabolism, Glutathione metabolism and Glycerophospholipid metabolism, etc. were explored. In addition, the system pharmacology paradigm revealed that HQD contains 141 active ingredients and is related to 265 genes, and 1404 disease genes are related to DLI. The construction of the HQD composition-target-DLI network identified a total of 161 intersection genes. We identified 10 key genes, which is partially compatible with the results of metabolomics. The integrated approach metabolomics and network pharmacology revealed that additional detailed investigation focused on five major targets, including CAT, PTGS2, MAPK3, AKT1, and MAPK8, and their essential metabolites (sphinganine, sphingosine, Glutahione, Oxidized gutahione, Dihydrolipoamide) and pathway (glycerol phospholipid metabolism and tryptophan metabolism). The significant affinity of the primary target for the HQD was confirmed by molecular docking. The results demonstrate that the combination of metabolomics and network pharmacology could be used to reflect the effects of HQD on the biological network and metabolic state of DLI and to evaluate the drug efficacy of HQD and its related mechanisms.