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Targeted therapy is an emerging treatment strategy for alcoholic liver disease (ALD). Inflammation plays an important role in the occurrence and development of ALD, and is a key choice for its targeted treatment, and anti-inflammatory treatment has been considered beneficial for liver disease. Surprisingly, immune checkpoint inhibitors have become important therapeutic agents for hepatocellular carcinoma (HCC). Moreover, studies have shown that the combination of inflammatory molecule inhibitors and immune checkpoint inhibitors can exert better effects than either alone in mouse models of HCC. This review discusses the mechanism of hepatic ethanol metabolism and the conditions under which inflammation occurs. In addition, we focus on the potential molecular targets in inflammatory signalling pathways and summarize the potential targeted inhibitors and immune checkpoint inhibitors, providing a theoretical basis for the targeted treatment of ALD and the development of new combination therapy strategies for HCC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: To investigate the effects of a Chinese herbal medicine Fufang-Zhenzhu Tiaozhi Capsule (FTZ) on restenosis and elucidate the mechanism of action., Methods: A restenosis model was established by balloon rubbing the endothelium of the abdominal aorta followed by high fat diet. Rabbits were divided into blank control group, restenosis group, FTZ group (0.66 mg/kg/day), atorvastatin group (5 mg/kg/day) and FTZ + atorvastatin group (n = 8). Vascular stenosis was analyzed by X-ray. Serum levels of chemokines and cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were measured by ELISA. The levels of NF-κB, IκB-α, P-IκBα, IKK-α, and P-IKKα/β from injured abdominal arteries were detected by Western blotting., Results: Restenosis was induced successfully via abdominal artery balloon injuries and high fat diet. Restenosis was significantly decreased in FTZ group compared with restenosis group (P < 0.05). FTZ group had markedly reduced serum lipid levels (P < 0.05). In addition, the levels of TNF-α, IL-1, IL-6, IL-8, IL-12, ICAM-1 and MCP-1 decreased by FTZ treatment (P < 0.05). The expression of NF-κB in the atherosclerotic lesions was significantly attenuated in FTZ group (P < 0.05)., Conclusion: FTZ could reduce restenosis via reducing NF-κB activity and inflammatory factor expression within the atherosclerotic lesion in a rabbit restenosis model. FTZ may be a new therapeutic agent for restenosis.

Background: In the previous in vitro study, we found that simvastatin decreased the protein expression of CD36, the scavenger receptor, and calpain-1, the Ca2+-sensitive cysteine protease, in oxidized low-density lipoprotein (oxLDL)-treated macrophages. In this in vivo study, we investigated whether simvastatin downregulates the expression of CD36 and calpain-1 and inhibits the inflammation and atherosclerosis in apolipoprotein E knockout (ApoE KO) mice., Methods: Twenty male 6-week-old ApoE KO mice were divided into 2 groups: the ApoE KO group and the ApoE KO + simvastatin (ApoE KO + Sim) group. Atherosclerotic lesions were evaluated and the expressions of CD68, CD36, and calpain-1 in aorta were examined., Results: Simvastatin inhibited the atherosclerotic lesion in ApoE KO mice. In addition, simvastatin reduced the contents of oxLDL, thiobarbituric acid reactive substances, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum, decreased the mRNA and protein expressions of CD36 and reduced the mRNA expression of TNF-α and IL-6 in the aortas. Furthermore, simvastatin reduced the calpain activity and the protein expression of calpain-1 in the aorta., Conclusion: The results suggested that the attenuation of atherosclerotic lesions in ApoE KO mice by simvastatin might be associated with the downregulations of CD36 and calpain-1 and with inflammation., (© 2017 S. Karger AG, Basel.)

The safety and efficacy of anti-diabetic drugs are critical for maximizing the beneficial impacts of well-controlled blood glucose on the prognosis of individuals with COVID-19 and pre-existing type 2 diabetes (T2D). Metformin is the most commonly prescribed first-line medication for T2D, but its impact on the outcomes of individuals with COVID-19 and T2D remains to be clarified. Our current retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality. Furthermore, metformin use was significantly associated with reduced heart failure and inflammation. Our findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research. TGR5 can serve as an effective target for the treatment of obesity by regulating thermogenesis, metabolism, inflammation and appetite. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/Aims: Fufang Zhenzhu Tiao Zhi (FTZ) capsule is a Chinese herbal preparation under the guidance of professor Guo Jiao’s new theory of “Tiaogan Qishu Huazhuo” for disorders of glucose and lipid metabolism for more than twenty yares, which has been demonstrated to exhibit potential anti-aging effects such as regulation of glucose and lipid metabolisms and antiinflammatory and antioxidative effects. This study attempts to reveal the anti-intestinal aging effect and possible mechanism of FTZ. Methods: The mice were divided into three groups: the control group, model group and treatment group. The treatment group was given 1.0 g/kg body weight of FTZ extract administered by oral gavage once a day for 12 consecutive weeks. Age-related alterations such as HE staining of intestinal tissue morphology, mRNA levels of intestinal telomerase and inflammatory cytokines were observed Fecal samples were used for ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) and 16S rRNA gene sequencing analyses to reveal age-related metabolic perturbations and gut flora disorders to demonstrate the effects of FTZ. Results: Emerged pathological morphology of intestinal tissues, upregulated relative expression level of gut inflammatory factors and decreased relative expression level of telomerase mRNA in aging mice illustrated characteristic senescent phenotypes in model group. FTZ treatment significantly lowered intestinal inflammation levels, enhanced telomerase activity, partially reversed the fecal metabolites abnormalities and restored the disorders of intestinal flora. Multiple potential metabolites were associated with linoleic acid, glycerophospholipid, α-linolenic acid, biosynthesis of unsaturated fatty acids and glycerolipid metabolisms. Several decreased beneficial butyrate-producing bacteria like S24-7, possible Alkaliphilus belonging to the Clostridia class and increased harmful bacteria such as potentially toxic metabolite hydrogen sulfide-producer Bilophila and Desulfovibrio, inflammation-mediator Mucispirillum were determined in present aging mice. These age-related poor alterations could be partially attenuated by FTZ treatment. Conclusion: The pathologic changes of intestinal senescence and the decrease of telomerase mRNA in elderly mice was observed. FTZ may sever as a novel delaying intestinal aging strategy via three pathways for anti-inflammatory, improving gut metabolites and gut flora. This study not only provided biological basis for the theory of treating different diseases with the same treatment in TCM, but also provided objective evidence for incorporating aging into the system of“glucose-lipid metabolism disease”.

Non-alcoholic fatty liver disease (NAFLD) is a liver disease syndrome. The prevalence of NAFLD has continued to increase globally, and NAFLD has become a worldwide public health problem. Glucosamine (GLC) is an amino monosaccharide derivative of glucose. GLC has been proven to not only be effective in anti-inflammation applications, but also to modulate the gut microbiota effectively. Therefore, in this study, the therapeutic effect of GLC in the NAFLD context and the mechanisms underlying these effects were explored. Specifically, an NAFLD model was established by feeding mice a high-fat and high-sugar diet (HFHSD), and the HFHSD-fed NAFLD mice were treated with GLC. First, we investigated the effect of treating NAFLD mice with GLC by analyzing serum- and liver-related indicator levels. We found that GLC attenuated insulin resistance and inflammation, increased antioxidant function, and attenuated serum and liver lipid metabolism in the mice. Then, we investigated the mechanism underlying liver lipid metabolism, inflammation, and intestinal barrier function in these mice. We found that GLC can improve liver lipid metabolism and relieve insulin resistance and oxidative stress levels. In addition, GLC treatment increased intestinal barrier function, reduced LPS translocation, and reduced liver inflammation by inhibiting the activation of the LPS/TLR4/NF-κB pathway, thereby effectively ameliorating liver lesions in NAFLD mice. [ABSTRACT FROM AUTHOR]

The treatment of nonalcoholic fatty liver disease (NAFLD) remains very challenging. This study investigated the therapeutic effect of galactose oligosaccharide (GOS), an important prebiotic, on NAFLD through in vivo and in vitro experiments and preliminarily explored the mechanism by which GOS improves liver lipid metabolism and inflammation through liver and intestinal microbiological analysis. The results of mouse liver lipidomics showed that GOS could promote body thermogenesis in mice with high-fat and high-sugar diet (HFHSD)-induced NAFLD, regulate lipolysis in liver fat cells, and accelerate glycine and cholesterol metabolism. GOS dose-dependently reduced the contents of total cholesterol (TC) and triglyceride (TG) in cells and reduced the accumulation of lipid droplets in cells. GOS also reduced the Firmicutes/Bacteroidetes ratio and altered the composition of the intestinal microbiota in mice fed a HFHSD. GOS can improve liver lipid metabolism and intestinal structure of NAFLD. These results provide a theoretical and experimental basis supporting the use of GOS as a health food with anti-NAFLD functions. [ABSTRACT FROM AUTHOR]

EpCAM deficiency causes congenital tufting enteropathy (CTE) which is considered as one kinds of very early onset inflammatory bowel disease (IBD). However, functions of EpCAM on regulating the immunity of intestines are still unclear. To study the mechanism of EpCAM on maintaining the intestinal immune homeostasis, the intestines of WT and EpCAM-/- mice at E18.5, P0 and P3 stages were collected for morphological, histological and gene expression tests. Serious inflammation was detected in the small intestines of P3 EpCAM-/- mice. Compared to WT mice, genes related to inflammatory factors and immunity cells, including TNFα, IL-1β, IL-6, IL-8rb, MIP2, MCP1, Ly6d and Ly6g, were all significantly upregulated and the expression of intestinal abundance matrix metalloproteinases (MMPs) was also significantly increased in the intestines of EpCAM-/- mice at E18.5, P0 and P3 stages. Signals of p38, ERK1/2 and JNK were hyper-activated in the intestines of EpCAM-/- mice. The expression of pIgR was significantly decreased and the expression and activation of transcriptional factors which promote the expression of pIgR were also reduced in the intestines of EpCAM-/- mice compared to WT controls. In conclusion, EpCAM could maintain the immune homeostasis of intestines via keeping the expression of pIgR in the intestinal epithelium. [ABSTRACT FROM AUTHOR]

Background. The pathogenesis and clinical features of diabetic cardiomyopathy (DCM) have been well studied in the past decade; however, effective approaches to prevent and treat this disease are limited. Fufang Zhenzhu Tiaozhi (FTZ) formula, a traditional Chinese prescription, is habitually used to treat dyslipidemia and diabetes. Recently, several studies have reported the therapeutic effects of FTZ on cardiovascular diseases. However, the effects of FTZ on DCM have not yet been fully elucidated. This study investigated the effects of FTZ on DCM and determined the mechanisms underlying its efficacy. Methods. Diabetes was induced in mice by intraperitoneal injection of streptozotocin; the mice were randomly divided into a control group (Con), diabetes group (DCM), and diabetes-treated with FTZ (DCM + FTZ). Myocardial structural alterations, fibrosis biomarkers, and inflammation were observed. Besides, the potential targets and their related signaling pathways were analyzed using network pharmacology and further verified by Western blot. Results. Diabetic mice showed significant body weight loss, hyperglycemia, and excessive collagen content in the cardiac tissue, while serum and myocardial inflammatory factors significantly increased. Nerveless, treatment with FTZ for 1 month significantly improved body weight, attenuated hyperglycemia, and alleviated diabetes-associated myocardial structure and function abnormalities. Furthermore, the serum levels of interleukin 12 (IL-12) and chemokine (C–C motif) ligand 2 (CCL2) as well as the mRNA levels of cardiac IL-12, IL-6, and C–C motif chemokine receptor 2 (Ccr2) reduced after FTZ treatment. Additionally, a total of 67 active compounds and 76 potential targets related to DCM were analyzed. Pathway and functional enrichment analyses showed that FTZ mainly regulates inflammation-related pathways, including MAPK and PI3K-AKT signaling pathways. Further investigation revealed that the activities of STAT3, AKT, and ERK were augmented in diabetic hearts but decreased in FTZ-treated cardiac tissues. Conclusion. Our results suggest that FTZ exhibits therapeutic properties against DCM by ameliorating hyperglycemia-induced inflammation and fibrosis via at least partial inhibition of AKT, ERK, and STAT3 signaling pathways. [ABSTRACT FROM AUTHOR]

Finger citron (FC) is one of many traditional Chinese herbs that have been used to treat obesity. The aim of this study was to elucidate the pharmacological effects and mechanisms of FC on obese rats. Rats were fed with a high-fat diet as a model of obesity and treated with FC at three different dosages for 6 weeks. Pathology in liver tissue was observed. Glucose levels, lipids levels, and inflammatory indicators in serum were evaluated by enzyme‐linked immunosorbent assay. Furthermore, the expression of G protein-coupled receptor 5 (TGR5) pathway genes in rat colon tissue was detected by reverse transcription-polymerase chain reaction analysis (RT-PCR). Our result revealed that FC alleviates obesity by reducing body weight (BW) and waist circumference, managing inflammation and improving glycolipid metabolism, liver function, and liver lipid peroxidation in vivo. In addition, the mechanism of FC on obesity is possibly the stimulation of glucagon-like peptide-1 (GLP-1) secretion by activating the TGR5 pathway in intestinal endocrine cells. Our studies highlight the obesity reduction effects of FC and one of the mechanisms may be the activation of the TGR5 pathway in intestinal endocrine cells. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in a wide variety of physiologic and pathologic processes. Plasticity and functional polarization are hallmarks of macrophages. Macrophages commonly exist in two distinct subsets: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2b, a subtype of M2 macrophages, has attracted increasing attention over the past decade due to its strong immune‐regulated and anti‐inflammatory effects. A wide variety of stimuli and multiple factors modulate M2b macrophage polarization in vitro and in vivo. M2b macrophages possess both protective and pathogenic roles in various diseases. Understanding the mechanisms of M2b macrophage activation and the modulation of their polarization might provide a great perspective for the design of novel therapeutic strategies. The purpose of this review is to discuss current knowledge of M2b macrophage polarization, the roles of M2b macrophages in a variety of diseases and the stimuli to modulate M2b macrophage polarization. [ABSTRACT FROM AUTHOR]

The high rate of Salmonella enterica serovar Infantis (S. Infantis) infection poses significant risk for the development of non-typhoidal Salmonella gastroenteritis. However, efficient strategies to prevent or treat the infection remain elusive. Here, we explored the effect of the probiotic Lactobacillus rhamnosus GG (LGG) administration in preventing S. Infantis infection in a pig model. Probiotic LGG (1.0 x 1010 CFU/day) was orally administered to newly weaned piglets for 1 week before S. Infantis challenge. LGG pretreatment reduced the severity of diarrhea and alleviated intestinal inflammation caused by S. Infantis. Pre-administration of LGG excluded Salmonella from colonization of the jejunal mucosa but increased the abundance of Bifidobacterium in the feces. LGG promoted the expansion of CD4+ T-bet+ IFNγ+ T cells but attenuated S. Infantis-induced increases in the percentage of CD4+ IFNγ+ T cells and seruminterleukin (IL)-22 levels in peripheral blood after S. Infantis challenge. In the small intestine, LGG pretreatment upregulated expression of the transcription factor T-bet but downregulated the S. Infantis-induced increase of CD4+ IFN“+ T cells in Peyer's patches and IL-7Rα expression in the jejunum. Notably, LGG-treated pigs had enhanced expression of IL-22 and activated STAT3 in the ileum in response to S. Infantis infection. Pretreatment of pigs with LGG also elevated intestinal IL-22-binding protein production in response to S. Infantis challenge. In contrast, LGG consumption reduced the S. Infantis-induced increase in the number of CCL20-expressing cells in the jejunum. Our results suggest that the mechanism by which LGG ameliorates the intestinal inflammation caused by S. Infantis involves the upregulation of T-bet, activation of STAT3, and downregulation of CCL20. [ABSTRACT FROM AUTHOR]

Hyperlipidemia, type 2 diabetes mellitus, nonalcoholic fatty liver and many other metabolic disorder are frequently co-existing in patients. In addition, these diseases are closely related in pathophysiological settings. However, increasing of the disease incidence, lacking of comprehensive prevention and control measurements against the key pathology point concomitant occurrence with the pattern of the single disease, single target therapy, that is leading therapeutic strategy for these metabolic disorders in the setting of Western medicine (WM). On the basis of the combination of the advantages of integrated Chinese medicine (CM) and WM, with unified understanding of such diseases, the new concept of glucolipid metabolic disease (GLMD) is introduced. In this new concept, disorders in glucose and lipid metabolism are recognized as the key trigger and major driving force for the progress of GLMD. The key points of pathology included dysfunction of neuronal-endocrine-immune system, insulin resistance, oxidative stress, inflammation and intestinal flora imbalance. In the core pathogenic perspective of CM, it can be explained as "Gan (Liver) Shi Shu Xie" (dysfunction of Gan in metabolism and emotion regulation) that will lead to the occurence/production of endogenous dampness and phlegm, blood stasis and turbid. This leads to the new concept of "Liver-based regulatory system for metabolic homeostasis" to be introduced further. The comprehensive prevention and control strategy "Tiao Gan Qi Shu Hua Zhuo" (modulating Gan, trigging key metabolic system to resolve pathogenic factors such as phlegm retention and dampness). Its representative formula Fufang Zhenzhu Tiaozhi Capsule (复方贞术调脂胶囊) is innovated under such rationales. Comment for some commonly-used CM GLMD therapeutic drugs was presented. High-level evidence-based and epidemiological and mechanism studies should be carried out to further interpret and explain of the scientific connotation of GLMD. [ABSTRACT FROM AUTHOR]

In the progression of chronic liver diseases, liver fibrosis is a reversible pathophysiologic event for liver diseases prognosis and risk of cirrhosis. Liver injury factors of different etiologies mediate this process. There is still a lack of effective medications for treating liver fibrosis. Additionally, the ameliorative effects of traditional herbs on liver fibrosis have been commonly reported. Tianhuang formula (THF) is a drug combination consisting of 2 traditional Chinese herbs, which has been showing significant improvement in metabolic liver diseases. However, the hepatoprotective effect and mechanism of THF in ameliorating liver fibrosis are still unclear. This study aimed to investigate the effects of THF on carbon tetrachloride (CCl 4)-induced and methionine-choline-deficient (MCD) diet-induced liver fibrosis model and to reveal the potential mechanisms. It can provide experimental evidence for THF as a therapeutic candidate for liver fibrosis. In this study, CCl 4 -induced mice were treated with THF (80 mg/kg, 160 mg/kg) or Fuzheng Huayu (FZHY) capsules (4.8 g/kg) for 6 weeks. MCD-induced mice received the same doses of THF or FZHY for 4 weeks. FZHY is used as a comparative study in these two models. Following that, using kit reagents detected changes in relevant serum and liver biochemical indicators. Histological changes in mouse liver were measured by staining of H&E and Sirius Red. The markers expression of liver fibrosis and inflammation were detected using qRT-PCR, western blotting and immunohistochemical staining analysis. The potential regulatory mechanism of THF to ameliorate liver fibrosis was performed by RNA-sequencing analysis. Finally, the analysis results were verified by immunofluorescence co-staining, qRT-PCR and western blotting. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic triglyceride (TG) levels in CCl 4 and MCD-induced liver fibrosis mice were significantly improved after THF treatment. Meanwhile, the expression of fibrosis and inflammation markers were significantly suppressed. Furthermore, THF downregulated the expression of the macrophage marker CD68. According to RNA-sequencing analysis, we found the CCL2-CCR2 axis and MAPK/NF-κB as the potential signaling pathway for THF against liver fibrosis. This study revealed that THF ameliorated liver injury, inflammation and fibrotic process by inhibiting CCL2-CCR2 axis and its downstream MAPK/NF-κB signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme. However, the roles of GSTM2 in NASH have not been elucidated. Multiple RNA-seq analyses were used to identify hepatic GSTM2 expression in NASH. In vitro and in vivo gain- or loss-of-function approaches were used to investigate the role and molecular mechanism of GSTM2 in NASH. We identified GSTM2 as a sensitive responder and effective suppressor of NASH progression. GSTM2 was significantly downregulated during NASH progression. Hepatocyte GSTM2 deficiency markedly aggravated insulin resistance, hepatic steatosis, inflammation and fibrosis induced by a high-fat diet and a high-fat/high-cholesterol diet. Mechanistically, GSTM2 sustained MAPK pathway signaling by directly interacting with apoptosis signal-regulating kinase 1 (ASK1). GSTM2 directly bound to the N-terminal region of ASK1 and inhibited ASK1 N-terminal dimerization to subsequently repress ASK1 phosphorylation and the activation of its downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction. These data demonstrated that hepatocyte GSTM2 is an endogenous suppressor that protects against NASH progression by blocking ASK1 N-terminal dimerization and phosphorylation. Activating GSTM2 holds promise as a therapeutic strategy for NASH. IIT-2021-277. New therapeutic strategies for non-alcoholic steatohepatitis are urgently needed. We identified that the protein GSTM2 exerts a protective effect in response to metabolic stress. Therapies that aim to increase the activity of GSTM2 could hold promise for the treatment of non-alcoholic steatohepatitis. [Display omitted] • GSTM2 is downregulated in patients and mice with NASH. • Deficiency of GSTM2 promotes steatosis, inflammation and fibrosis in preclinical models of NASH. • Deficiency of GSTM2 augments NASH by promoting ASK1 dimerization and activation in hepatocytes. • Targeting GSTM2 might be a valuable therapeutic approach in NASH. [ABSTRACT FROM AUTHOR]

[Display omitted] • SW033291 improves aberrant hepatic lipid metabolism by inhibiting lipid uptake, lipogenesis and promoting fatty acid β-oxidation. • SW033291 reduces ER stress by inhibiting eIF2α/CHOP pathway. • SW033291 ameliorates inflammation by inhibiting NF-κB signaling. • SW033291 alleviates hepatic abnormal lipid metabolism, ER stress, and inflammation at least partly through PGE 2 /EP4 signaling to meliorate T2DM. Type 2 diabetes mellitus (T2DM) is a rapidly growing epidemic that results in increased morbidity, mortality, and soaring medical costs. Prostaglandin E 2 (PGE 2), a vital lipid mediator, has been reported to protect against hepatic steatosis, inflammation, endoplasmic reticulum (ER) stress, and insulin resistance, indicating its potential therapeutic role in T2DM. PGE 2 can be degraded by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). SW033291, an inhibitor of 15-PGDH, has been reported to increase PGE 2 levels, however, the effect of SW033291 in T2DM remains to be explored. This study aims to evaluate whether SW033291 protects against T2DM and explore its potential mechanisms. A T2DM mouse model was established through high-fat diet/streptozotocin injection, while palmitic acid-treated mouse primary hepatocytes were used as insulin-resistant cell models. SW033291 treatment reduced body weight, fat weight, fasting blood glucose, and improved impaired glucose tolerance and insulin resistance in T2DM mice. More importantly, SW033291 alleviated steatosis, inflammation, and ER stress in the liver of T2DM mice. Mechanistically, SW033291 decreased the expressions of SREBP-1c and ACC1, and increased the expression of PPARα in T2DM mice. Additionally, SW033291 inhibited NF-κB and eIF2α/CHOP signaling in T2DM mice. Further, we showed that the protective effects of SW033291 on the above-mentioned pathophysiological processes could be hindered by inhibition of the PGE 2 receptor EP4. Overall, our study reveals a novel role of SW033291 in alleviating T2DM and suggests its potential as a new therapeutic strategy for T2DM. [ABSTRACT FROM AUTHOR]

Diabetes mellitus-related coronary heart disease (DM-CHD) is the most common cause of death in diabetic patients. Various studies have shown that Chinese medicine Fufang-Zhenzhu-Tiaozhi capsule (FTZ) has therapeutic effects on cardiovascular diseases. More research is required to determine the mechanism of FTZ protection against coronary atherosclerosis. To investigate the unique mechanism of FTZ in treatment of DM-CHD minipigs with coronary atherosclerosis. High-fat/high-sucrose/high-cholesterol diet combined with streptozotocin and coronary balloon injury were used to induce DM-CHD minipig model, which was then randomly divided into: DM-CHD model, DM-CHD treated with FTZ or positive drug (Metformin + Atorvastatin, M+A). After twenty-two weeks, ultrasonography, electrocardiography, and image detection were employed to detect cardiac functions and assess coronary artery stenosis and plaque. Human umbilical vein endothelial cells (HUVECs) were treated high glucose or/and FTZ. Pigs tissues and treated-cells were collected for further testing. In DM-CHD minipigs, FTZ treatment significantly reduced disordered glycolipid metabolism similar as M+A administration. FTZ and M+A also alleviated coronary stenosis and myocardial injury. In addition, IκB and NF-κB phosphorylation levels, as well as the protein levels of IL-1β, Bax, cleave-Caspase 3, Bcl-2, and α-SMA were dramatically increased in the DM-CHD coronary artery, whereas CD31 and VE-cadherin expressions were decreased. Similar to M+A, FTZ reversed these protein levels in the DM-CHD coronary artery. Furthermore, FTZ ameliorated the damage and high migration activity of HUVECs induced by high glucose. FTZ improves coronary atherosclerosis through modulating inflammation, alleviating apoptosis, and inhibiting EndMT of coronary artery to protects against DM-CHD. [Display omitted] • Coronary atherosclerosis is one of the major pathophysiological mechanisms of DM-CHD. • FTZ attenuates the atherosclerotic plaques in DM-CHD pigs. • Inhibiting coronary inflammation, apoptosis, and EndMT is underline mechanisms of FTZ. [ABSTRACT FROM AUTHOR]

Excessive serum uric acid (SUA) causes hyperuricemic nephropathy (HN), characterized by inflammatory infiltration and tubulointerstitial fibrosis. Most recently, we demonstrated that Fufang Zhenzhu Tiaozhi (FTZ) capsule attenuated diabetic nephropathy through inhibition of renal inflammation and fibrosis. However, whether FTZ ameliorates HN is still unclear. To determine the protective roles and mechanism of FTZ in mouse renal injury and fibrosis under hyperuricemic condition. HN mice, induced by potassium oxonate and hypoxanthine, were administrated with 600 and 1200 mg/kg FTZ (intragastrically) daily for three weeks. SUA levels, renal functions and histological changes were analyzed. Western blotting, quantitative real-time PCR (q-PCR) and RNA sequencing were used to identify the roles and underlying mechanism of FTZ in HN mice. We demonstrated that FTZ treatment mitigated renal injury in mice, as evidenced by the decrease in SUA, serum creatinine (SCr) and cystatin C (Cys C) levels, as well as improved renal histology. FTZ markedly attenuates inflammasome activation, collagen deposition and the imbalance of uric acid transporters. RNA-sequencing revealed a key mechanism involved in the protective effects on HN mice was related to PI3K/AKT/NF-κB pathway. Western blot also confirmed that FTZ diminished the phosphorylation of AKT and p65 in HN mice. FTZ prevents renal injury, inflammation and fibrosis in HN mice via promoting uric acid excretion and inhibiting PI3K/AKT/NF-κB signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Fufang Zhenzhu Tiaozhi capsule (FTZ) is a patented preparation of Chinese herbal medicine that has been used to treat hyperlipidemia, nonalcoholic fatty liver disease, atherosclerosis, and other glucolipid metabolic diseases (GLMDs) in the clinic for almost 10 years. However, how FTZ reduces albuminuria and attenuates diabetic kidney disease (DKD) progression is unknown. To clarify the effects of FTZ on DKD mice model and to explore the underlying mechanisms. We used streptozotocin (STZ) (40 mg/kg/d, i.p. for 5 days, consecutively) combined with a high-fat diet (HFD) to induce a DKD mouse model, followed by FTZ (1, 2 g/kg/d, i.g.) treatment for 12 weeks. Losartan (30 mg/kg/d, i.g.) was used as a positive control. Measurements of 24 h proteinuria, serum creatinine (SCr), fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C) levels and expression levels of fibronectin (FN), collagen IV, inflammatory cytokines, inflammatory cells, interleukin-17A (IL-17A) and the nuclear transcription factor-κB (NF-κB) signaling pathway in the kidney were examined. FTZ effectively decreased 24 h proteinuria, Scr, FBG, TC, TG, and LDL-C levels, inhibited mesangial cell expansion, reduced FN and collagen IV accumulation, and F4/80+ macrophage cell infiltration and Ly-6G+ neutrophil infiltration in glomerulus and tubulointerstitium. Furthermore, IL-17A production and the NF-κB signaling pathway were also downregulated after the administration of FTZ. FTZ might attenuate DKD progression, and inhibited kidney inflammation and fibrosis by inhibiting the expression of RORγT and IL-17A in vivo , offering novel insights for the clinical application of FTZ. [Display omitted] • Fufang Zhenzhu Tiaozhi capsule protects against renal injury, ECM accumulation and inflammation in DKD mice. • Fufang Zhenzhu Tiaozhi capsule inhibits the RORγT/IL-17A/NF-κB signaling pathway in DKD mice. • We provided a potential clinical drug for diabetic kidney disease in the future. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a major risk factor for coronary heart disease (CHD). Previous research has reported that the Fufang-Zhenzhu-Tiaozhi (FTZ) formula has obvious effects on the treatment of dyslipidemia and hyperglycemia. In the present study, we intended to establish a convenient DM-CHD model in minipigs and investigated the protective effect of FTZ against myocardial injury and its mechanism. The DM-CHD model was established by a high-fat/high-sucrose/high-cholesterol diet (HFSCD) combined with balloon injury in the coronary artery. Subsequently, sixteen Wuzhishan minipigs were assigned to three groups: control group, model group, and FTZ group. The model group and FTZ group were given a HFSCD, while the control group was given a normal diet (ND). FTZ was given with meals in the FTZ group. During this time, biochemical parameters, such as total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL-C), and fasting blood glucose (FBG), were measured by using testing kits. Insulin (INS) was determined by ELISA, and the homeostasis model assessment index of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance levels. After FTZ administration, the plasma levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), and cardiac troponin I (cTnI) were measured by using ELISA kits to evaluate myocardial injury. Coronary artery stenosis was analyzed by angiographic and HE staining. Myocardial ischemia was assayed with electrocardiogram (ECG). Moreover, cytokines, including interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), and tumor necrosis factor-alpha (TNF-α), were measured by ELISA kits to assess inflammation. The myocardial tissue was collected, and the pathological morphology was observed by transmission electron microscopy (TEM), HE staining, and Masson staining. Western blots were used to detect the expression of PI3K, AKT, p-AKT, p-NF-κB, and NF-κB. A DM-CHD model in minipigs with glucose-lipid metabolism disorder, coronary artery incrassation and myocardial damage was successfully established through balloon injury in the coronary artery combined with HFSCD. FTZ effectively inhibited coronary artery incrassation and protected the myocardium against injury in DM-CHD minipigs. FTZ decreased proinflammatory cytokine levels and upregulated the protein expression of the PI3K/Akt pathway in the myocardium. A novel DM-CHD model in minipigs was successfully established through balloon injury in the coronary artery combined with HFSCD. FTZ has a protective effect against myocardial injury in DM-CHD by inhibiting inflammation and activating the PI3K/AKT signaling pathway. [Display omitted] • A novel DM-CHD model was successfully established through balloon injury in the coronary artery combined with HFSCD. • FTZ can alleviate the disorder of glucose metabolism in minipigs of DM-CHD. • FTZ effectively inhibited the coronary artery incrassation and protected myocardium against injured in minipigs of DM-CHD. • FTZ alleviates inflammation cytokine levels and up-regulated the protein expression of the PI3K/Akt pathway in myocardium. [ABSTRACT FROM AUTHOR]

• Dextran sulfate sodium (DSS) could induce inflammatory bowel diseases in mice. • Dihydroartemisinin (DHA) could improve the diarrhea and bloody stool of DSS treated mice. • DHA could improve inflammation and tight junctions in the colon of DSS treated mice. • DHA could improve the gut microbiota dysbiosis caused by DSS in mice. • DHA has the potential to be used for the treatment of inflammatory bowel diseases. In the present study, the effects of dihydroartemisinin (DHA) on inflammatory bowel diseases (IBD) mice model induced by dextran sulfate sodium (DSS) were determined. Hematoxylin and eosin staining was used to assess the intestines of mice treated with DSS and DHA. The expression of inflammatory factors and cell junction-associated genes was measured using reverse transcription-quantitative PCR (RT-qPCR) and Western blot. The effects of DSS and DHA on the gut microbiome were measured using 16S recombinant (r) DNA gene analysis. DHA could improve the diarrhea and bloody stool induced by DSS, and decrease the serum levels of TNF-α, IL-1β and IL-23 of the DSS group. DHA could notably reduce the infiltration of the inflammatory cells and significantly decrease the expression of TNF-α and IL-1β in the intestines of the DSS treated mice. The expression of cell junction-associated genes such as EpCAM and Claudins, were down-regulated in the DSS group, and DHA could recover the expression of these cell junction-associated genes. The 16S rDNA gene analysis demonstrated that Bacteroidetes and Verrucomicrobia decreased, while Firmicutes and Proteobacteria increased in the DSS group, and DHA could recover the abundance of these gut bacteria altered by DSS. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that DHA could partly recover the pathways altered by DSS. DHA could obviously ameliorate the symptoms of IBD induced by DSS by regulation of the expression of inflammation and cell junction-associated genes and gut microbiota, suggesting its potential for the treatment of IBD. [ABSTRACT FROM AUTHOR]

Introduction: Aortic aneurysm and dissection (AAD) is caused by aortic inflammation and progressive aortic smooth muscle cell (SMC) loss. Identifying pathways responsible for SMC injury and inflammation is critical for developing effective pharmacologic treatment. Recent reports indicate that receptor-interacting protein (RIP) 3 kinase-mediated necroptosis, a programmed cell death pathway, plays an important role in tissue destruction and inflammation. In this study, we hypothesize that RIP3-mediated necroptosis accelerates aortic destruction and inflammation, leading to AAD development, and that pharmacologically blocking this pathway may prevent AAD formation. Methods: We studied the activation of the RIP3 kinase-mediated necroptosis pathway in human thoracic AAD (TAAD) samples. To determine the role of RIP3 in AAD development, we compared the incidence of AAD in wild-type (n=30) and Rip3-/- (n=20) male and female mice challenged with a high-fat diet for 8 weeks and an angiotensin II infusion during the last 4 weeks. We also examined the effects of necroptosis inhibitors on AAD development in challenged WT mice that were given daily intraperitoneal injections of the RIP1 inhibitor Nec-1 (n=14), the RIP3 inhibitor GSK'872 (n=14), the MLKL inhibitor NSA (n=15), or dimethyl sulfoxide (DMSO) (vehicle, n=20) during the angiotensin II infusion period. Results: We observed significant expression and phosphorylation of RIP1, RIP3, and MLKL kinases in TAAD patient samples, particularly in SMCs and macrophages. Compared with challenged WT mice, challenged Rip3-/- mice showed significantly reduced aortic destruction, inflammation, and AAD formation (P <0.001). Disease reduction was seen in both male (P <0.001) and female (P =0.004) Rip3-/- mice. Furthermore, treating mice with necroptosis inhibitors significantly inhibited aortic enlargement and AAD formation. The MLKL inhibitor NSA was particularly potent in reducing AAD formation (80% in challenged DMSO-treated controls vs 27% in the challenged NSA-treated group; P =0.02). Conclusion: Our findings suggest that the necroptosis pathway plays a critical role in aortic destruction and AAD formation and that this pathway may be a useful therapeutic target for treating AAD. [ABSTRACT FROM AUTHOR]

Introduction: During tissue injury, damaged cells activate inflammatory cells, which in turn produce destructive proteins and promote further injury, leading to disease progression. Understanding the initiation of inflammation and breaking the vicious cycle may prevent progressive tissue damage and inflammation. Here, in a setting of aortic aneurysm and dissection (AAD), we show that self DNA from dying smooth muscle cells acts as tissue damage signals (DAMPs) that drive inflammatory response and aggravate vascular injury by activating pro-inflammatory cytosolic DNA sensor stimulator of interferon genes (STING) in macrophages. Methods: The effects of SMC-derived DNA on macrophage activation and the involvement of STING in the process were examined in cultured cells. The role of STING in aortic inflammation and injury was examined in Sting-deficient (Sting gt/gt) mice in an AAD model induced by a high-fat diet and angiotensin II infusion. The activation of STING and IRF3 in macrophages was examined in aortic tissues from patients with sporadic ascending thoracic AAD (ATAAD). Results: In cultured macrophages, the engulfment of SMC-derived DNA activated STING and IRF3, which in turn induced the production of MMP-9. In a mouse model of sporadic AAD, Sting -deficient mice exhibited significantly less aortic macrophage infiltration, MMP-9 production and activity, aortic destruction, and AAD formation than did wild-type mice. Finally, in macrophages of aortic tissues from patients with ATAAD, we observed significant amount of cytosolic DNA and activation of the STING-IRF3 pathway, which was associated with MMP-9 production. Conclusions: DNA from damaged SMCs activates macrophage STING-IRF3 pathway, which triggers MMP-9 production, contributing to aortic destruction. This STING-IRF3 pathway mediates the cross-talk between vascular damage and inflammation. [ABSTRACT FROM AUTHOR]