Exploring pathogenesis and biomarkers through establishment of a rat model of male infertility with liver depression and kidney deficiency.

OBJECTIVES: To establish a rat model that accurately replicates the clinical characteristics of male infertility (MI) with Liver Depression and Kidney Deficiency (LD & KD) and investigate the pathogenesis. METHODS: After subjecting the rats to chronic restraint stress (CRS) and adenine treatment, a series of tests were conducted, including ethological assessments, evaluations of reproductive characteristics, measurements of biochemical parameters, histopathological examinations, and analyses of urinary metabolites. Additionally, bioinformatics predictions were performed for comprehensive analysis. RESULTS: Compared to the control, the model exhibited significant manifestations of MI with LD & KD, including reduced responsiveness, diminished frequency of capturing estrous female rats, and absence of mounting behavior. Additionally, the kidney coefficient increased markedly, while the coefficients of the testis and epididymis decreased significantly. Sperm counts and viabilities decreased notably, accompanied by an increase in sperm abnormalities. Dysregulation of reproductive hormone levels in the serum was observed, accompanied by an upregulation of proinflammatory cytokines expressions in the liver and kidney, as well as exacerbated oxidative stress in the penile corpus cavernosum and testis. The seminiferous tubules in the testis exhibited a loose arrangement, loss of germ cells, and infiltration of inflammatory cells. Furthermore, utilizing urinary metabolomics and bioinformatics analysis, 5 key biomarkers and 2 crucial targets most closely linked to MI were revealed. CONCLUSION: The study successfully established a clinically relevant animal model of MI with LD & KD. It elucidates the pathogenesis of the condition, identifies key biomarkers and targets, and provides a robust scientific foundation for the prediction, diagnosis, and treatment of MI with LD & KD.

4,4-Diallyl curcumin bis(2,2-hydroxymethyl)propanoate ameliorates nonalcoholic steatohepatitis in methionine-choline-deficient diet and Western diet mouse models.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that causes severe liver damage, fibrosis, and scarring. Despite its potential to progress to cirrhosis or hepatic failure, approved drugs or treatments are currently unavailable. We developed 4,4-diallyl curcumin bis(2,2-hydroxymethyl)propanoate, also known as 35e, which induces upregulation of mitochondrial proteins including carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II, heat shock protein 60, and translocase of the outer mitochondrial membrane 20. Among these proteins, the upregulated expression of CPT-I was most prominent. CPT-I plays a crucial role in transporting carnitine across the mitochondrial inner membrane, thereby initiating mitochondrial ß-oxidation of fatty acids. Given recent research showing that CPT-I activation could be a viable pathway for NASH treatment, we hypothesized that 35e could serve as a potential agent for treating NASH. The efficacy of 35e in treating NASH was evaluated in methionine- and choline-deficient (MCD) diet- and Western diet (WD)-induced models that mimic human NASH. In the MCD diet-induced model, both short-term (2 weeks) and long-term (7 weeks) treatment with 35e effectively regulated elevated serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) concentrations and histological inflammation. However, the antisteatotic effect of 35e was obtained only in the short-term treatment group. As a comparative compound in the MCD diet-induced model, curcumin treatment did not produce significant regulatory effects on the liver triglyceride/total cholesterol, serum ALT/AST, or hepatic steatosis. In the WD-induced model, 35e ameliorated hepatic steatosis and hepatic inflammation, while increasing serum AST and hepatic lipid content. A decrease in epididymal adipose tissue weight and serum free fatty acid concentration suggested that 35e may promote lipid metabolism or impede lipid accumulation. Overall, 35e displayed significant antilipid accumulation and antifibrotic effects in the two complementary mice models. The development of new curcumin derivatives with the ability to induce CPT-I upregulation could further underscore their efficacy as anti-NASH agents.

Hepatoprotective effects of baicalein against liver ischemia-reperfusion injury and partial hepatectomy in a rat model.

BACKGROUND: Baicalein is the main active flavonoid in Scutellariae Radix and is included in shosaikoto, a Kampo formula used for treating hepatitis and jaundice. However, little is known about its hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI), a severe clinical condition directly caused by interventional procedures. We aimed to investigate the hepatoprotective effects of baicalein against HIRI and partial hepatectomy (HIRI + PH) and its potential underlying mechanisms. METHODS AND RESULTS: Male Sprague-Dawley rats received either baicalein (5 mg/kg) or saline intraperitoneally and underwent a 70% hepatectomy 15 min after hepatic ischemia. After reperfusion, liver and blood samples were collected. Survival was monitored 30 min after hepatic ischemia and hepatectomy. In interleukin 1ß (IL-1ß)-treated primary cultured rat hepatocytes, the influence of baicalein on inflammatory mediator production and the associated signaling pathway was analyzed. Baicalein suppressed apoptosis and neutrophil infiltration, which are the features of HIRI + PH treatment-induced histological injury. Baicalein also reduced the mRNA expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α). In addition, HIRI + PH treatment induced liver enzyme deviations in the serum and hypertrophy of the remnant liver, which were suppressed by baicalein. In the lethal HIRI + PH treatment group, baicalein significantly reduced mortality. In IL-1ß-treated rat hepatocytes, baicalein suppressed TNF-α and chemokine mRNA expression as well as the activation of nuclear factor-kappa B (NF-κB) and Akt. CONCLUSIONS: Baicalein treatment attenuates HIRI + PH-induced liver injury and may promote survival. This potential hepatoprotection may be partly related to suppressing inflammatory gene induction through the inhibition of NF-κB activity and Akt signaling in hepatocytes.

Antioxidant Activity and Effectiveness of Fig Extract in Counteracting Carbon Tetrachloride-Induced Oxidative Damage in Rats.

Figs are the edible fruits of the fig tree, Ficus carica L., that have been used for centuries for human consumption and in traditional medicine, to treat skin problems, inflammation, and gastrointestinal disorders. Our previous study investigated the presence of phenolic compounds in aqueous extracts of two Algerian popular fig varieties, azendjar (Az) and taamriouth (Ta), as well as their in vitro antioxidant activity. In this study, we assessed hydroethanolic extracts of these fig varieties. The total phenolic content was measured, along with the phenolic profile. Rutin was determined to be the dominant phenolic compound, followed by vanillic acid, 3,4-dihydroxybenzoic acid, quercetin, 4-hydroxybenzoic acid, rosmarinic acid (in Az only), and cinnamic acid. The antioxidant activity of the extracts was evaluated both in vitro (DPPH and FRAP assays) and in vivo, in rats intoxicated with carbon tetrachloride. In all assays, the fig extract-especially the dark-peeled fig variety azendjar-showed antioxidant potency. The administration of fig extract resulted in a reduction in liver damage, expressed by both different biochemical markers and histopathological study (less degraded liver architecture, reduced fibrosis, and only mild inflammation). A dose-dependent therapeutic effect was observed. The extract from the dark-peeled fig variety, Az, was characterized by a higher phenolic content and a stronger antioxidant activity than the extract from the light-peeled variety-Ta. Our study justifies the use of figs in traditional healing and shows the potential of using fig extracts in natural medicines and functional foods.

Steatotic Donor Transplant Livers: Preservation Strategies to Mitigate against Ischaemia-Reperfusion Injury.

Liver transplantation (LT) is the only definitive treatment for end-stage liver disease, yet the UK has seen a 400% increase in liver disease-related deaths since 1970, constrained further by a critical shortage of donor organs. This shortfall has necessitated the use of extended criteria donor organs, including those with evidence of steatosis. The impact of hepatic steatosis (HS) on graft viability remains a concern, particularly for donor livers with moderate to severe steatosis which are highly sensitive to the process of ischaemia-reperfusion injury (IRI) and static cold storage (SCS) leading to poor post-transplantation outcomes. This review explores the pathophysiological predisposition of steatotic livers to IRI, the limitations of SCS, and alternative preservation strategies, including novel organ preservation solutions (OPS) and normothermic machine perfusion (NMP), to mitigate IRI and improve outcomes for steatotic donor livers. By addressing these challenges, the liver transplant community can enhance the utilisation of steatotic donor livers which is crucial in the context of the global obesity crisis and the growing need to expand the donor pool.

Antiphospholipid antibody-related hepatic vasculitis in a juvenile after non-severe COVID-19: a case report and literature review.

Antiphospholipid antibodies (aPL) are both laboratory evidence and causative factors for a broad spectrum of clinical manifestations of antiphospholipid syndrome (APS), with thrombotic and obstetric events being the most prevalent. Despite the aPL-triggered vasculopathy nature of APS, vasculitic-like manifestations rarely exist in APS and mainly appear associated with other concurrent connective tissue diseases like systemic lupus erythematous. Several studies have characterized pulmonary capillaritis related to pathogenic aPL, suggesting vasculitis as a potential associated non-thrombotic manifestation. Here, we describe a 15-year-old girl who develops hepatic infarction in the presence of highly positive aPL, temporally related to prior non-severe COVID-19 infection. aPL-related hepatic vasculitis, which has not been reported before, contributes to liver ischemic necrosis. Immunosuppression therapy brings about favorable outcomes. Our case together with retrieved literature provides supportive evidence for aPL-related vasculitis, extending the spectrum of vascular changes raised by pathogenic aPL. Differentiation between thrombotic and vasculitic forms of vascular lesions is essential for appropriate therapeutic decision to include additional immunosuppression therapy. We also perform a systematic review to characterize the prevalence and clinical features of new-onset APS and APS relapses after COVID-19 for the first time, indicating the pathogenicity of aPL in a subset of COVID-19 patients.

Morphometric and histopathological evaluation of modified Elnady's plastinated tissue compared to non-plastinated tissue: Highlighting its relevance for teaching and research.

The present study aims to evaluate the morphometric and histopathological properties of Modified Elnady's plastinated tissue after a period compared to non-plastinated tissue. The plastination technique is utilized in research and teaching due to the potential health risks associated with prolonged exposure to formalin. The tissues and organs are permanently dried during plastination and can be used for further anatomical, histopathological and surgical educational purposes. This method involves drying tissue and allowing synthetic materials like glycerin to permeate it. The study compared non-plastinated and plastinated tissue post-plastination to determine if structural alterations differed from those linked to plastination. The study examined the histopathological examination of dogs' skin, muscles, liver, lung, and intestine using formalin-fixed organs for paraffin embedding and previously plastinated organs for a plastinated group. The study examined non-plastinated and plastinated tissues, their histological composition and biometric parameters revealing typical structures in the non-plastinated group. Plasmodiumted tissues exhibited a compacted appearance, volume changes, nuclear clarity, and cytoplasmic hypereosinophilia, with statistical differences between the two groups. The study reveals that plastinated tissues, after 5 years of plastination, maintain their histological architecture well, with some exceptions. Plastinated tissues can be utilized in future microscopic and immunological studies and will be beneficial for teaching and research.

The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis.

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.

Sevoflurane blocks KLF5-mediated transcriptional activation of ITGB2 to inhibit macrophage infiltration in hepatic ischemia/reperfusion injury.

BACKGROUND: Sevoflurane (Sevo) preconditioning and postconditioning play a protective role against injury induced by hepatic ischemia/reperfusion (I/R). At the same time, the involvement of macrophage infiltration in this process and the precise mechanisms are unclear. Here, we designed this research to elucidate the protective effects of Sevo against hepatic I/R injury and the molecules involved. METHODS: The alleviating effect of Sevo on the liver injury was analyzed by liver function analysis, hematoxylin and eosin staining, Masson trichrome staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling, western blot analysis and an enzyme-linked immunosorbent assay. An in vitro cell model was developed using alpha mouse liver 12 (AML12) cells, and the cell model was treated with oxygen-glucose deprivation and reoxygenation and Sevo. Multiple bioinformatics databases were used to screen transcriptional regulators related to hepatic I/R injury and the targets of Krueppel-like factor 5 (KLF5). KLF5 expression was artificially upregulated alone or with integrin beta-2 (ITGB2) knockdown to substantiate their involvement in Sevo-mediated hepatoprotection. RESULTS: Sevo protected the liver against I/R injury by reducing cell apoptosis and inflammatory response. KLF5 was upregulated in liver tissues following I/R injury, whereas KLF5 overexpression aggravated macrophage infiltration and liver injury induced by I/R injury. KLF5 bound to the promoter of ITGB2 to enhance ITGB2 transcription. Knockdown of ITGB2 reversed the aggravation of injury caused by KLF5 overexpression in mice and AML12 cells. CONCLUSIONS: Sevo blocked KLF5-mediated transcriptional activation of ITGB2, thereby inhibiting macrophage infiltration in hepatic I/R injury.

Acoustic Delivery of Plasma Low-Density Lipoprotein into Liver via ApoB100-Targeted Microbubbles Inhibits Atherosclerotic Plaque Growth.

Atherosclerosis is the main risk factor for cardiovascular disease, which accounts for the majority of mortality worldwide. A significantly increased plasma level of low-density lipoprotein cholesterol (LDL-C), surrounded by a monolayer of phospholipids, free cholesterol, and one apolipoprotein B-100 (ApoB-100) in the blood, plays the most significant role in driving the development of atherosclerosis. Commercially available cholesterol-lowering drugs are not sufficient for preventing recurrent cardiovascular events. Developing alternative strategies to decrease the plasma cholesterol levels is desirable. Herein, we develop an approach for reducing LDL-C levels using gas-filled microbubbles (MBs) that were coated with anti-ApoB100 antibodies. These targeted MBApoB100 could selectively capture LDL particles in the bloodstream through forming LDL-MBApoB100 complexes and transport them to the liver for degradation. Further immunofluorescence staining and lipidomic analyses showed that these LDL-MBApoB100 complexes may be taken up by Kupffer cells and delivered to liver cells and bile acids, greatly inhibiting atherosclerotic plaque growth. More importantly, ultrasound irradiation of these LDL-MBApoB100 complexes that accumulated in the liver may induce acoustic cavitation effects, significantly enhancing the delivery of LDL into liver cells and accelerating their degradation. Our study provides a strategy for decreasing LDL-C levels and inhibiting the progression of atherosclerosis.

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. METHODS: Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7 y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. RESULTS: Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. CONCLUSIONS: Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

A case report of IgG4-related hepatic inflammatory pseudotumor in a 3-year old boy.

Background: Hepatic Inflammatory Pseudotumor (IPT) is an infrequent condition often masquerading as a malignant tumor, resulting in misdiagnosis and unnecessary surgical resection. The emerging concept of IgG4-related diseases (IgG4-RD) has gained widespread recognition, encompassing entities like IgG4-related hepatic IPT. Clinically and radiologically, corticosteroids and immunosuppressive therapies have proven effective in managing this condition. Case Presentation: A 3-year-old Chinese boy presented to the clinic with an 11-month history of anemia, fever of unknown origin, and a tender hepatic mass. Blood examinations revealed chronic anemia (Hb: 6.4 g/L, MCV: 68.6 fl, MCH: 19.5 pg, reticulocytes: 1.7%) accompanied by an inflammatory reaction and an elevated serum IgG4 level (1542.2 mg/L). Abdominal contrast-enhanced computed tomography unveiled a 7.6 cm low-density mass in the right lateral lobe, while magnetic resonance imaging demonstrated slight hypointensity on T1-weighted images and slight hyperintensity on T2-weighted images, prompting suspicion of hepatic malignancy. A subsequent liver biopsy revealed a mass characterized by fibrous stroma and dense lymphoplasmacytic infiltration. Immunohistochemical analysis confirmed the presence of IgG4-positive plasma cells, leading to the diagnosis of IgG4-related hepatic IPT. Swift resolution occurred upon initiation of corticosteroid and mycophenolate mofetil therapies. Conclusion: This study underscores the diagnostic approach to hepatic IPT, utilizing histopathology, immunostaining, imaging, serology, organ involvement, and therapeutic response. Early histological examination plays a pivotal role in clinical guidance, averting misdiagnosis as a liver tumor and unnecessary surgical interventions.

Regulatory effect of Yinchenhao decoction on bile acid metabolism to improve the inflammatory microenvironment of hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high mortality. The tumor microenvironment is the "soil" of its occurrence and development, and the inflammatory microenvironment is an important part of the "soil". Bile acid is closely related to the occurrence of HCC. Bile acid metabolism disorder is not only directly involved in the occurrence and development of HCC but also affects the inflammatory microenvironment of HCC. Yinchenhao decoction, a traditional Chinese medicine formula, can regulate bile acid metabolism and may affect the inflammatory microenvironment of HCC. To determine the effect of Yinchenhao decoction on bile acid metabolism in mice with HCC and to explore the possible mechanism by which Yinchenhao decoction improves the inflammatory microenvironment of HCC by regulating bile acid metabolism, we established mice model of orthotopic transplantation of hepatocellular carcinoma. These mice were treated with three doses of Yinchenhao decoction, then liver samples were collected and tested. Yinchenhao decoction can regulate the disorder of bile acid metabolism in liver cancer mice. Besides, it can improve inflammatory reactions, reduce hepatocyte degeneration and necrosis, and even reduce liver weight and the liver index. Taurochenodeoxycholic acid, hyodeoxycholic acid, and taurohyodeoxycholic acid are important molecules in the regulation of the liver inflammatory microenvironment, laying a foundation for the regulation of the liver tumor inflammatory microenvironment based on bile acids. Yinchenhao decoction may improve the inflammatory microenvironment of mice with HCC by ameliorating hepatic bile acid metabolism.

Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.

[Arbutin ameliorates liver fibrosis in mice by inhibiting macrophage recruitment and regulating the Akt/NF-κB and Smad signaling pathways].

OBJECTIVE: To investigate the protective effect of arbutin against CCl4-induced hepatic fibrosis in mice and explore the underlying mechanisms. METHODS: Twenty-four C57BL/6 mice were randomly divided into control group, model group, and low- and high-dose arbutin treatment (25 and 50 mg/kg, respectively) groups. Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4, and arbutin was administered daily via gavage for 6 weeks. After the treatments, serum biochemical parameters of the mice were tested, and liver tissues were taken for HE staining, Sirius Red staining and immunohistochemical staining. RT-qPCR was used to detect the mRNA levels of α-SMA, Pdgfb, Col1α1, Timp-1, Ccl2 and Tnf-a, and Western blotting was performed to detect α-SMA protein expression in the liver tissues. In the cell experiment, the effect of arbutin treatment for 24 h on THP-1 and RAW264.7 cell migration and recruitment was examined using Transwell migration assay and DAPI staining; The changes in protein levels of Akt, p65, Smad3, p-Akt, p-p65, p-Smad3 and α-SMA in arbutintreated LX-2 cells were detected with Western blotting. RESULTS: Arbutin treatment significantly lowered serum alanine aminotransferase and aspartate aminotransferase levels, alleviated liver tissue damage and collagen deposition, and reduced macrophage infiltration and α-SMA protein expression in the liver of the mouse models (P < 0.05 or 0.001). Arbutin treatment also significantly reduced CCl4-induced elevation of a-SMA, Pdgfb, Col1α1, Timp-1, Ccl2 and Tnf-a mRNA levels in mice (P < 0.05). In the cell experiment, arbutin treatment obviously inhibited migration and recruitment of THP-1 and RAW264.7 cells and lowered the phosphorylation levels of Akt, p65 and Smad3 and the protein expression level of α-SMA in LX-2 cells. CONCLUSION: Arbutin ameliorates liver inflammation and fibrosis in mice by inhibiting hepatic stellate cell activation via reducing macrophage recruitment and infiltration and suppressing activation of the Akt/NF-κB and Smad signaling pathways.

Protective role of 17ß-estradiol in alcohol-associated liver fibrosis is mediated by suppression of integrin signaling.

BACKGROUND: Alcohol-associated liver disease is a complex disease regulated by genetic and environmental factors such as diet and sex. The combination of high-fat diet and alcohol consumption has synergistic effects on liver disease progression. Female sex hormones are known to protect females from liver disease induced by high-fat diet. In contrast, they promote alcohol-mediated liver injury. We aimed to define the role of female sex hormones on liver disease induced by a combination of high-fat diet and alcohol. METHODS: Wild-type and protein arginine methyltransferase (Prmt)6 knockout female mice were subjected to gonadectomy (ovariectomy, OVX) or sham surgeries and then fed western diet and alcohol in the drinking water. RESULTS: We found that female sex hormones protected mice from western diet/alcohol-induced weight gain, liver steatosis, injury, and fibrosis. Our data suggest that these changes are, in part, mediated by estrogen-mediated induction of arginine methyltransferase PRMT6. Liver proteome changes induced by OVX strongly correlated with changes induced by Prmt6 knockout. Using Prmt6 knockout mice, we confirmed that OVX-mediated weight gain, steatosis, and injury are PRMT6 dependent, while OVX-induced liver fibrosis is PRMT6 independent. Proteomic and gene expression analyses revealed that estrogen signaling suppressed the expression of several components of the integrin pathway, thus reducing integrin-mediated proinflammatory (Tnf, Il6) and profibrotic (Tgfb1, Col1a1) gene expression independent of PRMT6 levels. Integrin signaling inhibition using Arg-Gly-Asp peptides reduced proinflammatory and profibrotic gene expression in mice, suggesting that integrin suppression by estrogen is protective against fibrosis development. CONCLUSIONS: Taken together, estrogen signaling protects mice from liver disease induced by a combination of alcohol and high-fat diet through upregulation of Prmt6 and suppression of integrin signaling.

A study on assessing the toxic effects of ethyl paraben on rohu (Labeo rohita) using different biomarkers; hemato-biochemical assays, histology, oxidant and antioxidant activity and genotoxicity.

Parabens are being used as preservatives due to their antifungal and antimicrobial effects. They are emerging as aquatic pollutants due to their excessive use in many products. The purpose of this study was to determine the toxic effect of ethyl paraben (C9H10O3) on the hematobiochemical, histological, oxidative, and anti-oxidant enzymatic and non-enzymatic activity; the study also evaluates the potential of ethyl paraben to cause genotoxicity in Rohu Labeo rohita. A number of 15 fish with an average weight of 35.45±1.34g were placed in each group and exposed to ethyl paraben for 21 days. Three different concentrations of ethyl paraben, i.e., T1 (2000µg/L), T2 (4000 µg/L), andT3 (6000 µg/L) on which fish were exposed as compared to the control T0 (0.00 µg/L). Blood was used for hematobiochemical and comet assay. Gills, kidneys, and liver were removed for histological alterations. The results showed a significant rise in all hemato-biochemical parameters such as RBCs, WBCs, PLT count, blood sugar, albumin, globulin, and cholesterol. An increase in aspartate aminotransferase (AST) and alanine transaminase (ALT) levels directed the hepatocytic damage. Histological alterations in the liver, gills and kidneys of fish were found. Ethylparaben induces oxidative stress by suppressing antioxidant enzyme activity such as SOD, GSH, CAT and POD. Based on the comet assay, DNA damage was also observed in blood cells, resulting in genotoxicity. Findings from the present study indicate that ethyl paraben induces hemato-biochemical alterations, tissue damage, oxidative stress, and genotoxicity.

Cannabidiol alleviates carbon tetrachloride-induced liver fibrosis in mice by regulating NF-κB and PPAR-α pathways.

Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death. Cannabidiol (CBD), which is an abundant nonpsychoactive component in the cannabis plant, exerts cytoprotective effects in many diseases and under pathological conditions. In our previous studies, CBD significantly attenuated liver injury induced by chronic and binge alcohol in a mouse model and oxidative bursts in human neutrophils. However, the effects of CBD on liver fibrosis and the underlying mechanisms still need to be further explored. A mouse liver fibrosis model was induced by carbon tetrachloride (CCl4) for 10 weeks and used to explore the protective properties of CBD and related molecular mechanisms. After the injection protocol, serum samples and livers were used for molecular biology, biochemical and pathological analyses. The results showed that CBD could effectively improve liver function and reduce liver damage and liver fibrosis progression in mice; the expression levels of transaminase and fibrotic markers were reduced, and histopathological characteristics were improved. Moreover, CBD inhibited the levels of inflammatory cytokines and reduced the protein expression levels of p-NF-κB, NF-κB, p-IκBα, p-p38 MAPK, and COX-2 but increased the expression level of PPAR-α. We found that CBD-mediated protection involves inhibiting NF-κB and activating PPAR-α. In conclusion, these results suggest that the hepatoprotective effects of CBD may be due to suppressing the inflammatory response in CCl4-induced mice and that the NF-κB and PPAR-α signaling pathways might be involved in this process.