Dendropanoxide, a Triterpenoid from Dendropanax morbifera, Ameliorates Hepatic Fibrosis by Inhibiting Activation of Hepatic Stellate Cells through Autophagy Inhibition

Hepatic fibrosis results from chronic liver damage and is characterized by excessive accumulation of extracellular matrix (ECM). In this study, we showed that dendropanoxide (DPX), isolated from Dendropanax morbifera, had anti-fibrotic effects on hepatic fibrosis by inhibiting hepatic stellate cell (HSC) activation. DPX suppressed mRNA and protein expression of α-SMA, fibronectin, and collagen in activated HSCs. Moreover, DPX (40 mg/kg) treatment significantly lowered levels of liver injury markers (aspartate aminotransferase and alanine transaminase), expression of fibrotic markers, and deposition of ECM in a carbon tetrachloride-induced mouse model. Anti-fibrotic effects of DPX were comparable to those of silymarin in a hepatic fibrosis mouse model. As a possible mechanism of anti-fibrotic effects, we showed that DPX inhibited autophagosome formation (LC3B-II) and degradation of p62, which have important roles in HSC activation. These findings suggest that DPX inhibits HSC activation by inhibiting autophagy and can be utilized in hepatic fibrosis therapy.

Chemotherapeutic Drug-Regulated Cytokines Might Influence Therapeutic Efficacy in HCC

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the second leading cause of cancer-related mortality worldwide. Processes involved in HCC progression and development, including cell transformation, proliferation, metastasis, and angiogenesis, are inflammation-associated carcinogenic processes because most cases of HCC develop from chronic liver damage and inflammation. Inflammation has been demonstrated to be a crucial factor inducing tumor development in various cancers, including HCC. Cytokines play critical roles in inflammation to accelerate tumor invasion and metastasis by mediating the migration of immune cells into damaged tissues in response to proinflammatory stimuli. Currently, surgical resection followed by chemotherapy is the most common curative therapeutic regimen for HCC. However, after chemotherapy, drug resistance is clearly observed, and cytokine secretion is dysregulated. Various chemotherapeutic agents, including cisplatin, etoposide, and 5-fluorouracil, demonstrate even lower efficacy in HCC than in other cancers. Tumor resistance to chemotherapeutic drugs is the key limitation of curative treatment and is responsible for treatment failure and recurrence, thus limiting the ability to treat patients with advanced HCC. Therefore, the capability to counteract drug resistance would be a major clinical advancement. In this review, we provide an overview of links between chemotherapeutic agents and inflammatory cytokine secretion in HCC. These links might provide insight into overcoming inflammatory reactions and cytokine secretion, ultimately counteracting chemotherapeutic resistance.

Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice

The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.

Anti-Fibrotic and Anti-Angiogenic Activities of Osbeckia octandra Leaf Extracts in Thioacetamide-Induced Experimental Liver Cirrhosis

Chronic liver inflammation has become a major global health concern. In the absence of clinical surrogate markers to diagnose inflammatory liver disease, the intervention with effective drugs in modern medicine tends to be late. In Sri Lanka, traditional medical practitioners prescribe herbal preparations from Osbeckia octandra for the prevention and treatment of liver disorders. To test the efficacy of such treatments, we have administered thioacetamide (TAA) to male Wistar rats to induce chronic liver damage (disease control; DC) and examined how various leaf extracts: crude leaf suspension (CLS), boiled leaf extract (BLE), sonicated leaf extract (SLE), methanol leaf extract (MLE) and hexane leaf extract (HLE) of O. octandra ameliorate TAA-induced liver disease. The CLS, BLE and SLE treatments in cirrhotic rats significantly attenuated disease-related changes, such as liver weight and hepato-enzymes. The mRNA levels of Tnf-α were significantly decreased by 3.6, 10 and 3.9 times in CLS, BLE and SLE compared to DC. The same treatments resulted in significantly lower (19.5, 4.2 and 2.4 times) α-Sma levels compared to DC. In addition, Tgf-β1 and Vegf-R2 mRNA expressions were significantly lower with the treatments. Moreover, BLE expressed a strong anti-angiogenic effect. We conclude that CLS, BLE and SLE from O. octandra have potent hepatic anti-fibrotic effects in TAA-induced liver cirrhosis.

Coronavirus infection in patients with HIV infection, features of the course

Purpose. Analyze and identify the features of the course of the new coronavirus infection (COVID-19) in HIV-infected patients.Materials and methods. An analysis of the course of coronavirus infection (COVID-19) was carried out in 16 patients with HIV infection who were hospitalized at the St. Petersburg State Budgetary Healthcare Institution Center for the Prevention and Control of AIDS and Infectious Diseases from April to October 2020. All patients underwent a study of biological material from the oropharynx and nasopharynx for COVID-19 and diagnosed based on a positive PCR result.Results. In HIV-infected patients with diagnosed coronavirus infection caused by COVID-19, signs of progression of HIV infection, clinical, immunological, virological (75%), opportunistic diseases and comorbidities (chronic viral hepatitis in the cirrhotic decompensated stage, cardiovascular diseases and others) (94%). A small sample of patients did not allow to determine with reliable accuracy the mutual influence of existing diseases and pathologies, but, of course, multiple comorbid pathologies play a role in the development of severe conditions and unfavorable outcomes. A clinical case is presented.Conclusion. The provoking factors have been identified that play a role in the development of infection and more severe forms of coronavirus infection caused by COVID-19 in HIV-infected patients (injecting drug use, alcohol abuse, late stage of HIV infection (4B, 4C) and progression of earlier stages (4A ), a low number of CD4 lymphocytes (less than 200 cells / μl), multiple comorbid pathology (HIV infection, opportunistic diseases, comorbidities, especially chronic liver damage in the stage of decompensated cirrhosis), absence, interrupted antiretroviral therapy, multiple changes of regimens, absence prevention of opportunistic diseases). A patient with HIV infection at ART. 4B with multiple comorbidity, the possibility of long-term persistence of the COVID-19 virus coronavirus with positive and negative results for more than 2 months and later development of lung damage caused by COVID-19 was established.

The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics

Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic liver damage and leading to cirrhosis, liver cancer, and liver failure. To date, there is no effective and specific therapy for patients with hepatic fibrosis. As a result of their various advantages such as biocompatibility, imaging contrast ability, improved tissue penetration, and superparamagnetic properties, magnetic nanoparticles have a great potential for diagnosis and therapy in various liver diseases including fibrosis. In this review, we focus on the molecular mechanisms and important factors for hepatic fibrosis and on potential magnetic nanoparticles-based therapeutics. New strategies for the diagnosis of liver fibrosis are also discussed, with a summary of the challenges and perspectives in the translational application of magnetic nanoparticles from bench to bedside.

Saikosaponin-d protects against liver fibrosis by regulating Estrogen receptor-β/NLRP3 inflammasome pathway

Liver fibrosis is the ultimate common pathway in most types of chronic liver damage characterized by imbalance of extracellular matrix degradation and synthesis. Saikosaponin-d (SSd) possesses anti-inflammatory and anti-liver fibrosis effects. However, the underlying mechanism of SSd in repressing hepatic stellate cells (HSCs) activation remains unclear. Here we found that SSd alleviated remarkably carbon tetrachloride (CCl4)-induced liver fibrosis, as evidenced by decreased collagen level and profibrotic markers (COl1a1 and α-smooth muscle actin (SMA)) expression. SSd repressed CCl4-induced NOD-like receptor family pyrin-domain-containng-3 (NLRP3) activation in fibrotic livers, as suggested by decreased level of NLRP3, IL-18, and IL-β. The primary HSCs of CCl4 mice exhibited a significant increase in profibrotic markers expression and NLRP3 activation, but SSd treatment reversed the effect. SSd also repressed TGF-β-induced profibrotic markers expression and NLRP3 activation in vitro. Mechanistically, TGF-β decreased the expression of Estrogen receptor-β (ERβ) in HSCs, whereas SSd treatment reversed the effect. ERβ inhibition enhanced NLRP3 activation in HSCs. More important, ERβ or NLRP3 inhibition destroyed partially the function of SSd on anti-liver fibrosis. In summary, the current data suggest that SSd prevents hepatic fibrosis through regulating ERβ/NLRP3 inflammasome pathway, and suggest SSd as a potential agent for treating liver fibrosis.

Aqueous Mulberry Leaf Extract Ameliorates Alcoholic Liver Injury Associating with Upregulation of Ethanol Metabolism and Suppression of Hepatic Lipogenesis

Excessive alcohol intake is a major cause of chronic liver damage and is highly associated with the development of a spectrum of hepatic disorders, including steatohepatitis, liver cirrhosis, and liver cancer. Thus, we aimed to explore the hepatoprotective effects of an aqueous mulberry leaf extract (AME) on alcoholic fatty liver disorder (AFLD) by using a mouse model fed with excessive ethanol. Compared with the normal diet, the ethanol diet significantly increased the body weight of the mice, while the AME supplement reduced the weight gain caused by the ethanol diet. The ethanol diet also attenuated the activity of alcohol dehydrogenase and antioxidant enzymes but increased lipid peroxidation in the liver, which were reversed by AME supplementation. Additionally, AME supplementation diminished the ethanol diet-induced hepatic leukocyte infiltration and expressions of IL-6 and TNFα. Moreover, AME supplementation also reduced the ethanol-diet-induced lipid accumulation and expression of 1-acylglycerol-3-phosphate acyltransferase, acetyl-CoA carboxylase, low-density lipoprotein receptor, and sterol regulatory element-binding protein-1/2 in the liver. Collectively, AME supplementation improved liver lipid accumulation and proinflammatory response in mice induced by the ethanol diet, which was associated with the upregulation of ethanol-metabolizing enzymes and the downregulation of lipogenesis components.

How Diet-Induced Changes in the “Gut-Liver” Axis Affect Chronic Liver Disease Outcome?

Hepatocellular carcinoma (HCC) occurs in patients with chronic liver damage, inflammation and cirrhosis. The facilitators involved in increasing the HCC risk in the damaged liver are yet to be discovered. Diet and lifestyle have a profound effect on the liver inflammation and HCC. The term “gut liver axis” describes the bidirectional relationship between the liver and the gut, which are both anatomically and functionally related. Chronic liver damage is characterised by increased intestinal permeability that allows the translocation of various components and metabolites from the gut microbiota to the liver, resulting in liver inflammation and fibrosis. In this review, we discuss how diet-induced changes in gut microbiome composition, such as lipopolysaccharide and lipoteichoic acid, and its metabolites, such as bile acids, play a role in the pathogenesis of liver fibrosis and HCC.

Editorial Expression of Concern: Tumor necrosis factor-inducible gene 6 protein ameliorates chronic liver damage by promoting autophagy formation in mice

An Editorial Expression of Concern to this paper has been published: https://doi.org/10.1038/s12276-021-00554-6