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1.
Life Sci ; 345: 122565, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38521388

ABSTRACT

Phosphodiesterase 4 (PDE4), crucial in regulating the cyclic adenosine monophosphate (cAMP) signaling pathway, significantly impacts liver pathophysiology. This article highlights the comprehensive effects of PDE4 on liver health and disease, and its potential as a therapeutic agent. PDE4's role in degrading cAMP disrupts intracellular signaling, increasing pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). This contributes to liver inflammation in conditions such as hepatitis and non-alcoholic steatohepatitis (NASH). Additionally, PDE4 is a key factor in liver fibrosis, characterized by excessive extracellular matrix deposition. Inhibiting PDE4 shows promise in reducing liver fibrosis by decreasing the activation of hepatic stellate cells, which is pivotal in fibrogenesis. PDE4 also influences hepatocyte apoptosis a common feature of liver diseases. PDE4 inhibitors protect against hepatocyte apoptosis by raising intracellular cAMP levels, thus activating anti-apoptotic pathways. This suggests potential in targeting PDE4 to prevent hepatocyte loss. Moreover, PDE4 regulates hepatic glucose production and lipid metabolism, essential for liver function. Altering cAMP levels through PDE4 affects enzymes in these metabolic pathways, making PDE4 a target for metabolic disorders like type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Since PDE4 plays a multifaceted role in liver pathophysiology, influencing PDE4's mechanisms in liver diseases could lead to novel therapeutic strategies. Still, extensive research is required to explore the molecular mechanisms and clinical potential of targeting PDE4 in liver pathologies.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4 , Hepatitis , Liver , Non-alcoholic Fatty Liver Disease , Humans , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Diabetes Mellitus, Type 2/metabolism , Hepatitis/metabolism , Hepatitis/pathology , Liver/metabolism , Liver/pathology , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Non-alcoholic Fatty Liver Disease/metabolism
2.
J Pediatr Gastroenterol Nutr ; 78(3): 534-538, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38327256

ABSTRACT

In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplant or had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology.


Subject(s)
Hepatitis , Liver Diseases , Liver Transplantation , Humans , Child , Liver/pathology , Hepatitis/pathology , Liver Diseases/pathology , Biopsy
3.
Int J Surg Pathol ; 32(3): 619-624, 2024 May.
Article in English | MEDLINE | ID: mdl-37461217

ABSTRACT

Garcinia cambogia, a weight control herbal, can cause mild liver toxicity with nonspecific histologic changes. Herein, we reported a case of herbal-induced fulminant cholestatic giant cell hepatitis due to garcinia cambogia use. A 65-year-old woman with breast cancer treated 18 years earlier was admitted for obstructive jaundice for 2 weeks. She started using garcinia cambogia 3 months ago for weight loss. Physical exam showed scleral icterus. Serum studies excluded Wilson's disease, systemic infection including COVID-19 (coronavirus disease 2019), autoimmune hepatitis, and metabolic or toxicologic causes. An urgent liver biopsy showed severe giant cell hepatitis in absence of HSV-1/2, cytomegalovirus, HBsAg and HBcAg (immunostain), and EBV (in situ hybridization). Despite supportive therapy, the patient developed grade 2-3 hepatic encephalopathy and necessitated liver transplant. The explanted liver was markedly atrophy, in which the most striking histologic finding was diffuse distribution of multinucleated giant hepatocytes with syncytial pattern in a background of extensive zone-1 accentuated, geographic, hemorrhagic, confluent hepatocytic necrosis, along with remarkable hepatocytic and canalicular cholestasis. Marked hepatocellular and sinusoidal iron orverload present. The patient recovered uneventfully.


Subject(s)
Hemochromatosis , Hepatitis , Liver Failure, Acute , Female , Humans , Aged , Garcinia cambogia , Hepatitis/complications , Hepatitis/pathology , Hemochromatosis/complications , Liver/pathology , Liver Failure, Acute/chemically induced
4.
Ir J Med Sci ; 193(1): 149-156, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37191870

ABSTRACT

AIM: Brucellosis is a zoonotic infection that can affect almost every organ. A mild elevation of aminotransferase levels is usually observed in liver involvement. However, the development of clinical hepatitis is rare. In this study, we aimed to present the hospitalized cases with brucellosis hepatitis in our clinic in a 13-year period. METHODS: A hundred and three patients with significant hepatobiliary involvement, diagnosed by microbiological analysis, were included in the study. For the presence of hepatitis, it was required that the aminotransferases must be ≥ 5 times more than the upper limit and/or the total bilirubin level must be ≥ 2 mg/dl and/or the local hepatic lesion must be demonstrated. RESULTS: Of the cases, 35.9%, 17.5%, and 46.6% had clinical hepatitis, cholestatic hepatitis, and both clinical and cholestatic hepatitis, respectively. The most frequent symptom was fever (85.4%) while the most preferred treatment options were combinations containing aminoglycosides. It was observed that the mean time-interval to decrease to normal values of ALT, AST, and bilirubin values was 15.2 ± 7.8 days while the patients having their treatment regimens. In our study, which focused on liver involvement, it was found that a chronic liver disease did not develop in any of the cases. CONCLUSION: Our study showed that, even in the presence of hepatitis, clinical response and laboratory improvement were high with appropriate treatment. It was observed that the improvement in aminotransferases and total bilirubin values delayed in the cases with blood culture positivity, secondary organ involvement, and alanine aminotransferase/aspartate aminotransferase > 1.


Subject(s)
Brucellosis , Hepatitis , Humans , Hepatitis/complications , Hepatitis/pathology , Alanine Transaminase , Brucellosis/complications , Brucellosis/drug therapy , Brucellosis/pathology , Aspartate Aminotransferases/therapeutic use , Bilirubin/therapeutic use , Liver/pathology
5.
Int Immunopharmacol ; 126: 111305, 2024 Jan 05.
Article in English | MEDLINE | ID: mdl-38043264

ABSTRACT

BACKGROUND: Severe heat stroke is often complicated by multiple organ failure, including liver injury. Recent evidence indicates that the underlying mechanism constitutes sterile inflammation triggered by cell damage, in which hepatocyte NOD-like receptor family pyrin domain-containing 3 inflammasome activation and pyroptosis play key roles. As extracellular histones act as damage-associated molecular patterns and mediate tissue toxicity and inflammation, we aimed to investigate whether extracellular histones contribute to inducing hepatocyte pyroptosis following heat stroke, promoting the development of liver inflammation and injury, and elucidate the potential underlying mechanisms. METHODS: Exogenous histones were administered to AML-12 murine hepatocytes or male aged 8-12 week mice following hyperthermic treatment (at 39 °C in a chamber with 60 % relative humidity). Prior to heat exposure, endogenous histones were neutralized using neutralizing antibodies, inflammasomes were inhibited by RNA silencing, and Toll-like receptor 9 was modulated using a pharmacological agonist or antagonist. Inflammasome assembly, caspase-1 activation, histological changes, and liver enzyme levels were measured. Statistical comparison of more than two groups was performed using one-way ANOVA with Tukey's post-hoc testing. The correlations were analyzed using Pearson's correlation test. All experiments were repeated thrice. A p-value < 0.05 was considered significant. RESULTS: Heat stroke induced histone release into the extracellular space at levels correlating with liver injury. Moreover, extracellular histones augmented heat stroke-induced liver injury both in vitro and in vivo in a dose- and time-dependent manner, whereas neutralizing histones conferred protection following heat stroke. Histones mediated NOD-like receptor family pyrin domain-containing 3 inflammasome activation through the Toll-like receptor 9 signaling pathway, which resulted in hepatocyte pyroptosis and liver inflammation. CONCLUSIONS: Our findings show that histones are critical mediators of hepatocyte pyroptosis that aggravate liver injury in a heat stroke setting. Therefore, we suggest extracellular histones as potential therapeutic targets to limit heat stroke-induced cell death and liver injury.


Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Heat Stroke , Hepatitis , Male , Mice , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Histones/metabolism , Inflammasomes/metabolism , Pyroptosis , Toll-Like Receptor 9/metabolism , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Hepatocytes/metabolism , Inflammation , Hepatitis/pathology , Heat Stroke/complications , Heat Stroke/pathology
6.
Pediatr Dev Pathol ; 27(1): 13-22, 2024.
Article in English | MEDLINE | ID: mdl-37801635

ABSTRACT

Liver histology in infants with cystic fibrosis (CF) and persistent cholestasis is seldom reported in detail. We extend previous observation of a distinctive intrahepatic cholangiopathy (ICCF) to 3 additional infants homozygous for CFTR pathological variants and a fourth infant with a heterozygous CFTR variant, summarizing our experience in 10 infants with CFTR variants and persistent cholestasis. Cholangiograms demonstrate abnormal extrahepatic ducts in 2 infants with CF, 1 with uniform dilatation interpreted as a choledochal cyst and the other with narrow patent ducts. Liver histology in 3 CF homozygotes had prominent ductular reaction with a focally destructive cholangiolitis (inflammation of small bile ducts). The CFTR heterozygote had generalized portal edema with ductular reaction and paucity but no cholangitis. Cholestasis slowly subsided in all infants. ICCF is characterized by severe ductular reaction, prominent cholangiocyte injury, and multifocal necrotizing cholangiolitis. Local aggregates of portal ceroid might suggest previous bile leakage from damaged ducts. ICCF in liver biopsies from infants with cystic fibrosis and persistent cholestasis is unrelated to the specific CFTR genotype. Liver biopsy findings and intraoperative cholangiogram help rule out biliary atresia. ICCF is an early manifestation of CF, a likely prototype for pathogenesis of cystic fibrosis liver disease later in life.


Subject(s)
Biliary Atresia , Cholestasis, Intrahepatic , Cholestasis , Cystic Fibrosis , Hepatitis , Infant , Humans , Cystic Fibrosis/complications , Cystic Fibrosis/genetics , Cystic Fibrosis/pathology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cholestasis/diagnosis , Cholestasis/etiology , Liver/pathology , Biliary Atresia/pathology , Hepatitis/pathology , Cholestasis, Intrahepatic/pathology
7.
Histopathology ; 84(5): 765-775, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38114289

ABSTRACT

AIMS: Ocrelizumab is a humanized anti-CD20-monoclonal antibody that has recently been approved for the treatment of certain types of multiple sclerosis. Isolated case reports of ocrelizumab-associated colitis have been reported in the literature. We present a case series of ocrelizumab-associated intestinal injury with a focus on histopathologic features and report a case of ocrelizumab-associated hepatitis. METHODS AND RESULTS: A retrospective computerized search was conducted from 03/2017 to 08/2022, which identified six patients with suspected or clinically confirmed ocrelizumab-associated intestinal injury and one patient with hepatic injury. Pertinent clinical, endoscopic, and histopathologic findings were reviewed and recorded. Seven patients (six female, one male) were identified with ages ranging from 24 to 68 years. The presenting symptoms included diarrhoea (n = 5), abdominal pain (n = 3), hematochezia (n = 2), and vomiting (n = 1), nausea (n = 1) fever (n = 1), and weight loss (n = 1). Endoscopic findings ranged from normal (n = 1) to patchy colonic inflammation with or without ulceration (n = 4) and decreased mucosal vascular pattern in the rectum (n = 1). Crohn's disease was clinically suspected in two patients and ulcerative colitis in one patient. None of the patients had a prior confirmed diagnosis of inflammatory bowel disease. Histologic patterns of initial colonic injury included acute colitis/proctitis (n = 5), and chronic active colitis (n = 1). Follow-up ranged from 1 to 3 years and 10 months. All patients were alive at follow-up. Follow-up biopsies were available for four patients and findings included focal acute colitis (n = 1), apoptotic colopathy (n = 1) lymphocytic colitis (n = 1), and normal mucosa (n = 1). Four patients were treated with steroids and ocrelizumab was discontinued in three patients. Two patients were symptomatically managed with subsequent resolution of symptoms. The liver biopsy from the patient with a marked hepatic pattern of liver enzyme elevation showed an acute hepatitis pattern of injury with prominent centrilobular necrosis, which resolved upon discontinuation of the drug and treatment with steroids and azathioprine. CONCLUSIONS: The histologic manifestations of ocrelizumab-associated intestinal injury are variable and can mimic inflammatory bowel disease. Hepatic injury can rarely manifest as an acute hepatitis pattern of injury with necrosis. Identifying ocrelizumab-associated injury is paramount in determining management, which often includes discontinuation of ocrelizumab therapy, and/or administration of immunosuppressive therapy.


Subject(s)
Antibodies, Monoclonal, Humanized , Colitis , Hepatitis , Inflammatory Bowel Diseases , Multiple Sclerosis , Female , Humans , Male , Colitis/chemically induced , Colitis/complications , Hepatitis/pathology , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/pathology , Multiple Sclerosis/complications , Multiple Sclerosis/pathology , Necrosis/pathology , Retrospective Studies , Steroids , Young Adult , Adult , Middle Aged , Aged
8.
Exp Mol Med ; 55(11): 2332-2345, 2023 11.
Article in English | MEDLINE | ID: mdl-37907736

ABSTRACT

Lactobacillus is a probiotic with therapeutic potential for several diseases, including liver disease. However, the therapeutic effect of L. plantarum against nonalcoholic steatohepatitis (NASH) and its underlying mechanisms remain unelucidated. Therefore, we delineated the L. plantarum-mediated NASH regulation in a mouse model to understand its therapeutic effect. We used a choline-deficient high-fat diet (CD-HFD)-induced murine model that recapitulated the critical features of human metabolic syndrome and investigated the effect of L. plantarum on NASH pathogenesis using transcriptomic, metagenomic, and immunohistochemistry analyses. Validation experiments were performed using liver organoids and a murine model fed a methionine-choline-deficient (MCD) diet. L. plantarum treatment in mice significantly decreased liver inflammation and improved metabolic phenotypes, such as insulin tolerance and the hepatic lipid content, compared with those in the vehicle group. RNA-sequencing analysis revealed that L. plantarum treatment significantly downregulated inflammation-related pathways. Shotgun metagenomic analysis revealed that L-arginine biosynthesis-related microbial genes were significantly upregulated in the L. plantarum group. We also confirmed the elevated arginine levels in the serum of the L. plantarum group. We further used liver organoids and mice fed an MCD diet to demonstrate that L-arginine alone was sufficient to alleviate liver inflammation. Our data revealed a novel and counterintuitive therapeutic effect of L. plantarum on alleviating NASH-related liver inflammation by increasing circulating L-arginine.


Subject(s)
Hepatitis , Lactobacillus plantarum , Non-alcoholic Fatty Liver Disease , Mice , Humans , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/etiology , Lactobacillus plantarum/metabolism , Disease Models, Animal , Liver/metabolism , Inflammation/metabolism , Hepatitis/pathology , Methionine , Choline/metabolism , Diet, High-Fat/adverse effects , Mice, Inbred C57BL
9.
PLoS One ; 18(11): e0294257, 2023.
Article in English | MEDLINE | ID: mdl-38033027

ABSTRACT

INTRODUCTION: Hepatic fibrosis is a progressive pathological process involving the exhaustion of hepatocellular regenerative capacity and ultimately leading to the development of cirrhosis and even hepatocellular carcinoma. Brg1, the core subunit of the SWI/SNF chromatin-remodeling complex, was recently identified as important for liver regeneration. This study investigates the role of Brg1 in hepatic fibrosis development. METHODS: Hepatocyte-specific Brg1 knockout mice were generated and injected with carbon tetrachloride (CCl4) for 4, 6, 8, and 12 weeks to induce liver fibrosis. Afterwards, liver fibrosis and liver damage were assessed. RESULTS: Brg1 expression was significantly increased in the fibrotic liver tissue of wild-type mice, as compared to that of untreated wild-type mice. The livers of the Brg1 knockout animals showed reduced liver inflammation, extracellular matrix accumulation, and liver fibrosis. TNF-α and NF-κB-mediated inflammatory response was reduced in Brg1 knockout animals. CONCLUSION: Brg1 promotes the progression of liver fibrosis in mice and may therefore be used as a potential therapeutic target for treating patients with liver fibrosis due to chronic injury.


Subject(s)
Carcinoma, Hepatocellular , Hepatitis , Liver Neoplasms , Animals , Mice , Carbon Tetrachloride/toxicity , Carcinoma, Hepatocellular/pathology , Extracellular Matrix/metabolism , Fibrosis , Hepatitis/pathology , Inflammation/pathology , Liver/metabolism , Liver Cirrhosis/chemically induced , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Neoplasms/pathology , Mice, Knockout
10.
Int Immunopharmacol ; 124(Pt B): 111036, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37832236

ABSTRACT

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is characterized by hepatocyte destruction, leading to lymphocyte and macrophage accumulation in the liver. However, the specific mechanisms of how macrophages participate in the occurrence and development of AIH are still unclear. In this study, we investigated the effect of monocyte-derived macrophages on Con A-induced immunological liver injury in mice and we hypothesized that inhibition of CCR2 with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate Con A-induced hepatitis in mice by reducing the recruitment of monocytes into the liver. METHODS: Murine experimental AIH was established by concanavalin A (Con A) injection intravenously. Macrophages were depleted by injection of clodronate liposomes in Con A-treated mice. Moreover, inhibition of the CCR2/5 signaling pathway in Con A mice is achieved by CVC. Liver injury and infiltration of monocyte-derived macrophages were assessed by serum transaminase levels, histopathology, immunohistochemistry, flow cytometry, RT-qPCR, ELISA, TUNEL assay and dihydroethidium staining. RESULTS: The number of macrophages in the mouse livers increased in the Con A-induced hepatitis mouse model, and flow cytometry showed a significant increase in the proportion of F4/80loCD11bhi monocyte-derived macrophages, while there was no significant change in the proportion of F4/80hiCD11blo Kupffer cells. After the depletion of liver macrophages by clodronate liposomes, the levels of serum ALT and AST, and the degree of liver tissue damage were alleviated in Con A-treated mice. Furthermore, Con A leaded an increase in the expression of a group of CC chemokines in mouse livers, and the elevation of CCL2 was prevented with the depletion of macrophages. Additionally, CVC reduced macrophage infiltration in the liver and ameliorated Con A-induced liver injury. Meanwhile, CVC reduced the apoptosis and oxidative damage of hepatocytes caused by Con A. CONCLUSIONS: Our research demonstrates that there is an increase in monocyte-derived macrophages in the livers due to the monocyte infiltration resulted from the activation of the CCL2-CCR2 axis in Con A-induced liver injury mouse model. Pharmacological inhibition of CCR2 monocyte recruitment by CVC efficiently ameliorates the hepatic inflammation, indicating the therapeutic potential of CVC in patients with AIH.


Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Hepatitis , Humans , Animals , Mice , Clodronic Acid/pharmacology , Clodronic Acid/therapeutic use , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Liposomes/metabolism , Liver/pathology , Macrophages , Monocytes/metabolism , Hepatitis/pathology , Mice, Inbred C57BL
11.
Mod Pathol ; 36(11): 100298, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37544363

ABSTRACT

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.


Subject(s)
Alkaline Phosphatase , Hepatitis , Adult , Humans , Middle Aged , Retrospective Studies , Liver/pathology , Hepatitis/etiology , Hepatitis/pathology , Fibrosis , Allografts/pathology
12.
Int J Mol Sci ; 24(14)2023 Jul 24.
Article in English | MEDLINE | ID: mdl-37511628

ABSTRACT

Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.


Subject(s)
Hepatitis , Liver Neoplasms , Humans , Liver/pathology , Hepatocytes , Hepatitis/pathology , Hepatic Stellate Cells , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Tumor Microenvironment
13.
Front Cell Infect Microbiol ; 13: 1140126, 2023.
Article in English | MEDLINE | ID: mdl-36968098

ABSTRACT

The liver is a vital metabolism and detoxification organ of human body, which is involved in the biotransformation and metabolism of the organism. Hepatitis - cirrhosis - liver cancer are significant and common part of liver diseases. The pathogenesis of liver diseases is generally as followed: inflammation and other pathogenic factors cause persistent damage to the liver, leading to the activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix. Patients with chronic hepatitis have a high risk of developing into liver fibrosis, cirrhosis, and even life-threatening liver cancer, which poses a great threat to public health.As the first organ to come into contact with blood from the gut, the liver is profoundly affected by the intestinal flora and its metabolites, with leaky gut and flora imbalance being the triggers of the liver's pathological response. So far, no one has reviewed the role of intestinal flora in this process from the perspective of the progression of hepatitis-cirrhosis-liver cancer and this article reviews the evidence supporting the effect of intestinal flora in the progression of liver disease.


Subject(s)
Gastrointestinal Microbiome , Hepatitis , Liver Neoplasms , Humans , Gastrointestinal Microbiome/physiology , Liver Cirrhosis/pathology , Liver/pathology , Hepatitis/pathology , Fibrosis , Liver Neoplasms/etiology , Liver Neoplasms/pathology
14.
Nat Commun ; 14(1): 1062, 2023 02 24.
Article in English | MEDLINE | ID: mdl-36828835

ABSTRACT

To date, a biopsy is mandatory to evaluate parenchymal inflammation in the liver. Here, we evaluated whether molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) could be used as an alternative non-invasive tool to detect liver inflammation in the setting of chronic liver disease. To do so, we radiolabeled anti-VCAM-1 nanobody (99mTc-cAbVCAM1-5) and used single-photon emission computed tomography (SPECT) to quantify liver uptake in preclinical models of non-alcoholic fatty liver disease (NAFLD) with various degree of liver inflammation: wild-type mice fed a normal or high-fat diet (HFD), FOZ fed a HFD and C57BL6/J fed a choline-deficient or -supplemented HFD. 99mTc-cAbVCAM1-5 uptake strongly correlates with liver histological inflammatory score and with molecular inflammatory markers. The diagnostic power to detect any degree of liver inflammation is excellent (AUROC 0.85-0.99). These data build the rationale to investigate 99mTc-cAbVCAM1-5 imaging to detect liver inflammation in patients with NAFLD, a largely unmet medical need.


Subject(s)
Hepatitis , Non-alcoholic Fatty Liver Disease , Mice , Animals , Non-alcoholic Fatty Liver Disease/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Liver/metabolism , Hepatitis/pathology , Inflammation/pathology , Molecular Imaging/methods , Diet, High-Fat , Mice, Inbred C57BL
15.
Mol Biol Rep ; 50(2): 1477-1485, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36507969

ABSTRACT

BACKGROUND: The Janus kinase (JAK) is a crucial intracellular signaling hub for numerous cytokines, which is extensively involved in the activation of inflammatory cascade and the induction of inflammatory injury. JAK inhibition provides protective effects in several inflammation-based disorders, but the potential effects of JAK inhibitor in inflammation-based acute hepatitis remain to be investigated. METHODS AND RESULTS: Acute hepatitis is induced by Lipopolysaccharide/D-galactosamine (LPS/D-Gal) in mice with or without the JAK inhibitor Tofacitinib administration. The degree of liver injury, the production of pro-inflammatory cytokines and induction of hepatocytes apoptosis were determined. The results indicated that treatment with Tofacitinib decreased the levels of aminotransferases, attenuated the histological abnormalities in liver and decreased the plasma levels of TNF-α and IL-6 in LPS/D-Gal-insulted mice. In addition, Tofacitinib suppressed the activation of the caspase cascade, decreased the level of cleaved caspase-3, and reduced the count of TUNEL-positive cells. CONCLUSION: Treatment with Tofacitinib alleviated LPS/D-Gal-induced acute hepatitis. JAK maybe become a promising target for the control of inflammation-based liver disorders.


Subject(s)
Chemical and Drug Induced Liver Injury , Hepatitis , Janus Kinase Inhibitors , Mice , Animals , Janus Kinase Inhibitors/pharmacology , Lipopolysaccharides/toxicity , Galactosamine/pharmacology , Hepatitis/pathology , Liver , Inflammation/pathology , Apoptosis , Cytokines , Tumor Necrosis Factor-alpha/pharmacology , Janus Kinases , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/pathology
16.
Cell Mol Gastroenterol Hepatol ; 15(5): 1117-1133, 2023.
Article in English | MEDLINE | ID: mdl-36581078

ABSTRACT

BACKGROUND & AIMS: Liver macrophage-mediated inflammation contributes to the pathogenesis of the nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Odd skipped-related 1 (Osr1) is a putative transcription factor previously reported to be involved in NASH progression; however, the underlying mechanisms remain unknown. The current study focused on the role of Osr1 in macrophage polarization and metabolism and its associated functions in the inflammation-induced pathogenesis of NASH. METHODS: OSR1/Osr1 expression patterns were compared in normal and NASH patients and mouse livers. NASH was established and compared between hepatocyte-specific Osr1 knockout (Osr1ΔHep), macrophage-specific Osr1 knockout (Osr1ΔMφ), and wild-type (Osr1F) mice fed with 3 different chronic obesogenic diets and methionine choline-deficient diet. Using genetic and therapeutic strategies in vitro and in vivo, the downstream targets of Osr1 and the associated mechanisms in inflammation-induced NASH were established. RESULTS: Osr1 was expressed in both hepatocytes and macrophages and exhibited different expression patterns in NASH. In NAFLD and NASH murine models, deleting Osr1 in myeloid cells (Osr1ΔMφ), but not hepatocytes, aggravated steatohepatitis with pronounced liver inflammation. Myeloid Osr1 deletion resulted in a polarization switch toward a pro-inflammatory phenotype associated with reduced oxidative phosphorylation activity. These inflamed Osr1ΔMφ macrophages promoted steatosis and inflammation in hepatocytes via cytokine secretion. We identified 2 downstream transcriptional targets of Osr1, c-Myc, and PPARγ and established the Osr1-PPARγ cascade in macrophage polarization and liver inflammation by genetic study and rosiglitazone treatment in vivo. We tested a promising intervention strategy targeting Osr1-PPARγ by AAV8L-delivered Osr1 expression or rosiglitazone that significantly repressed NAFLD/NASH progression in Osr1F and Osr1ΔMφ mice. CONCLUSIONS: Myeloid Osr1 mediates liver immune homeostasis and disrupting Osr1 aggravates the progression of NAFLD/NASH.


Subject(s)
Hepatitis , Non-alcoholic Fatty Liver Disease , Animals , Mice , Hepatitis/pathology , Inflammation/pathology , Macrophages/metabolism , Non-alcoholic Fatty Liver Disease/pathology , PPAR gamma/metabolism , Rosiglitazone
17.
Exp Biol Med (Maywood) ; 248(2): 117-129, 2023 01.
Article in English | MEDLINE | ID: mdl-36426712

ABSTRACT

Immune-mediated hepatitis is marked by liver inflammation characterized by immune cell infiltration, chemokine/cytokine production, and hepatocyte injury. C-X3C motif receptor 1 (CX3CR1), as the receptor of chemokine C-X3C motif ligand 1 (CX3CL1)/fractalkine, is mainly expressed on immune cells including monocytes and T cells. Previous studies have shown that CX3CR1 protects against liver fibrosis, but the exact role of CX3CL1/CX3CR1 in acute immune-mediated hepatitis remains unknown. Here, we investigate the role of the CX3CL1/CX3CR1 axis in immune-mediated hepatitis using concanavalin A (ConA)-induced liver injury model in CX3CR1-deficient (Cx3cr1-/-) mice. We observed that Cx3cr1-/- mice had severe liver injury and increased pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interferon-gamma [IFN-γ], interleukin-1 beta [IL-1ß], and IL-6) in serum and liver compared to wild-type (Cx3cr1+/+) mice after ConA injection. The deficiency of CX3CR1 did not affect ConA-induced immune cell infiltration in liver but led to elevated production of TNF-α in macrophages as well as IFN-γ in T cells after ConA treatment. On the contrary, exogenous CX3CL1 attenuated ConA-induced cytokine production in wild type, but not CX3CR1-deficient macrophages and T cells. Furthermore, in vitro results showed that CX3CR1 deficiency promoted the pro-inflammatory cytokine expression by increasing the phosphorylation of nuclear factor kappa B (NF-κB) p65 (p-NF-κB p65). Finally, pre-treatment of p-NF-κB p65 inhibitor, resveratrol, attenuated ConA-induced liver injury and inflammatory responses, especially in Cx3cr1-/- mice. In conclusion, our data show that the deficiency of CX3CR1 promotes pro-inflammatory cytokine production in macrophages and T cells by enhancing the phosphorylation of NF-κB p65, which exacerbates liver injury in ConA-induced hepatitis.


Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Hepatitis , Mice , Animals , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha/metabolism , T-Lymphocytes/metabolism , Cytokines/metabolism , Hepatitis/pathology , Macrophages/metabolism , Interferon-gamma/metabolism , Mice, Inbred C57BL , CX3C Chemokine Receptor 1
18.
Front Immunol ; 13: 1049518, 2022.
Article in English | MEDLINE | ID: mdl-36569905

ABSTRACT

Background: Human epidermal growth factor receptor 2 (HER2) is the most prominent therapeutic target for advanced gastric (G)/GEJ cancer. However, targeted therapy did not significantly improve survival. Currently, there are no regimens for the treatment of HER-2 amplification that exclude targeted agents. Case presentation: A 42-year-old man was diagnosed with adenocarcinoma of GEJ (stage IV) with liver metastasis and lung metastasis. The patient was enrolled in a trial that excluded patients with known HER2-positivity: AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (mXELOX) as first-line therapy for advanced gastric G/GEJ cancer (NCT03852251). After six cycles of AK104 combined with chemotherapy therapy, immune-related pulmonary toxicity was observed. We rechallenged AK104 after hormone therapy, and no further pulmonary toxicity was observed. Immune-related hepatitis occurred in the patient during immunotherapy combined with single-drug capecitabine therapy. After combining steroid therapy with mycophenolate mofetil, the patient's immune hepatitis improved. Nevertheless, the patient was excluded from the clinical study due to the long-term absence of medication. Antitumor therapy was also discontinued in view of the patient's adverse immune response. The patient did not receive subsequent immune antitumor therapy, and immune-related hepatitis still occurred intermittently, but the disease evaluation was maintained at PR. A complete response was confirmed by PET/CT and the biopsy specimen from gastroscopy on 2020-06-10. Next generation sequencing of biopsy tissue was used to guide subsequent therapy at a recent follow-up visit. The results indicated that ERBB2 mutations occurred at copy number 58.4934 (HER-2), TMB = 3.1, MSS. IHC: EBV (-), PD-L1 CPS = 3, HER-2 (3+). Conclusion: Patients with HER-2-positive advanced GEJ cancer received PD-1/CTLA-4 bispecific immunotherapy combined with chemotherapy and achieved complete remission. It offers a novel, highly specific, and highly potent therapeutic option for HER-2-positive patients. Its use should be considered as a new treatment when trastuzumab is not viable. Currently, we are working to overcome this resistance.


Subject(s)
Esophageal Neoplasms , Hepatitis , Stomach Neoplasms , Humans , Male , Adult , Programmed Cell Death 1 Receptor , CTLA-4 Antigen , Positron Emission Tomography Computed Tomography , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Hepatitis/pathology
19.
Egypt J Immunol ; 29(4): 12-24, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36197150

ABSTRACT

Spontaneous bacterial peritonitis (SBP) is most common infection in patients with liver cirrhosis with ascites. SBP is diagnosed by the presence of ≥250 polymorphonuclear leukocyte (PMNL)/mm3 in the ascetic fluid with absence of surgical and treatable causes of intra-abdominal infection. This study intended to evaluate platelet indices and neutrophil to lymphocyte ratio (NLR) as predictors marker of SBP. This study included 106 patients: 53 cirrhotic with SBP, 53 cirrhotic without SBP and 53 sex and age matched normal non cirrhotic controls. The mean platelet volume (MPV), platelet distribution width (PDW), platelet crit (PCT), NLR and C reactive protein (CRP) were compared between study groups. Patients with SBP had significantly higher MPV, PDW, PCT NLR and platelet-lymphocyte ratio (PLR) than patients without SBP (P< 0.001 for all). Patients with SBP had significantly higher MPV, PDW, PCT NLR and PLR than the control group (P< 0.001). MPV, PDW, PCT, PLR, and NLR had positive significant correlations with CRP and ascetic fluid PMNL (P< 0.001). In conclusion, our study findings indicated that platelet indices in cirrhotic patients may be novel, simple, low-cost, non-invasive, and valuable diagnostic marker for diagnosis of SBP. They could be considered reliable and surrogate marker for PMNL.


Subject(s)
Hepatitis , Peritonitis , Biomarkers , Blood Platelets , C-Reactive Protein/analysis , Hepatitis/metabolism , Hepatitis/pathology , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Lymphocytes/metabolism , Neutrophils/metabolism , Peritonitis/complications , Peritonitis/diagnosis , Retrospective Studies
20.
Semin Liver Dis ; 42(4): 475-488, 2022 11.
Article in English | MEDLINE | ID: mdl-36208620

ABSTRACT

The excessive accumulation of extracellular matrix proteins results in fibrosis-a condition implicated in several diseased conditions, such as nonalcoholic steatohepatitis, viral hepatitis, and autoimmune hepatitis. Despite its prevalence, direct and effective treatments for fibrosis are lacking, warranting the development of better therapeutic strategies. Accumulating evidence has shown that liver fibrosis-a condition previously considered irreversible-is reversible in specific conditions. Immune cells residing in or infiltrating the liver (e.g., macrophages) are crucial in the pathogenesis of fibrosis. Given this background, the roles and action mechanisms of various immune cells and their subsets in the progression and recovery of liver fibrosis, particularly concerning nonalcoholic steatohepatitis, are discussed in this review. Furthermore, the development of better therapeutic strategies based on stage-specific properties and using advanced techniques as well as the mechanisms underlying recovery are elaborated. In conclusion, we consider the review comprehensively provides the present achievements and future possibilities revolving around fibrosis treatment.


Subject(s)
Hepatitis , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/metabolism , Liver Cirrhosis/pathology , Liver/metabolism , Hepatitis/pathology , Fibrosis
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