Prevention and Management of Bacterial Infections in Cirrhosis

Patients with cirrhosis of liver are at risk of developing serious bacterial infections due to altered immune defenses. Despite the widespread use of broad spectrum antibiotics, bacterial infection is responsible for up to a quarter of the deaths of patients with liver disease. Cirrhotic patients with gastrointestinal bleed have a considerably higher incidence of bacterial infections particularly spontaneous bacterial peritonitis. High index of suspicion is required to identify infections at an early stage in the absence of classical signs and symptoms. Energetic use of antibacterial treatment and supportive care has decreased the morbidity and mortality over the years; however, use of antibiotics has to be judicious, as their indiscriminate use can lead to antibiotic resistance with potentially disastrous consequences. Preventive strategies are still in evolution and involve use of antibiotic prophylaxis in patients with gastrointestinal bleeding and spontaneous bacterial infections and selective decontamination of the gut and oropharynx

Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for study of the liver

Hepatic encephalopathy (HE) is a major complication that develops in some form and at some stage in a majority of patients with liver cirrhosis. Overt HE occurs in approximately 30-45% of cirrhotic patients. Minimal HE (MHE), the mildest form of HE, is characterized by subtle motor and cognitive deficits and impairs health-related quality of life. The Indian National Association for Study of the Liver (INASL) set up a Working Party on MHE in 2008 with a mandate to develop consensus guidelines on various aspects of MHE relevant to clinical practice. Questions related to the definition of MHE, its prevalence, diagnosis, clinical characteristics, pathogenesis, natural history and treatment were addressed by the members of the Working Party

Viral Proteins Mediate Upregulation of Negative Regulatory Factors Causing Down-Modulated Dendritic Cell Functions In Chronic Hepatitis C Virus Infection

Stunted cellular immune response against a narrow range of epitopes is the hallmark of chronic hepatitis C infection, but the underneath molecular mechanisms have not been well elucidated. Suboptimal antigen presentation through defective antigen presenting cells, have been suggested. The myeloid dendritic cells as professional antigen presenting cells have been found to be phenotypically and functionally defective in chronic hepatitis C-infected patients in our recently published study. In order to find out if the maturation defects in dendritic cells (DC) are induced by the persistence of virus, we tried to differentiate CD14+ monocytes isolated from the peripheral blood of a healthy volunteer in dendritic cell culture medium containing GM-CSF and IL-4 supplemented with hepatitis C virus (HCV) proteins, core and NS5. The results indicated that a lesser number of monocytes differentiated to DC in presence of HCV proteins. Moreover, the differentiated cells depicted immature phenotype, which will not respond to the TLR-4 mediated stimulation ex vivo with significantly lesser upregulation of activation markers, HLA-DR, CD83, CD80 and CD86 as compared to cells differentiated in the absence of HCV proteins. Besides, these immature cells showed characteristics of defective antigen presentation, with significantly lower allostimulatory capacity towards lymphocytes from a healthy donor. Semi-quantitative reverse-transcription polymerase chain reaction (RT- PCR) showed upregulated expression of negative regulatory genes SOCS3, PDL1 and IDO in cells grown in presence of HCV proteins, suggesting the role of HCV and associated antigens in functional down- modulation of dendritic cells. This may correlate with the antigen persistence and maturation-defective status of dendritic cells in chronic HCV infection

miR-23b-3p Modulating Cytoprotective Autophagy and Glutamine Addiction in Sorafenib Resistant HepG2, a Hepatocellular Carcinoma Cell Line

Background: Hepatocellular carcinoma (HCC) is the second most common malignancy with increasing cancer deaths worldwide. HCC is mainly diagnosed at its advanced stage, and treatment with FDA-approved sorafenib, the multikinase inhibitor drug, is advised. Acquired resistance against sorafenib develops through several pathways involving hypoxia, autophagy, high glycolysis, or glutaminolysis. Small non-coding RNAs, similar to microRNAs (miRNAs), are also known to affect sorafenib resistance in HCC. However, there is a lack of information regarding the significance of differentially expressed miRNA (if any) on autophagy and glutamine regulation in sorafenib-resistant HCC. Methods: The expression of autophagy and glutaminolysis genes was checked in both parental and sorafenib resistant HepG2 cell lines by real-time PCR. MTT and Annexin/PI assays were also performed in the presence of inhibitors such as chloroquine (autophagy inhibitor) and BPTES (glutaminolysis inhibitor). Next generation sequencing and in silico analysis were performed to select autophagy and glutamine addiction-specific microRNA. Selected miRNA were transfected into both HepG2 cells to examine its effect on autophagy and glutamine addiction in regulating sorafenib-resistant HCC. Results: Our in vitro study depicted a higher expression of genes encoding autophagy and glutaminolysis in sorafenib-resistant HepG2 cells. Moreover, inhibitors for autophagy (chloroquine) and glutaminolysis (BPTES) showed a diminished level of cell viability and augmentation in cell apoptosis of sorafenib-resistant HepG2 cells. NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results. Conclusion: Our study highlights the cytoprotective role of autophagy and glutamine addiction modulated by miR-23b-3p (tumor suppressor), suggesting new approaches to curb sorafenib resistance in HCC