Sepsis - which is a severe life-threatening infection with organ dysfunction - initiates a complex interplay of host pro-inflammatory and anti-inflammatory processes. Sepsis can be considered a race to the death between the pathogens and the host immune system, and it is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses provides a novel approach for treating this highly lethal condition. Biomarker-guided immunotherapy that is administered to patients at the proper immune phase of sepsis is potentially a major advance in the treatment of sepsis and in the field of infectious disease.

/pdf/sepsis-induced-immunosuppression-from-cellular-dysfunctions-425knwqbvv.pdf

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

https://www.naspghan.org/files/documents/pdfs/training/curriculum-resources/biliary-disease/aasld-guidelines/EASL_Cholestatic_Dz.pdf

EASL Clinical Practice Guidelines: management of cholestatic liver diseases

Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.

/pdf/bile-acid-microbiota-crosstalk-in-gastrointestinal-57g75bmlel.pdf

Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.

The current status of superoxide dismutase (SOD) is that it is an enzyme with diverse ramifications. This review attempts an understanding of SOD as a structural, functional, and biological entity. Accordingly, the review is in three parts. The first part discusses SOD in terms of protein structure, proceeding from primary to secondary and three-dimensional structure for the three forms of SOD: copper/zinc SOD, manganese SOD, and iron SOD. This is the order of structural knowledge of the enzyme. Iron SOD is an enzyme of prokaryotes and some higher plants. Manganese SOD is an enzyme of prokaryotes and eukaryotes. Copper/zinc SOD is an enzyme of eukaryotes and certain prokaryotes. The evolutionary relationships of the three forms of SOD, the status of the copper/zinc SOD gene in prokaryotes, and the cloning and sequencing of SOD genes are discussed. The second part of the review deals with the catalytic mechanism of SOD in the three forms of the enzyme. Structural and mechanistic conclusions from various spectroscopic studies are critically considered. A detailed picture is given of the active site of copper/zinc SOD. The third part is a review of SOD in the general context of oxygen toxicity. After consideration of the question of superoxide toxicity and superoxide pathology, several areas in which SOD has been investigated or used as a tool in a biochemical, pharmacological, or clinical context are discussed, including population genetics; trisomy 21; development and senescence; the nutritional copper, zinc, and manganese status; hemolysis and anemia; oxygen toxicity in the lung and nervous system; inflammation, autoimmune disease and chromosome breakage, ischemia and degenerative changes; radiation damage; and malignancy. A comprehensive picture is given of measurements of SOD activity in disease states, and the question of superoxide-related disease is considered at several points.

Aspects of the structure, function, and applications of superoxide dismutase

Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.

From NASH to HCC: current concepts and future challenges.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.21287

Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.

Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section.

Serum serotonin, lactate and pyruvate levels in infantile autistic children.

We investigated natural killer (NK) cell cytotoxicity in healthy preterm and full-term newborns in comparison to adults, to elucidate the possible role of delivery mode in influencing the NK activity and to evaluate the NK activity in severe neonatal pathological conditions such as bacterial sepsis and recurrent infections. NK cell cytotoxicity was investigated using a 4 h 51Cr release assay with K562 cells as targets expressed as percentage kill in the following study groups: full-term normal spontaneous vaginal delivery (n=55), full-term caesarean section (n=51), preterm normal spontaneous vaginal delivery (n=34), preterm caesarean section (n=28), bacterial sepsis (n=15), recurrent neonatal infections (n=8) and healthy adults aged between 22–42 years (n=89). NK activity for the normal newborns was determined in paired cord and 2–4 day-old neonate blood. The NK cell cytotoxicity in healthy newborns was significantly lower than in adults (P < 0.01). Prematurity was associated with a significant decrease in NK cell activity compared to full-term neonates (P < 0.05). The mode of delivery did not influence the NK cytotoxicity. In sepsis and recurrent infections, a dramatic decrease in NK cell cytotoxicity was seen related to healthy newborns (P < 0.01). 
Conclusion Natural killer cell cytotoxicity is deficient in both neonatal sepsis and recurrent infections.

Aranka László

Papers

Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.

Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section.

Serum serotonin, lactate and pyruvate levels in infantile autistic children.

Natural killer cell cytotoxicity is deficient in newborns with sepsis and recurrent infections

A comparative study of superoxide dismutase, catalase and lipid peroxidation in red blood cells from muscular dystrophy patients and normal controls