Galectin-3 and IL-33/ST2 axis roles and interplay in dietinduced steatohepatitis

Immune reactivity and chronic low-grade inflammation(metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease(NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis(NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3(Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin(IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R(ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis.

Metabolic syndrome attenuates ulcerative colitis: Correlation with interleukin-10 and galectin-3 expression

BACKGROUND Ulcerative colitis(UC)is a chronic disease characterized by inflammation of intestinal epithelium,primarily of the colon.An increasing prevalence of metabolic syndrome(MetS)in patients with UC has been documented recently.Still,there is no evidence that MetS alters the course of the UC.AIM To test the influence of the MetS on the severity of UC and the local and systemic immune status.METHODS Eighty nine patients with de novo histologically confirmed UC were divided in two groups,according to ATP III criteria:Group without MetS(no MetS)and group with MetS.RESULTS Clinically and histologically milder disease with higher serum level of immunosuppressive cytokine interleukin-10(IL-10)and fecal content of Galectin-3(Gal-3)was observed in subjects with UC and MetS,compared to subjects suffering from UC only.This was accompanied with predomination of IL-10 over pro-inflammatory cytokines tumor necrosis factorα(TNF-α),interleukin-6(IL-6),and interleukin-17(IL-17)in the sera as well as Gal-3 over TNF-αand IL-17 in feces of UC patients with MetS.Further,the patients with both conditions(UC and MetS)had higher percentage of IL-10 producing and Gal-3 expressing innate and acquired immune cells in lamina propria.CONCLUSION Local dominance of Gal-3 and IL-10 over pro-inflammatory mediators in patients with MetS may present a mechanism for limiting the inflammatory process and subsequent tissue damage in UC.

Nitric oxide and tumour necrosis factor alpha in the process of pseudoexfoliation glaucoma

AIMTo establish the role of nitric oxide (NO), ascorbic acid and tumour necrosis factor-α (TNF-α) in the pathogenesis of pseudoexfoliation glaucoma (XFG).METHODSOur study included 120 patients who were referred for cataract surgery. All patients were divided into four groups according to clinical findings: XFG, early and late pseudoexfoliation syndrome (XFS), and cataract (without pseudoexfoliation). Serum and aqueous humour levels of the ascorbic acid, NO and TNF-α were measured. The concentrations of the ascorbic acid and NO were measured by an appropriate spectrophotometric method. Enzyme-linked immunosorbent assay (ELISA) was used to determine TNF-α level.RESULTSAqueous humour concentration of ascorbic acid was significantly lower in patients with late XFS (0.61±0.11 mmol/L) and XFG (0.48±0.15 mmol/L) compared to patients with early XFS (0.9±0.15 mmol/L) and cataract (1.16±0.22 mmol/L), while there was no difference in serum concentration in all examined groups. Aqueous humour concentration of NO was significantly higher in patients with XFG (77.7±11.4 µmol/L) compared to patients with early XFS (50.27±9.34 µmol/L) and cataract (49.77±7.1 µmol/L), while serum concentration was increased in the early stage of XFS (73.26±8.29 µmol/L). Aqueous humour level of proinflammatory cytokine TNF-α was increased in patients with XFS (early 460.04±18.32 pg/mL; late 502.42±53.23 pg/mL) and XFG (510.34±43.07 pg/mL), while there was no difference in serum level in all examined groups of patients.CONCLUSIONReduced ascorbic acid and elevated NO and inflammation related cytokine TNF-α level in aqueous humour of the patients with developed XFG suggest that oxidative stress induces local inflammation.

Galectin-3 mediated risk of inflammation in stable schizophrenia,with only possible secondary consequences for cognition

BACKGROUND Evidence suggests that cytokines cause immune disturbances,shape immunological sequelae later in life,and modulate the risk of schizophrenia(SC).Galectin-3(Gal-3),a multifaceted molecule of the glycan family,is involved in the formation of the immunological synapse and modulates the signalling pathway and effector functions of T lymphocytes,which are major producers of cytokines.We have previously reported elevated serum Gal-3 levels in stable SC patients.However,Gal-3 as a link between cognitive functioning and inflammation has not yet been investigated in SC.AIM To investigate the relationship between serum Gal-3 levels and cognitive performance,serum cytokines,and white blood cell count in three-month stably treated SC patients.METHODS Twenty-seven patients with SC in remission and 18 healthy volunteers participated in this casecontrol and correlational study.Clinical assessment was performed using the Positive and Negative Syndrome Scale and the Montreal-Cognitive Assessment.The results of previously measured serum levels of Gal-3,interleukin(IL)-33,soluble suppression of tumorigenicity 2(sST2),tumor necrosis factor-alpha(TNF-α),IL-6 and IL-17 were used for further statistical analyses,and IL-4,IL-23,IL-1βand transforming growth factor-beta(TGF-β)were now additionally measured with a sensitive enzyme-linked immunosorbent assay.The number of leukocytes in the blood and the percentage of neutrophils,lymphocytes,and monocytes were determined with a standardized routine measurement procedure(Sysmex Technology).Statistical analyses were performed using SPSS 20.0 software.RESULTS We found no correlation between serum Gal-3 levels and cognitive functioning in SC patients.A positive correlation was found between the levels of Gal-3 and TNF-α(r=0.476;P=0.012),Gal-3and IL-23(r=0.417;P=0.031),and Gal-3 and sST2(r=0.402;P=0.038).The binary logistic model,which included all nine cytokines measured in this patient sample,indicated the particular role of Gal-3 and TGF-βin the duration of SC.In the stabilization phase of SC,we observed a moderate and negative correlation between serum Gal-3 levels and leukocytes(r=-0.449;P<0.019).Additional linear regression analysis showed a positive correlation between Gal-3 expression and risperidone dose(F:4.467;P<0.045;r^(2)=0.396).CONCLUSION The combined activity of Gal-3 and proinflammatory cytokines,TGF-βdownregulation and lower counts of leukocytes influence the SC duration.Gal-3 likely manifests indirect immunometabolic regulation of cognition in SC.

Diabetes mellitus type 2 as an underlying,comorbid or consequent state of mental disorders

Somatic disturbances that occur in parallel with psychiatric diseases are a major challenge in clinical practice.Various factors contribute to the development of mental and somatic disorders.Type 2 diabetes mellitus(T2DM)is a significant health burden worldwide,and the prevalence of diabetes in adults is increasing.The comorbidity of diabetes and mental disorders is very common.By sharing a bidirectional link,both T2DM and mental disorders influence each other in various manners,but the exact mechanisms underlying this link are not yet elucidated.The potential mechanisms of both mental disorders and T2DM are related to immune and inflammatory system dysfunction,oxidative stress,endothelial dysfunction,and metabolic disturbances.Moreover,diabetes is also a risk factor for cognitive dysfunction that can range from subtle diabetesassociated cognitive decline to pre-dementia and dementia.A complex relationship between the gut and the brain also represents a new therapeutic approach since gut-brain signalling pathways regulate food intake and hepatic glucose production.The aim of this minireview is to summarize and present the latest data on mutual pathogenic pathways in these disorders,emphasizing their complexity and interweaving.We also focused on the cognitive performances and changes in neurodegenerative disorders.The importance of implementing integrated approaches in treating both of these states is highlighted,along with the need for individual therapeutic strategies.