Dimethyl fumarate-mediated Nrf2/ARE pathway activation and glibenclamide-mediated NLRP3 inflammasome cascade inhibition alleviate type II diabetes-associated fatty liver in rats by mitigating oxidative stress and inflammation

The prevalence of nonalcoholic fatty liver disease (NAFLD) is much higher in patients with type II diabetes (T2D). Inflammasomes are multimolecular complexes reported to involve inflammatory conditions. The nuclear factor (erythroid-derived 2)-like factor 2/antioxidant responsive element (Nrf2/ARE) pathway is an important regulator of antioxidant status in cells. Antidiabetic drug glibenclamide (GLB) is reported as  NACHT, leucine-rich repeat, and pyrin domain domains-containing protein 3 (NLRP3) inflammasome inhibitor, whereas anti-multiple sclerosis drug dimethyl fumarate (DMF) is reported as an Nrf2/ARE pathway activator. Both GLB and DMF possess anti-inflammatory and antioxidant properties, therefore, the hypothesis was made to look into the alone as well as the combination potential of GLB, DMF, and GLB + DMF, against NAFLD in diabetic rats. This study was aimed to investigate (1) the involvement of NLRP3 inflammasome and Nrf2/ARE signaling in diabetes-associated NAFLD (2) the effect of GLB, DMF, GLB + DMF, and metformin (MET) interventions on NLRP3 inflammasome and Nrf2/ARE signaling in diabetes-associated NAFLD. The rats were injected with streptozotocin (STZ) 35 mg/kg and fed a high-fat diet (HFD) for 17 consecutive weeks to induce diabetic NAFLD. The oral treatment of GLB 0.5 mg/kg/day, DMF 25 mg/kg/day, their combination and MET 200 mg/kg/day, were provided from the 6th to the 17th week. Treatment with GLB, DMF, GLB + DMF, and MET significantly alleviated HFD + STZ-induced plasma glucose, triglycerides, cholesterol, %HbA1c, hepatic steatosis, NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain, CARD, caspase-1, interleukin-1β (IL-1β), nuclear factor-κB (NF-κB), Nrf2, superoxide dismutase 1, catalase, IGF 1, heme oxygenase 1, receptor for the advanced glycation end product (RAGE), and collagen-1 in diabetic rats. Further, a mechanistic molecular study employing other specific NLRP3 inhibitors and Nrf2 activators will significantly contribute to the development of novel therapy for fatty liver diseases.     

A Modified Risk Set Approach to Biomarker Evaluation Studies

There is tremendous scientific and medical interest in the use of biomarkers to better facilitate medical decision making. In this article, we present a simple framework for assessing the predictive ability of a biomarker. The methodology requires use of techniques from a subfield of survival analysis termed semi-competing risks; results are presented to make the article self-contained. As we show in the article, one natural interpretation of semi-competing risks model is in terms of modifying the classical risk set approach to survival analysis that is more germane to medical decision making. A crucial parameter for evaluating biomarkers is the predictive hazard ratio, which is different from the usual hazard ratio from Cox regression models for right-censored data. This quantity will be defined; its estimation, inference, and adjustment for covariates will be discussed. Aspects of causal inference related to these procedures will also be described. The methodology is illustrated with an evaluation of serum albumin in terms of predicting death in patients with primary biliary cirrhosis.     

Retinal endothelial cell apoptosis

Retinal endothelial cell (REC) apoptosis occurs in response to a number of stressors, including high glucose, oxidative stress, hypoxia. Because these stressors are common factors in a number of ocular diseases, it is critical to understand the cellular mechanisms by which apoptosis occurs in REC. This review discusses the various models of REC used in ophthalmological research. The mechanisms responsible for REC apoptosis are discussed, as well as potential therapeutics currently under development to prevent REC apoptosis. The primary goal of this review is provide the reader with a background knowledge of the current state of research ongoing in REC apoptosis and potential avenues for future testing.     

Rice with SUB1 QTL possesses greater initial leaf gas film thickness leading to delayed perception of submergence stress

Background and AimsSubmergence tolerance in rice is primarily attributed to the action of the SUB1 gene, but other associated traits such as leaf gas film (LGF) thickness, leaf hydrophobicity, porosity and leaf density have been known to aid submergence tolerance in rice. However, association of these traits with SUB1 quantitative trait locus (QTL) has not been demonstrated. In this study, we aim to investigate (1) whether the presence of the SUB1 QTL in the genetic background has any influence on the thickness of the LGF and (ii) whether its removal has any impact on stress perception and submergence tolerance in Sub1 and non-Sub1 rice.MethodsWe examined 12 genotypes (including both Sub1 and non-Sub1 types) for different leaf traits such as initial LGF thickness, leaf hydrophobicity, tissue porosity and leaf density in order to work out the relatioship of these traits to the SUB1 QTL in rice. Furthermore, we investigated the changes in the gene expression profile and different metabolic processes in selected genotypes in the presence and absence of their LGF to study its impact on stress perception and adaptation.Key ResultsThe initial thickness of the LGF and hydrophobicity seemed to have a highly positive correlation with the presence of the SUB1 QTL in the genetic background of rice; however, other leaf traits such as porosity and density seemed to be independent of it. Artificial removal of the LGF resulted in partial loss of tolerance, showing increased ethylene production and early induction of anoxia-related genes (SUB1A-1, ACS5, Ramy3D and ADH1) which manifested symptoms such as increased stem elongation, faster chlorophyll and starch breakdown, and partial loss of quiescence in SUB1-containing rice genotypes. Stripping of the LGF resulted in early and enhanced induction of SUB1A-1, indicating a quicker perception of stress.ConclusionsThe presence of SUB1 in the genetic background positively influences surface hydrophobicity and the concomitant LGF thickness of rice. Furthermore, LGF helps in terms of providing better ethylene dissipation and reduced in planta accumulation, owing to the slowing down of ethylene-induced leaf senescence under submergence stress.     

Paternal contributors in recurrent pregnancy loss: Cues from comparative proteome profiling of seminal extracellular vesicles

Recent evidence entail paternal factors as plausible contributors in spontaneous recurrent pregnancy loss (RPL). Seminal extracellular vesicles secreted from cells of male reproductive tract carry regulatory proteins and RNAs. They are proposed to regulate sperm maturation and function while their fusion to endometrial stromal cells helps in decidualization. Nevertheless, the mechanism(s) involved in these processes are poorly understood. This study aims at elucidating the molecular basis of paternal contribution by comparative proteomics (label‐free LC‐MS/MS) of isolated seminal extracellular vesicles from fertile men and partners of patients with RPL (n = 21 per group). Bioinformatics analysis revealed the identified differentially expressed proteins to be involved in DNA replication, recombination and repair, gene expression, cellular assembly and organization, cell death, and survival. Major disease pathways affected were identified as developmental, hereditary, and immunological disorders. Of the three identified hub genes regulating the above disease pathways, two (HNRNPC and HNRNPU) are overexpressed while RUVBL1 is underexpressed along with over expression of HIST1H1C, DDX1, surmising defective chromatin packaging, and histone removal in spermatozoa resulting in improper expression in paternal genes thereby leading to abnormal embryo development. Besides, alteration in GSTP1 expression points oxidative predominance in RPL group. Differential expression of C3, C4a/C4b, CFB, and GDF 15 may be involved in altered maternal immune response to paternal antigens resulting in impaired decidualization.