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β-Thalassemia major is a congenital hemoglobin disorder that requires regular blood transfusion. The disease is often associated with iron overload and diabetes mellitus, among other complications. Pancreatic iron overload in β-thalassemia patients disrupts β-cell function and insulin secretion and induces insulin resistance. Several risk factors, including family history of diabetes, sedentary lifestyle, obesity, gender, and advanced age increase the risk of diabetes in β-thalassemia patients. Precautionary measures such as blood glucose monitoring, anti-diabetic medications, and healthy living in β-thalassemia patients notwithstanding, the prevalence of diabetes in β-thalassemia patients continues to rise. This review aims to address the relationship between β-thalassemia and diabetes in an attempt to understand how the pathology and management of β-thalassemia precipitate diabetes mellitus. The possible employment of surrogate biomarkers for early prediction and intervention is discussed. More work is still needed to better understand the molecular mechanism(s) underlying the link between β-thalassemia and diabetes and to identify novel prognostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

The mammary gland is a dynamic organ with various physiological processes like cellular proliferation, differentiation, and apoptosis during the pregnancy-lactation-involution cycle. It is essential to understand the molecular changes during the lactogenic differentiation of mammary epithelial cells (MECs, the milk-synthesizing cells). The MECs are organized as luminal milk-secreting cells and basal myoepithelial cells (responsible for milk ejection by contraction) that form the alveoli. The branching morphogenesis and lactogenic differentiation of the MECs prepare the gland for lactation. This process is governed by many molecular mediators including hormones, growth factors, cytokines, miRNAs, regulatory proteins, etc. Interestingly, various signalling pathways guide lactation and understanding these molecular transitions from pregnancy to lactation will help researchers design further research. Manipulation of genes responsible for milk synthesis and secretion will promote augmentation of milk yield in dairy animals. Identifying protein signatures of lactation will help develop strategies for persistent lactation and shortening the dry period in farm animals. The present review article discusses in details the physiological and molecular changes occurring during lactogenic differentiation of MECs and the associated hormones, regulatory proteins, miRNAs, and signalling pathways. An in-depth knowledge of the molecular events will aid in developing engineered cellular models for studies related to mammary gland diseases of humans and animals. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally, emphasizing the need for effective treatments. Autophagy may play role in cancer metastasis through enhancing epithelial-mesenchymal Transition (EMT). Targeting ATG5 and ATG7 (using CRISPR/Cas9) revealed upregulated expression of KLF8, an oncogene associated with EMT induction in cancer cells. Investigating these pathways could offer insights into potential therapeutic strategies for CRC metastasis. Methods: Initially, we utilized qPCR to validate increased KLF8 expression in parental HCT116 cells compared to HCT116 knockout (KO) lines, and in metastatic cell lines LOVO and SKCOl. Additionally, we examined KLF8 expression in an isogenic HCT116 MLH1+/- line alongside its MLH1-/- parental line. Subsequently, bioinformatics analyses were conducted using publicly available dataseis (TIMER2, UALCAN, GSCALite). Subsequent biological assays involved dual inhibition of autophagy via chloroquine (CQ) and KLF8 knockdown using siKLF8, evaluating effects on migration (wound healing assay), invasion (Matrigel assay), and focal adhesion maturation via paxillin and zyxin levels (immunofluorescence staining). Results: In our investigation of KLF8's role in CRC, we utilized publicly available data and web -based tools, revealing a notable correlation between KLF8 and autophagy gene expression in CRC specifically with UVRAG, ULK2 and Beclinl with Spearman Rho 0.49, 0.44, and 0.5, respectively, with p < 0.00001 for all of the tested autophagy genes. Co-expression analysis with EMT markers consistently showed significant p-values (< 0.00001 for all); specifically, with Zebl, N-cadherin, and e-cadherin, Spearman Rho correlations of 0.66, 0.47, and 0.54 respectively. KLF8 expression exhibited consistent elevation across various tumor stages and CRC subtypes, particularly heightened in metastatic cell lines LOVO and SKCOl compared to HCT116. Pharmacological inhibition of autophagy using Chloroquine (CQ) in con junction with KLF8 downregulation significantly reduced CRC cell migration and invasion. Notably, our study explored the modulation of focal adhesion molecules, demonstrating increased zyxin expression upon concurrent autophagy inhibition and KLF8 downregulation, indicative of enhanced mature focal adhesion assembly. Conclusion: Our research suggests that targeting both KLF8 and autophagy simultaneously could offer a promising therapeutic strategy for combating metastatic colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that bone marrow cells might possess a much broader differentiation potential than previously appreciated. In most cases, the reported efficiency of such plasticity has been rather low and, at least in some instances, is a consequence of cell fusion. After myocardial infarction, however, bone marrow cells have been suggested to extensively regenerate cardiomyocytes through transdifferentiation. Although bone marrow-derived cells are already being used in clinical trials, the exact identity, longevity and fate of these cells in infarcted myocardium have yet to be investigated in detail. Here we use various approaches to induce acute myocardial injury and deliver transgenically marked bone marrow cells to the injured myocardium. We show that unfractionated bone marrow cells and a purified population of hematopoietic stem and progenitor cells efficiently engraft within the infarcted myocardium. Engraftment was transient, however, and hematopoietic in nature. In contrast, bone marrow-derived cardiomyocytes were observed outside the infarcted myocardium at a low frequency and were derived exclusively through cell fusion., Author(s): Jens M Nygren [1]; Stefan Jovinge [1, 2]; Martin Breitbach [3]; Petter Sawen [1]; Wilhelm Roll [4]; Jurgen Hescheler [5]; Jalal Taneera [1]; Bernd K Fleischmann [3]; Sten Eirik [...]

Research has been conducted on the bile-tolerant Helicobacter spp. Growth-enhancing substances for this bacterium and their effect on the coccoid conversion have been investigated and the results suggest that the growth enhancement may be caused by the ability of the activated charcoal to remove toxic compounds in the culture media.