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Global climate change has increased the frequency and intensity of heat waves, posing a significant threat to livestock production. During heat exposure, the disruption of intestinal barrier integrity is a pivotal event in the pathogenesis of heat stress-induced intestinal injury. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are key consequences of heat stress at the cellular level. However, direct causal evidence linking ER stress to mitochondrial dysfunction in heat-stressed enterocytes remains limited. To investigate this, we used an integrated transcriptomic, metabolomic, and functional validation strategy to assess mitochondrial bioenergetics and cellular ultrastructure in porcine intestinal epithelial (IPEC-J2) cells under acute heat stress. Transcriptomic analysis revealed extensive reprogramming, highlighting the significant enrichment of pathways related to protein processing in the endoplasmic reticulum, apoptosis, and MAPK signaling. Untargeted metabolomics identified significant perturbations in amino acid and energy metabolism, as well as altered bile acid profiles. Functional assessments confirmed that heat stress severely impaired mitochondrial bioenergetics, as evidenced by reduced maximal respiration and ATP production, and induced ultrastructural damage to mitochondria. The pharmacological inhibition of ER stress by 4-phenylbutyric acid (4-PBA) significantly attenuated the mitochondrial bioenergetic impairment and ultrastructural damage, whereas ER stress induction recapitulated these defects. We demonstrate that heat stress induces profound transcriptional and metabolic remodeling characterized by ER stress activation, which critically mediates subsequent mitochondrial bioenergetic dysfunction and ultrastructural damage. Our findings suggest that targeting ER stress may represent a promising therapeutic strategy to ameliorate enterocyte mitochondrial dysfunction and mitigate heat stress-induced intestinal injury in livestock.

Background: Type 1 diabetes (T1D) shares clinical characteristics with other forms of diabetes, particularly monogenic diabetes such as maturity-onset diabetes of the young (MODY). Differential diagnosis is complicated by the existence of intermediate phenotypes. We aimed to delineate the phenotypic continuum between T1D and monogenic diabetes.

Methods: The multicentric GENEPEDIAB study included patients aged 6 months to 18 years diagnosed with diabetes and treated for either T1D or monogenic diabetes. Analyses comprised glycemic variability, continuous glucose monitoring metrics, application of the DIAMODIA criteria, and genetic investigations.

Results: A gradient was observed across T1D, atypical diabetes (Adia), and MODY cohorts for several glycemic parameters. T1D patients exhibited values furthest from treatment targets, whereas MODY patients showed better glycemic control. Stratification of the Adia cohort according to the number of positive DIAMODIA criteria further supported this trend, as demonstrated by glycemic measures and multiple correspondence analysis. Genetic analyses did not identify a uniform causative variant in the Adia cohort; however, several rare variants, including variants of uncertain significance and likely pathogenic variants in diabetes-related genes, were detected.

Conclusions: These findings showed, in our specific cohort of pediatric patients, the existence of a phenotypic gradient between T1D and monogenic diabetes, with atypical diabetes occupying an intermediate position, including when stratified by DIAMODIA criteria.

Type 2 diabetes (T2D) is a pressing global health challenge, primarily driven by modern dietary and lifestyle patterns. Central to T2D progression is the dysfunction of insulin-secreting pancreatic β-cells, which critically disrupts glucose homeostasis. The progression to T2D relies on the β-cells' inability to compensate for increasing insulin resistance. Initially, β-cells enhance the insulin output, but chronic nutrient overload, ER stress and inflammation ultimately compromise their function and survival. This review examines the molecular and cellular drivers of β-cell failure, focusing on endoplasmic reticulum stress, mitochondrial dysfunction and inflammatory pathways amid chronic metabolic stress. We also explore the loss of β-cell identity and altered interactions within the islet microenvironment. Understanding these mechanisms is essential for developing strategies to prevent β-cell dysfunction and slow T2D progression, ultimately supporting better metabolic health outcomes.

Data suggest that both pancreatic and intestinally produced glucagon-like peptide-1 (GLP-1) increases in response to inflammation. Here, we set out to determine the tissue-specific function of increased GLP-1 during inflammatory stimuli. Using our innovative mouse model of tissue-specific Gcg (the gene that encodes GLP-1) expression, we explored the function of GLP-1 under severe inflammatory conditions induced by lipopolysaccharide (LPS) administration in lean and obese mice. High-fat diet (HFD) increased the LPS-induced suppression of feeding and increased the plasma levels of pro-inflammatory cytokines and GLP-1. Both pancreatic and intestinal Gcg expression contribute to LPS-induced increases in GLP-1, but Gcg was not necessary for the glucoregulatory or suppressed feeding responses to LPS. While Gcg was not necessary for systemic cytokine increases with LPS in either chow- or HFD-fed mice, whole-body Gcg-null animals had increased macrophage accumulation and an increased expression of genes reflecting pro-inflammatory signaling in the pancreas. We then performed flow cytometry on the pancreas from mice expressing a fluorescent marker on the GLP-1 receptor (GLP-1R). In response to LPS, we found that pancreatic CD64+/CD11b+ macrophages expressed the GLP-1R. We conclude that under severe inflammatory conditions, pancreatic production of GLP-1 functions in an immunological rather than a metabolic role to directly regulate local macrophage accumulation.

Colitis-associated carcinoma (CAC) represents ~1% of colorectal carcinomas and has important differences from sporadic colorectal carcinoma (sCRC). The precursors and carcinomas that arise in the setting of IBD are uniquely challenging to visualize by endoscopy and diagnose via histology, and the rising prevalence of IBD amplifies the challenges of surveillance to informed management. Although in broad strokes, CAC and sCRC share molecular features (~85% chromosomal instability pathway 15% microsatellite instability high (MSI-H)), CAC has a distinct distribution of molecular abnormalities, including lower frequencies of APC and KRAS mutations, greater prevalence of IDH1R132H, and more frequent copy number alterations (e.g., MYC amplifications), and functional data indicate that most CACs show far less dependence on Wnt signaling than sCRC, suggesting a distinct pathogenesis from the earliest stages. Although there are significant gaps in our knowledge of the pathogenesis of CAC, our understanding is growing. This review summarizes how chronic colitis reshapes epithelial homeostasis and somatic evolution, resulting in the distinctive pathogenesis of CAC, and highlights knowledge gaps that could be addressed by applying multimodal technologies to well-annotated clinical material. The review is structured in two sections, the first introducing the IBDs and the homeostatic mechanisms that preserve integrity and prevent colorectal neoplasia. The second section compares failure modes in sporadic and colitic settings and describes the differences in the resulting neoplasms.

Mutations in the TANK-binding kinase 1 (TBK1) gene represent a significant genetic link across the Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) spectrum. As a multifunctional serine/threonine kinase, TBK1 serves as a central orchestrator of the autophagy-lysosome pathway, regulating critical stages from initial cargo recognition and autophagosome biogenesis to vesicle maturation and lysosomal fusion. This review examines the mechanisms by which TBK1 coordinates these diverse autophagic functions. We then focus on how ALS/FTD-associated mutations-ranging from truncating variants causing haploinsufficiency to domain-specific missense mutations-disrupt these essential processes.

Retromer is an evolutionarily conserved protein complex first identified in budding yeast. It was originally described for its essential role in endosome-to-Golgi retrieval of lysosomal hydrolase receptors. Retromer is now known to mediate trafficking of many endosomal cargoes. The mammalian retromer is constituted by a core heterotrimer encoded by the vacuolar protein sorting (VPS) gene products VPS26, VPS35, and VPS29. To mediate cargo recognition and endosomal sorting into various pathways, this trimer can cooperate with phosphoinositide-binding sorting nexin family members. Defective retromer functioning has been associated with alterations in cellular homeostasis, leading to disease. To gain insights into how it may mediate these broad processes, a proteomic strategy in polarized Madin-Darby canine kidney cells was devised to identify retromer-interacting proteins. Subsequent validation of one of the candidates, i.e., cytokeratin 19, led to the unexpected finding that retromer localizes to the pericentriolar region in dividing cells and subsequently translocates to the midbody during cytokinesis. Retromer was found interacting with CK19, and its antisense depletion led to delocalization from CK19. Subcellular fractionation and live cell monitoring of depleted cells provided evidence of a role by retromer in post-metaphase progression and in epithelial cell migration, thereby connecting retromer with key processes of cellular dynamics.

Transforming growth factor-β (TGF-β) signaling plays a central role in lung tissue homeostasis, coordinating epithelial repair, immune resolution, and stromal remodeling following injury. However, persistent or dysregulated TGF-β activation is a hallmark of both idiopathic pulmonary fibrosis (IPF) and lung cancer, two devastating pulmonary diseases that are traditionally studied as distinct entities. Emerging evidence suggests that this dichotomous view may obscure shared pathogenic mechanisms driven by aberrant TGF-β signaling dynamics. In this review, we synthesize experimental, translational, and clinical findings to propose a unifying framework in which IPF and lung cancer represent endpoints along a shared TGF-β-driven pathological continuum. We highlight how the duration and intensity of TGF-β signaling determine divergent cellular outcomes across epithelial cells, fibroblasts, and immune compartments-ranging from physiological wound repair to irreversible fibrotic remodeling and the establishment of a pro-tumorigenic niche. Particular emphasis is placed on the temporal transition from acute injury responses to chronic signaling states that promote epithelial plasticity, fibroblast fixation, immune suppression, and genomic instability. By integrating fibrosis and tumorigenesis into a single pathophysiological model, this review reframes TGF-β signaling as a time-dependent disease modifier rather than a disease-specific factor. This perspective provides a conceptual basis for therapeutic strategies targeting TGF-β signaling windows to intercept disease progression before irreversible fibrosis or malignant transformation occurs.