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Signal Transduction and Targeted Therapy Jan 2024Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the... (Review)
Review
Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.
Topics: Animals; Reperfusion Injury; Reperfusion; Wnt Signaling Pathway; Apoptosis; Ischemia
PubMed: 38185705
DOI: 10.1038/s41392-023-01688-x -
Frontiers in Physiology 2023Osteoarthritis (OA) is the most prevalent chronic joint disease, with physical exercise being a widely endorsed strategy in its management guidelines. Exerkines, defined... (Review)
Review
Osteoarthritis (OA) is the most prevalent chronic joint disease, with physical exercise being a widely endorsed strategy in its management guidelines. Exerkines, defined as cytokines secreted in response to acute and chronic exercise, function through endocrine, paracrine, and/or autocrine pathways. Various tissue-specific exerkines, encompassing exercise-induced myokines (muscle), cardiokines (heart), and adipokines (adipose tissue), have been linked to exercise therapy in OA. Exerkines are derived from these kines, but unlike them, only kines regulated by exercise can be called exerkines. Some of these exerkines serve a therapeutic role in OA, such as irisin, metrnl, lactate, secreted frizzled-related protein (SFRP), neuregulin, and adiponectin. While others may exacerbate the condition, such as IL-6, IL-7, IL-15, IL-33, myostatin, fractalkine, follistatin-like 1 (FSTL1), visfatin, activin A, migration inhibitory factor (MIF), apelin and growth differentiation factor (GDF)-15. They exerts anti-/pro-apoptosis/pyroptosis/inflammation, chondrogenic differentiation and cell senescence effect in chondrocyte, synoviocyte and mesenchymal stem cell. The modulation of adipokine effects on diverse cell types within the intra-articular joint emerges as a promising avenue for future OA interventions. This paper reviews recent findings that underscore the significant role of tissue-specific exerkines in OA, delving into the underlying cellular and molecular mechanisms involved.
PubMed: 38107476
DOI: 10.3389/fphys.2023.1302769 -
Clinical Cancer Research : An Official... Sep 2023Cemiplimab is approved for the treatment of locally advanced basal cell carcinomas (BCC), although with mitigated results. We sought to interrogate the cellular and...
PURPOSE
Cemiplimab is approved for the treatment of locally advanced basal cell carcinomas (BCC), although with mitigated results. We sought to interrogate the cellular and molecular transcriptional reprogramming underlying BCC resistance to immunotherapy.
EXPERIMENTAL DESIGN
Here, we combined spatial and single-cell transcriptomics to deconvolute the spatial heterogeneity of the tumor microenvironment in regard with response to immunotherapy, in a cohort of both naïve and resistant BCCs.
RESULTS
We identified subsets of intermingled cancer-associated fibroblasts (CAF) and macrophages contributing the most to CD8 T-cell exclusion and immunosuppression. Within this spatially resolved peritumoral immunosuppressive niche, CAFs and adjacent macrophages were found to display Activin A-mediated transcriptional reprogramming towards extracellular matrix remodeling, suggesting active participation to CD8 T-cell exclusion. In independent datasets of human skin cancers, Activin A-conditioned CAFs and macrophages were associated with resistance to immune checkpoint inhibitors (ICI).
CONCLUSIONS
Altogether, our data identify the cellular and molecular plasticity of tumor microenvironment (TME) and the pivotal role of Activin A in polarizing the TME towards immune suppression and ICI resistance.
Topics: Humans; Cancer-Associated Fibroblasts; Skin Neoplasms; Carcinoma, Basal Cell; Macrophages; Immunotherapy; Tumor Microenvironment
PubMed: 37327314
DOI: 10.1158/1078-0432.CCR-23-0219 -
Proceedings of the National Academy of... Aug 2023Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (, activin E) loss-of-function variants are...
Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing β-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E-ACVR1C as a metabolic rheostat promoting liver-adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals.
Topics: Humans; Mice; Animals; Lipolysis; Activins; Adiposity; Diabetes Mellitus, Type 2; PPAR gamma; Obesity; Adipose Tissue; Activin Receptors, Type I
PubMed: 37523551
DOI: 10.1073/pnas.2309967120 -
Blood Advances Jul 2023Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and...
Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113).
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Anemia; Thrombocytopenia
PubMed: 37042865
DOI: 10.1182/bloodadvances.2022009311 -
Molecular Metabolism Feb 2024Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight...
OBJECTIVE
Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight loss is fat mass, there is also a loss of lean mass, similar to other approaches that induce calorie deficit. Targeting signaling pathways that regulate skeletal muscle hypertrophy is a promising avenue to preserve lean mass and modulate body composition. Myostatin and Activin A are TGFβ-like ligands that signal via the activin type II receptors (ActRII) to antagonize muscle growth. Pre-clinical and clinical studies demonstrate that ActRII blockade induces skeletal muscle hypertrophy and reduces fat mass. In this manuscript, we test the hypothesis that combined ActRII blockade and GLP-1 receptor agonism will preserve muscle mass, leading to improvements in skeletomuscular and metabolic function and enhanced fat loss.
METHODS
In this study, we explore the therapeutic potential of bimagrumab, a monoclonal antibody against ActRII, to modify body composition alone and during weight loss induced by GLP-1 receptor agonist semaglutide in diet-induced obese mice. Mechanistically, we define the specific role of the anabolic kinase Akt in mediating the hypertrophic muscle effects of ActRII inhibition in vivo.
RESULTS
Treatment of obese mice with bimagrumab induced a ∼10 % increase in lean mass while simultaneously decreasing fat mass. Daily treatment of obese mice with semaglutide potently decreased body weight; this included a significant decrease in both muscle and fat mass. Combination treatment with bimagrumab and semaglutide led to superior fat mass loss while simultaneously preserving lean mass despite reduced food intake. Treatment with both drugs was associated with improved metabolic outcomes, and increased lean mass was associated with improved exercise performance. Deletion of both Akt isoforms in skeletal muscle modestly reduced, but did not prevent, muscle hypertrophy driven by ActRII inhibition.
CONCLUSIONS
Collectively, these data demonstrate that blockade of ActRII signaling improves body composition and metabolic parameters during calorie deficit driven by GLP-1 receptor agonism and demonstrate the existence of Akt-independent pathways supporting muscle hypertrophy in the absence of ActRII signaling.
Topics: Animals; Mice; Activin Receptors, Type II; Activins; Antibodies, Blocking; Glucagon-Like Peptide-1 Receptor; Hypertrophy; Mice, Obese; Muscle, Skeletal; Proto-Oncogene Proteins c-akt; Weight Loss; Antibodies, Monoclonal, Humanized; Obesity
PubMed: 38218536
DOI: 10.1016/j.molmet.2024.101880 -
Nature Cell Biology Oct 2023Germline commitment following primordial germ cell (PGC) specification during early human development establishes an epigenetic programme and competence for...
Germline commitment following primordial germ cell (PGC) specification during early human development establishes an epigenetic programme and competence for gametogenesis. Here we follow the progression of nascent PGC-like cells derived from human embryonic stem cells in vitro. We show that switching from BMP signalling for PGC specification to Activin A and retinoic acid resulted in DMRT1 and CDH5 expression, the indicators of migratory PGCs in vivo. Moreover, the induction of DMRT1 and SOX17 in PGC-like cells promoted epigenetic resetting with striking global enrichment of 5-hydroxymethylcytosine and locus-specific loss of 5-methylcytosine at DMRT1 binding sites and the expression of DAZL representing DNA methylation-sensitive genes, a hallmark of the germline commitment programme. We provide insight into the unique role of DMRT1 in germline development for advances in human germ cell biology and in vitro gametogenesis.
Topics: Humans; Cell Differentiation; DNA Methylation; Germ Cells; Human Embryonic Stem Cells; Signal Transduction
PubMed: 37709822
DOI: 10.1038/s41556-023-01224-7 -
Biomolecules Dec 2023Myostatin (growth differentiation factor 8) is a member of the transforming growth factor-β superfamily. It is secreted mostly by skeletal muscles, although small... (Review)
Review
Myostatin (growth differentiation factor 8) is a member of the transforming growth factor-β superfamily. It is secreted mostly by skeletal muscles, although small amounts of myostatin are produced by the myocardium and the adipose tissue as well. Myostatin binds to activin IIB membrane receptors to activate the downstream intracellular canonical Smad2/Smad3 pathway, and additionally acts on non-Smad (non-canonical) pathways. Studies on transgenic animals have shown that overexpression of myostatin reduces the heart mass, whereas removal of myostatin has an opposite effect. In this review, we summarize the potential diagnostic and prognostic value of this protein in heart-related conditions. First, in myostatin-null mice the left ventricular internal diameters along with the diastolic and systolic volumes are larger than the respective values in wild-type mice. Myostatin is potentially secreted as part of a negative feedback loop that reduces the effects of the release of growth-promoting factors and energy reprogramming in response to hypertrophic stimuli. On the other hand, both human and animal data indicate that myostatin is involved in the development of the cardiac cachexia and heart fibrosis in the course of chronic heart failure. The understanding of the role of myostatin in such conditions might initiate a development of targeted therapies based on myostatin signaling inhibition.
Topics: Mice; Humans; Animals; Myostatin; Muscle, Skeletal; Myocardium; Signal Transduction; Proteins
PubMed: 38136649
DOI: 10.3390/biom13121777 -
Gastroenterology Jan 2024The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current...
BACKGROUND & AIMS
The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs.
METHODS
By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling pathway.
RESULTS
Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs.
CONCLUSIONS
Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.
Topics: Animals; Humans; Mice; Bromodomain Containing Proteins; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Transformation, Neoplastic; Gemcitabine; Neoplastic Stem Cells; Pancreatic Neoplasms; Smad2 Protein; Transcription Factors
PubMed: 37739089
DOI: 10.1053/j.gastro.2023.09.021