Transcriptional activation of Jun and Fos members of the AP‐1 complex is a conserved signature of immune aging that contributes to inflammaging

Aging Cell, Journal Year: 2023, Volume and Issue: 22(4)

Published: Feb. 24, 2023

Diverse mouse strains have different health and life spans, mimicking the diversity among humans. To capture conserved aging signatures, we studied long-lived C57BL/6J short-lived NZO/HILtJ by profiling transcriptomes epigenomes of immune cells from peripheral blood spleen young old mice. Transcriptional activation AP-1 transcription factor complex, particularly Fos, Junb, Jun genes, was most significant signature across tissues strains. ATAC-seq data analyses showed that chromatin around these genes more accessible with age there were significantly binding sites for TFs all tissues, targeting pro-inflammatory molecules including Il6. Age-related increases in JUN FOS factors also human data. Single-cell RNA-seq cell atlas Tabula Muris Senis expression increased B, T, NK cells, macrophages, macrophages mice expressing abundantly than other cells. Functional upon myeloid via poly(I:C), levels protein its activity compared to In addition, activation, produced IL6 sum, aging-related transcriptional Fos family members complex is long- short-living strains, possibly contributing inflammation age.

Language: Английский

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Multimodal cell atlas of the ageing human skeletal muscle

Nature, Journal Year: 2024, Volume and Issue: 629(8010), P. 154 - 164

Published: April 22, 2024

Abstract Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty critical contributors to morbidity mortality in older people 1 . Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing 2 Yet, progress been slow, partly due difficulties characterizing skeletal muscle niche heterogeneity (whereby myofibres most abundant) obtaining well-characterized samples 3,4 Here we generate a single-cell/single-nucleus transcriptomic chromatin accessibility map limb muscles encompassing over 387,000 cells/nuclei from individuals aged 15 99 years with distinct fitness levels. We describe how cell populations change during ageing, including emergence new people, cell-specific multicellular network features (at epigenetic levels) associated these changes. On basis cross-comparison genetic data, also identify key elements architecture that mark susceptibility sarcopenia. Our study provides identifying targets amenable medical, pharmacological lifestyle interventions late life.

Language: Английский

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Targeting MAPK-ERK/JNK pathway: A potential intervention mechanism of myocardial fibrosis in heart failure

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 173, P. 116413 - 116413

Published: March 9, 2024

Myocardial fibrosis is a significant pathological basis of heart failure. Overactivation the ERK1/2 and JNK1/2 signaling pathways MAPK family members synergistically promotes proliferation myocardial fibroblasts accelerates development fibrosis. In addition to some small molecule inhibitors Western drugs, many Chinese medicines can also inhibit activity JNK1/2, thus slowing down fibrosis, are generally safe effective. However, specific biological mechanisms in still need be fully understood, there no systematic review existing drugs methods them from improving This study aims summarize roles cross-linking systematically sort out small-molecule inhibitors, traditional medicines, non-pharmacological therapies that alleviate future, we hope conduct more in-depth research perspective precision-targeted therapy, using this as for developing new provide perspectives on prevention treatment

Language: Английский

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A cell atlas of the human fallopian tube throughout the menstrual cycle and menopause

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 3, 2025

The fallopian tube undergoes extensive molecular changes during the menstrual cycle and menopause. We use single-cell RNA ATAC sequencing to construct a comprehensive cell atlas of healthy human tubes Our scRNA-seq comparison 85,107 pre- 46,111 post-menopausal cells reveals substantial shifts in type frequencies, gene expression, transcription factor activity, cell-to-cell communications menopause cycle. Menstrual dependent hormonal regulate distinct states secretory epithelial cells. Postmenopausal show high chromatin accessibility factors associated with aging such as Jun, Fos, BACH1/2, while hormone receptors were generally downregulated, small proportion had expression ESR2, IGF1R, LEPR. While pre-menopausal cluster is enriched immunoreactive subtype, subset genes expressed enrichment mesenchymal high-grade serous ovarian cancer. cellular aging. Here, Weigert et al. present normal revealing transition throughout

Language: Английский

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The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(8), P. 1858 - 1881.e23

Published: July 2, 2024

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin transcriptional changes across 22 murine cell types, analyzed alongside previous mouse human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining throughout life have lower abundance of TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation TFs, as driving early-life cCRE loss altering developmental metabolic gene expression. Such remodeling can be triggered by elevating or depleting repressive H3K27me3. propose that AP-1-linked opening drives disrupting thereby reprogramming transcriptome function, mechanism hijacked through ongoing opening.

Language: Английский

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Interactions between toll‐like receptors signaling pathway and gut microbiota in host homeostasis

Immunity Inflammation and Disease, Journal Year: 2024, Volume and Issue: 12(7)

Published: July 1, 2024

Abstract Background Toll‐like receptors (TLRs) are a family of fundamental pattern recognition in the innate immune system, constituting first line defense against endogenous and exogenous antigens. The gut microbiota, collection commensal microorganisms intestine, is major source components metabolites microbiota interact with specific TLRs to contribute whole‐body metabolic homeostasis. Objective This review aims summarize interaction between TLR signaling pathways enumerate role dysbiosis‐induced obesity, inflammatory bowel disease (IBD), colorectal cancer (CRC). Results Through TLRs, facilitates development both adaptive systems, while system monitors dynamic changes bacteria maintain balance host‐microorganism symbiosis. Dysbiosis can induce cascade responses mediated by pathways, potentially resulting various diseases. Conclusion Understanding crosstalk contributes potential therapeutic applications related diseases, offering new avenues for treatment strategies conditions like IBD, CRC.

Language: Английский

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Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 13, 2025

Abstract The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion exocrine digestive enzymes. Complex interactions signaling mechanisms between functions of pancreas play a crucial role in maintaining metabolic homeostasis overall health. Compelling evidence indicates direct indirect crosstalk parts, influencing development diseases affecting both. From developmental perspective, parts share same origin—the “tip-trunk” domain. In certain circumstances, pancreatic cells may transdifferentiate into endocrine-like cells, insulin-secreting cells. Additionally, several diseases, including cancer, pancreatitis, diabetes, exhibit potential relevance to both functions. Endocrine communicate directly cytokines or indirectly regulating immune microenvironment. This affects onset progression these diseases. review summarizes history milestones findings related their embryonic development, phenotypic transformations, roles health disease, endocrine-exocrine from perspective therapeutic targets. Elucidating regulatory provide novel insights for understanding treatment

Language: Английский

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The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience

Frontiers in Aging, Journal Year: 2024, Volume and Issue: 5

Published: Oct. 16, 2024

As we age, our immune system’s ability to effectively respond pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising function leading chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in cell populations impaired functionality, resulting increased susceptibility infections, diminished vaccine efficacy, higher prevalence of diseases. Chronic low-grade further exacerbates these issues, contributing decline overall health resilience. review delves into the characteristics immunosenescence examines various intrinsic extrinsic factors aging how hallmarks fates can play crucial role this process. Additionally, it discusses impact sex, social determinants, gut microbiota on aging, illustrating complex interplay altering function. Furthermore, concept resilience explored, focusing metrics for assessing identifying strategies enhance These include lifestyle interventions such diet, regular physical activity, stress management, use gerotherapeutics other approaches. Understanding mitigating effects are developing support robust responses aged individuals.

Language: Английский

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Activating mutations in JAK2 and CALR differentially affect intracellular calcium flux in store operated calcium entry

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: March 21, 2024

Abstract Background Calcium (Ca 2+ ) signaling regulates various vital cellular functions, including integrin activation and cell migration. Store-operated calcium entry (SOCE) via release-activated (CRAC) channels represents a major pathway for Ca influx from the extracellular space in multiple types. The impact of JAK2-V617F CALR mutations which are disease initiating myeloproliferative neoplasms (MPN) on SOCE, flux endoplasmic reticulum (ER) to cytosol, related key pathways presence or absence erythropoietin (EPO) thrombopoietin (TPO) is poorly understood. Thus, this study aimed elucidate effects these aforementioned dynamics, models MPN. Methods Intracellular levels were measured over time frame 0–1080 s Fura-2 AM labeled myeloid progenitor 32D cells expressing (JAK2-WT/EpoR, JAK2-V617F/EpoR; CALR-WT/MPL, CALR-ins5/MPL, del52/MPL). Basal concentrations assessed 0–108 s. Subsequently, stimulated with EPO/TPO -free Ringer solution, measuring 109–594 (store depletion). Then, 2 mM buffer resembling physiological was added induce 595–1080 emission ratios (F340/380) used quantify integrated signal. Statistical significance by unpaired Student's t-test Mann–Whitney-U-test, one-way two-way ANOVA followed Tukey's comparison test. Results Following EPO stimulation, area under curve (AUC) representing SOCE significantly increased 32D-JAK2-V617F compared JAK2-WT cells. In TPO-stimulated cells, we observed elevated during store depletion CALR-WT CALR-ins5 del52 Notably, upon components pathways, PLCγ-1 IP3R, differentially affected lines. Hyper-activated IP3R but not mutated Inhibition regulatory mechanisms suppressed growth induced apoptosis Conclusions This report highlights JAK2 SOCE) response stimulation TPO. shows that mutation strongly alters mechanism EpoR/JAK2-dependent intracellular balance, affecting baseline levels, EPO-induced entry, pathways. Our results reveal an important role homeostasis positive

Language: Английский

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Oral Administration of Deer Bone Collagen Peptide Can Enhance the Skin Hydration Ability and Antioxidant Ability of Aging Mice Induced by D-Gal, and Regulate the Synthesis and Degradation of Collagen

Nutrients, Journal Year: 2024, Volume and Issue: 16(11), P. 1548 - 1548

Published: May 21, 2024

Skin problems caused by aging have attracted much attention, and marine collagen peptides been proved to improve these problems, while mammalian are rarely reported. In this study, fermented deer bone peptide (FCP) non-fermented (NCP) were extracted from bone, respectively, their sequences differential proteins analyzed using LC-MS/MS technology. After they applied mice induced with D-gal, the skin hydration ability, antioxidant synthesis, degradation ability of studied. The results show that FCP NCP mainly constitute type Ⅰ collagen, segments different. vivo experiments can richness fibers in mice; skin; promote activity antioxidant-related enzymes; also through TGF-β MAPK pathways, synthesis regulated. These aging, capacity mice, regulate pathway.

Language: Английский

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