STAT3 Signaling Pathway in Health and Disease

MedComm, Год журнала: 2025, Номер 6(4)

Опубликована: Март 30, 2025

ABSTRACT Signal transducer and activator of transcription 3 (STAT3) is a critical factor involved in multiple physiological pathological processes. While STAT3 plays an essential role homeostasis, its persistent activation has been implicated the pathogenesis various diseases, particularly cancer, bone‐related autoimmune disorders, inflammatory cardiovascular neurodegenerative conditions. The interleukin‐6/Janus kinase (JAK)/STAT3 signaling axis central to activation, influencing tumor microenvironment remodeling, angiogenesis, immune evasion, therapy resistance. Despite extensive research, precise mechanisms underlying dysregulated disease progression remain incompletely understood, no United States Food Drug Administration (USFDA)‐approved direct inhibitors currently exist. This review provides comprehensive evaluation STAT3's health disease, emphasizing involvement cancer stem cell maintenance, metastasis, inflammation, drug We systematically discuss therapeutic strategies, including JAK (tofacitinib, ruxolitinib), Src Homology 2 domain (S3I‐201, STATTIC), antisense oligonucleotides (AZD9150), nanomedicine‐based delivery systems, which enhance specificity bioavailability while reducing toxicity. By integrating molecular mechanisms, pathology, emerging interventions, this fills knowledge gap STAT3‐targeted therapy. Our insights into crosstalk, epigenetic regulation, resistance offer foundation for developing next‐generation with greater clinical efficacy translational potential.

Язык: Английский

---

Emerging roles of astrocytes as immune effectors in the central nervous system

Trends in Immunology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

---

Mechanisms of astrocyte aging in reactivity and disease

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Фев. 21, 2025

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor they contribute to neuronal dysfunction disease risk as organisms age. Here, we examine the transcriptional, cell biology, functional differences in across normal aging. Astrocytes at baseline heterogenous, responsive their environments, critical regulators of microenvironments function. With increasing age, adopt different immune-related senescence-associated states, which relate organelle loss homeostasis maintenance, both autonomously non-cell autonomously. These perturbed states increasingly associated with age-related onset neurodegeneration, suggesting that astrocyte a compelling target for future manipulation prevention disease.

Язык: Английский

---

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8–800 murine model of Friedreich ataxia

Neurobiology of Disease, Год журнала: 2024, Номер 200, С. 106631 - 106631

Опубликована: Авг. 6, 2024

Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in FXN gene. This deficiency causes progressive degeneration specific neuronal populations cerebellum and consequent loss movement coordination equilibrium, which are some main symptoms observed affected individuals. Like other diseases, previous studies suggest that glial cells could be involved process disease progression patients with ataxia. In this work, we followed characterized changes cerebellar cortex latest version humanized mouse model, YG8–800 (Fxnnull:YG8s(GAA)>800), carries human transgene containing >800 repeats. Comparative analyses behavioral, histopathological, biochemical parameters were conducted between control strain Y47R mice at different time points. Our findings revealed exhibit ataxic phenotype by poor motor coordination, decreased body weight, atrophy, loss, synaptic proteins. Additionally, early activation cells, predominantly astrocytes microglia, was preceding degeneration, as increased expression key proinflammatory cytokines downregulation neurotrophic factors. Together, our results show model exhibits stronger than experimental murine models, reliably recapitulating features humans. Accordingly, represent valuable tool for studying molecular mechanisms preclinical evaluation possible therapies.

Язык: Английский

---

Progression of mesenchymal stem cell regulation on imbalanced microenvironment after spinal cord injury

Stem Cell Research & Therapy, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 1, 2024

Язык: Английский

---

Mettl3-m6A-NPY axis governing neuron–microglia interaction regulates sleep amount of mice

Cell Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 4, 2025

Abstract Sleep behavior is regulated by diverse mechanisms including genetics, neuromodulation and environmental signals. However, it remains completely unknown regarding the roles of epitranscriptomics in regulating sleep behavior. In present study, we showed that deficiency RNA m 6 A methyltransferase Mettl3 excitatory neurons specifically induces microglia activation, neuroinflammation neuronal loss thalamus mice. remarkably disrupts rhythm reduces amount non-rapid eye movement sleep. We also regulates neuropeptide Y ( NPY ) via modification conditional knockout (cKO) mice displayed significantly decreased expression thalamus. addition, dynamic distribution pattern observed during wake-sleep cycle cKO Ectopic inhibits activation thalamus, restores disrupted Collectively, our study has revealed critical function Mettl3-m A-NPY axis

Язык: Английский

---

A critical opinion on adult endogenous neurogenesis as a brain repair mechanism after traumatic brain injury

Frontiers in Behavioral Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Фев. 6, 2025

Traumatic brain injury (TBI) affects more than 50 million people each year worldwide (Blaya et al., 2022) and leads to diverse functional impairments. Depending on the damaged regions, alterations may compromise different functions, which recover along time.Brain responses include events at molecular, cellular circuit levels (Zepeda 2004;Lim 2014;Kang 2022). However, study of plastic in humans a subcellular poses many difficulties. Therefore, loss recovery functions have been mainly assessed through behavioral evaluation, as well neuroimaging neurophysiological studies. When comparing animal models like rodents, we can only suggest potential contributions observed some but not all (Kozlowski 2013).Adding up complexity using experimental TBI proxy explore nervous humans, is difference outcomes male female clinical populations. Adult neurogenesis, has clearly demonstrated rats mice (for review, see Denoth-Lippuner Jessberger, 2021), beyond doubt (Sorrells 2018;Moreno-Jiménez 2019, for critical Oppenheim, 2019) explored mechanism subserving after damage, it our opinion that scientific community still far from reaching conclusion regarding its role repair.For purpose this opinion, would address four main questions: (1) Are there established sex-dependent differences outcome mirror humans? (2) To what extent possible extrapolate results obtained animals (3) Is neurogenesis adult rats? (4) non-debatable human brain?(1) From total pre-clinical research 2016 Pubmed, 7% studies females focus importance sex modeling (Späni 2018). Clinical trials observations are based populations under argument how hormonal fluctuations influence therefore results. Thus, hormones treated "problem" instead receiving proper attention unveil impact process recovery. occurs circumstances males compared females. In males, commonly produced several types contact collision or result military combat 2018); women falls, concussive impacts, intimate partner violence (St. Ivany Schminkey, 2016) presented together with multiorgan trauma (Biegon, 2021).Although sex-related damage matter debate, body work shows tend show better especially moderate-severe (Gupte 2019). This related increase hormone areas surrounding lesion review Stein, 2007). variations during estrous cycle also results: High progesterone time correlate females, while estrogens be detrimental 2007).While shown molecular including reduction excitotoxicity, antioxidant responses, synaptogenesis dendritic arborization 2001), context scarcely studied. Actually, knowledge one publication (Xiong 2007) addressed considering found constitutive number new neurons did differ between exposed TBI, cell proliferation (but neurogenesis) documented (Neale 2023). It worth mentioning documented, sexual dimorphisms response become evident pharmacological treatment other approaches aimed promoting 2007;Gómez-Porcuna 2024).The evidence ultimately factors subserve rats, positively long cycling appears. report worse 2019;Mikolic 2021) consider severity among variables, plays (Mikolic 2021). Thus extrapolating clinics accurate.(2) Animal capacity restore altered TBI. extrapolation lab needs evolution depends such age injury, location type always replicate models. Yet common resolve involving particular inflammation-involved mechanisms shared Liddelow 2024). Also, overcoming forms diaschisis (impairments remote communicated structure) recruitment regions initially involved performance provide means partial (Wiese 2004;Carrera Tononi, 2014;Boggs Among associated neuroplasticity rather alleviation upregulation neurotrophic signaling, modulation neurotransmitters, serotonin GABA (as previously discussed) (McGuire 2019;Shinoda 2021;Fox contrast, do yet support view constitutively born serve source recovery.(3) Neurogenesis species (Bonfanti Amrein, resident neural stem cells located two defined niches: subventricular zone lateral ventricles dentate gyrus hippocampus (Lois Alvarez-Buylla, 1993;Kuhn 1996) proliferate life give rise described steps (Kempermann 2004;Rasetto 2024).It strongly suggested these participate hippocampaldependent learning memory, spatial memory pattern separation (Miller Sahay, neurogenic positive negative conditions (i.e running vs inflammation) (van Praag 2002;Monje 2003;Perez-Dominguez 2019; Pérez-Domínguez 2017). although consistently reported (Arvidsson 2002;Aguilar-Arredondo Zepeda, 2018;Bielefeld 2024) newly-born integrate survive 2002;Kang their neurorepair remains unclear.The pioneering Arvidsson al. (2002), was first middle cerebral occlusion led increased zone. New acquired neuronal phenotype migrated towards striatum failed into circuit. Since then, works (Parent 2002;Yamashita 2006;Blaiss 2011;Sun 2015) evaluated endogenous induced cortical mostly affected similar even (Cuartero when generated bottle-neck effect prevents them significantly participating repair.Results hippocampal (which suffer TBI) since Nakatomi groups ours within functionally same structure (Aguilar-Arredondo 2018) does necessarily mean replenish area nor responsible reorganization. Yet, could reorganization focally circuit.During feedback inhibition granule increases physiological maturation (Groisman After newly hyperexcitable, potentially leading post-traumatic epilepsy due recurrent excitatory synapses sprouted mossy (Butler 2015;Neuberger Following sixfold, driven by just before parvalbumin + (PV) interneurons. Moreover, activation contribute hyperexcitability, suggesting young specifically enhance inputs onto PV interneurons (Kang Overall, prior around (just after) differentially excitation/inhibition balance shifts occur inconclusive.(4) brain, 1998 (Eriksson 1998). supported observation. Recent studies, colocalization markers refer presence Moreno-Jiménez claim interpretation data (see Alvarez-Buylla transcriptomic analyses revealed immature brains (Hochgerner 2018;Zhou detect (Cipriani 2018;Sorrells 2018;Franjic Transcriptomic meta-analysis sets mouse-based best comparison analyze given evolutionary primates humans. doublecortin cytoskeletal protein migrating neurons, used present non-neurogenic (Klempin 2011;Hagihara absence doublecortin, enough argue existence lack (Tosoni diversity concluded determined rodent markers, arguments against finding postmortem The re-analysis performed Tosoni (2023), yields possibility controversy arise methodological, conceptual biological confounders across studies.Interestingly, (Boldrini 2019;Tobin patients neurodegenerative diseases. considered an attempt compensation early triggered disease (Moreno-Jiménez supports showing population maintain "young phenotype" activate demand, meaning they post-mitotic plasticity complete local cues Palazzo 2018;Oppenheim, 2019;Jungenitz press).In article resumed findings Female outcomes. severe both outcomes, topic deserves close attention. Even rodents important look widen multiple processes accompany repair. Efforts being conducted stimulate promote reprogramming integration transplants understand repair.Plasticity traumatic widely lesser latter. often expected animals, equally case. pose questions approach limitations sex/gender focusing consequence are: sexdependent ( 2) nondebatable brain?

Язык: Английский

---

Astrocyte gap junction dysfunction activates JAK2-STAT3 pathway to mediate inflammation in depression

Pharmacology Biochemistry and Behavior, Год журнала: 2025, Номер unknown, С. 173987 - 173987

Опубликована: Март 1, 2025

Язык: Английский

---

Refining the interactions between microglia and astrocytes in Alzheimer’s disease pathology

Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

---

Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy

Genes, Год журнала: 2025, Номер 16(5), С. 590 - 590

Опубликована: Май 17, 2025

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, same mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting middle-aged adults. The accumulation undegraded VLCFA glial cell membranes and myelin has long been thought to be central mechanism X-ALD. Methods: This review discusses studies mouse drosophila models that have modified our views pathogenesis. Results: In Abcd1 knockout (KO) mimics disease, late manifestations are rapidly reversed transfer oligodendrocytes (OLs). peroxin-5 KO model, selective impairment peroxisomal biogenesis OLs achieves an almost perfect phenocopy cerebral ALD. A model revealed myelinating cells production toxic lipid able poison axons activate cells. Other showed critical role providing energy substrates axons. addition, on microglial changing substates improved understanding neuroinflammation. Conclusions: Animal supporting primary axonal pathology secondary microglia allow us revisit mechanisms. Beyond mutations, pathogenesis depends unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, stochasticity crosstalk between multiple types among billions neurons.

Язык: Английский

---