Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

Biomolecules, Journal Year: 2024, Volume and Issue: 14(3), P. 305 - 305

Published: March 4, 2024

The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital the successful development clinically useful medications. Stroke is generally accepted as leading cause adult disability globally and ischemic stroke accounts most common form two main types. Despite its health socioeconomic burden, there still minimal availability effective pharmacological treatment. In this review, we take an in-depth look at etiology stroke, including molecular cellular changes. This followed by a highlight drugs, therapies, complementary medicines that or undergoing clinical trials treatment management stroke. We also identify unexplored potential targets in pathogenesis can be exploited increase pool anti-stroke neuroprotective agents through de novo drug repurposing.

Language: Английский

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NLRP inflammasomes in health and disease

Molecular Biomedicine, Journal Year: 2024, Volume and Issue: 5(1)

Published: April 22, 2024

Abstract NLRP inflammasomes are a group of cytosolic multiprotein oligomer pattern recognition receptors (PRRs) involved in the pathogen-associated molecular patterns (PAMPs) and danger-associated (DAMPs) produced by infected cells. They regulate innate immunity triggering protective inflammatory response. However, despite their role, aberrant NLPR inflammasome activation gain-of-function mutations sensor proteins occurrence enhancement non-communicating autoimmune, auto-inflammatory, neurodegenerative diseases. In last few years, significant advances have been achieved understanding physiological functions mechanisms activation, as well therapeutics that target activity Here, we provide latest research progress on inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRP7, NLRP2, NLRP9, NLRP10, NLRP12 regarding structural assembling features, signaling transduction mechanisms. Importantly, highlight associated with dysregulation numerous human Overall, summarize discoveries biology, forming role health diseases, therapeutic strategies perspectives for future studies about inflammasomes.

Language: Английский

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Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Feb. 20, 2023

Sensorineural deafness becomes an inevitable worldwide healthy problem, yet the current curative therapy is limited. Emerging evidences demonstrate mitochondrial dysfunction plays a vital role of in pathogenesis deafness. Reactive oxygen species (ROS)-induced combined with NLRP3 inflammasome activation involved cochlear damage. Autophagy not only clears up undesired proteins and damaged mitochondria (mitophagy), but also eliminate excessive ROS. Appropriate enhancement autophagy can reduce oxidative stress, inhibit cell apoptosis, protect auditory cells. In addition, we further discuss interplays linking ROS generation, activation, underlying deafness, including ototoxic drugs-, noise- aging-related hearing loss.

Language: Английский

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Biologics for Hidradenitis suppurativa: evolution of the treatment paradigm

Expert Review of Clinical Immunology, Journal Year: 2023, Volume and Issue: 20(5), P. 525 - 545

Published: Dec. 22, 2023

Introduction Hidradenitis suppurativa (HS) is an autoinflammatory skin disease with a high unmet need for effective medical management. Clinically, it characterized by inflammatory nodules that may progress into abscesses, draining tunnels and extensive scarring, mainly affecting apocrine gland-bearing areas.

Language: Английский

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Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging

Cells, Journal Year: 2024, Volume and Issue: 13(17), P. 1413 - 1413

Published: Aug. 24, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer's disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form soluble (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by produces active IL-1β, pores cell death (pyroptosis). In accord, countered injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces inflammation, improves repair following injury. inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Language: Английский

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The double sides of NLRP3 inflammasome activation in sepsis

Clinical Science, Journal Year: 2023, Volume and Issue: 137(5), P. 333 - 351

Published: March 1, 2023

Abstract Sepsis is defined as a life-threatening organ dysfunction induced by dysregulated host immune response to infection. Immune sepsis complex and dynamic. It schematically described an early systemic inflammatory leading failures deaths, followed the development of persistent alterations affecting both innate adaptive responses associated with increased risk secondary infections, viral reactivations, late mortality. In this review, we will focus on role NACHT, leucin-rich repeat pyrin-containing protein 3 (NLRP3) inflammasome in pathophysiology sepsis. NLRP3 multiproteic intracellular activated infectious pathogens through two-step process resulting release pro-inflammatory cytokines IL-1β IL-18 formation membrane pores gasdermin D, inducing form cell death called pyroptosis. The can be ambivalent. Indeed, although it might protect against when moderately after initial infection, excessive activation induce inflammation multiple failure during acute phase disease. Moreover, become exhausted contribute post-septic immunosuppression, driving impaired functions cells. Targeting could thus attractive option either antagonists or inhibition pathway downstream components. Available treatments results first clinical trials discussed.

Language: Английский

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Mechanisms of NLRP3 inflammasome activation and the development of peptide inhibitors

Cytokine & Growth Factor Reviews, Journal Year: 2023, Volume and Issue: 74, P. 1 - 13

Published: Oct. 1, 2023

Language: Английский

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The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(1), P. 626 - 626

Published: Jan. 3, 2024

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage bone. RA commonly accompanied extra-articular comorbidities. The pathogenesis its comorbidities complex not completely elucidated. assembly NOD-, LRR- pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces maturation interleukin (IL)-1β IL-18 leads to cleavage gasdermin D with promoting pyroptosis. Accumulative evidence indicates pathogenic role NLRP3 signaling in comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, interstitial lung diseases. Although available therapeutic agents are effective for treatment, their high cost increased infection rate causes concern. Recent revealed components as potential targets In this review, we searched MEDLINE database using PubMed interface reviewed English-language literature on from 2000 2023. current reveals that contributes Consequently, pathway represent promising targets, ongoing research might lead development new, treatments

Language: Английский

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Inhibition of macrophages inflammasome activation via autophagic degradation of HMGB1 by EGCG ameliorates HBV-induced liver injury and fibrosis

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: April 14, 2023

Background Liver fibrosis is a reversible wound-healing response that can lead to end-stage liver diseases without effective treatment, in which HBV infection major cause. However, the underlying mechanisms for development of HBV-induced remains elusive, and efficacious therapies this disease are still lacking. In present investigation, we investigated effect mechanism green tea polyphenol epigallocatechin-3-gallate (EGCG) on injury fibrosis. Methods The EGCG was examined recombinant cccDNA (rcccDNA) chronic mouse model by immunohistochemical staining, Sirius red Masson’s trichrome staining. functional relevance between high mobility group box 1 (HMGB1) inflammasome activation role it were analyzed Western blotting. autophagic flux determined blotting flow cytometric analysis. Results treatment efficiently found alleviate model, proven suitable research platform Mechanistically, revealed repress macrophage NLRP3 inflammasome, critical trigger Further study suppressed through downregulating level extracellular HMGB1. Furthermore, our data demonstrated downregulated levels HMGB1 activating degradation cytoplasmic hepatocytes. Accordingly, autophagy blockade significantly reverse EGCG-mediated inhibition HMGB1-activated thus suppress therapeutic Conclusion ameliorates via subsequent suppression activation. These provided new pathogenic involving HMGB1-mediated activation, also suggested administration as promising strategy disease.

Language: Английский

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Targeting NLRP3 Inflammasome: Structure, Function, and Inhibitors

Current Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 31(15), P. 2021 - 2051

Published: Feb. 4, 2024

Abstract: Inflammasomes are multimeric protein complexes that can detect various physiological stimuli and danger signals. As a result, they perform crucial function in the innate immune response. The NLRP3 inflammasome, as vital constituent of inflammasome family, is significant defending against pathogen invasion preserving cellhomeostasis. dysregulation connected to pathological conditions, including inflammatory diseases, cancer, cardiovascular neurodegenerative diseases. This profile makes an applicable target for treating related therefore, there rising inhibitors disclosed therapy. Herein, we summarized updated advances structure, function, inflammasome. Moreover, aimed provide overview existing products future directions drug research development.

Language: Английский

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