Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation

Frontiers in Nutrition, Journal Year: 2022, Volume and Issue: 9

Published: Nov. 1, 2022

Many local and systemic diseases especially that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease stroke, cancer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing 19 (COVID-19), involve both, (1) oxidative stress excessive production reactive oxygen species (ROS) lower glutathione (GSH) levels, (2) inflammation. The GSH tripeptide (γ- L-glutamyl-L-cysteinyl-glycine), the most abundant water-soluble non-protein thiol in cell (1–10 mM) is fundamental for life by (a) sustaining adequate redox signaling needed to maintain physiologic levels control processes, (b) limiting tissue damage. activity facilitated activation Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related (Nrf2)-antioxidant response element (ARE) regulator pathway, releasing Nrf2 regulates expression genes controlling antioxidant, inflammatory immune system responses. exists thiol-reduced (>98% total GSH) disulfide-oxidized (GSSG) forms, concentrations GSSG their molar ratio indicators functionality cell. depletion may play a central role COVID-19 pathophysiology, host severity mortality. Therapies enhancing could become cornerstone reduce fatal outcomes increasing prevent subdue these diseases. value makes paramount research field biology medicine be key against inflammation SARS-CoV-2 infection disease. In this review, we emphasize on as risk (ischemic stroke), importance antioxidants (3) significance counteract persistent damaging inflammation, inflammaging early (premature) associated damage caused lack antioxidant defenses younger individuals, (4) new therapies include restoration.

Language: Английский

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Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 5037 - 5037

Published: May 5, 2024

Toll-like receptors (TLRs) are vital components of the innate immune system, serving as first line defense against pathogens by recognizing a wide array molecular patterns. This review summarizes critical roles TLRs in surveillance and disease pathogenesis, focusing on their structure, signaling pathways, implications various disorders. We discuss intricacies TLRs, including ligand specificity, cascades, functional consequences activation. The involvement infectious diseases, autoimmunity, chronic inflammation, cancer is explored, highlighting potential therapeutic targets. also examine recent advancements TLR research, such development specific agonists antagonists, application immunotherapy vaccine development. Furthermore, we address challenges controversies surrounding research outline future directions, integration computational modeling personalized medicine approaches. In conclusion, represent promising frontier medical with to significantly impact novel strategies for range diseases.

Language: Английский

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Small molecule-based immunomodulators for cancer therapy

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 12(12), P. 4287 - 4308

Published: Nov. 12, 2022

Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages regard pharmacodynamics (e.g., specificity and efficacy). However, they have limitations terms pharmacokinetics including long half-lives, poor tissue/tumor penetration, little/no oral bioavailability. In addition, therapeutic antibodies immunogenic, may cause unwanted adverse effects. Therefore, researchers shifted their efforts towards development small molecule-based immunotherapy, as molecules overcome above disadvantages associated with antibodies. Further, immunomodulators complementary modalities for treatment, be combined elicit synergistic Recent years witnessed rapid immunotherapy. this review, we describe current progress (inhibitors/agonists/degraders) therapy, those targeting PD-1/PD-L1, chemokine receptors, stimulator interferon genes (STING), Toll-like receptor (TLR), etc. The tumorigenesis mechanism various targets respective modulators that entered clinical trials also summarized.

Language: Английский

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Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions

Trends in Pharmacological Sciences, Journal Year: 2022, Volume and Issue: 43(9), P. 726 - 739

Published: June 23, 2022

Language: Английский

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Adjuvant physiochemistry and advanced nanotechnology for vaccine development

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(15), P. 5172 - 5254

Published: Jan. 1, 2023

This review provides an introduction of basic principles adjuvanted human vaccines in clinics and summarizes emerging nanotechnology adjuvants vaccine development against cancer infectious diseases.

Language: Английский

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Toll-like receptors and NLRP3 inflammasome-dependent pathways in Parkinson’s disease: mechanisms and therapeutic implications

Journal of Neurology, Journal Year: 2022, Volume and Issue: 270(3), P. 1346 - 1360

Published: Dec. 3, 2022

Abstract Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterized by motor and non-motor disturbances as result of complex not fully understood pathogenesis, probably including neuroinflammation, oxidative stress, formation alpha-synuclein (α-syn) aggregates. As age the main risk factor for several disorders PD, aging immune system leading to inflammaging immunosenescence may contribute neuroinflammation PD onset progression; abnormal α-syn aggregation in context dysfunction favor activation nucleotide-binding oligomerization domain-like receptor (NOD) family pyrin domain containing 3 (NLRP3) inflammasome within microglial cells through interaction with toll-like receptors (TLRs). This process would further lead Caspase (Cas)-1, increased production pro-inflammatory cytokines (PC), subsequent impairment mitochondria damage dopaminergic neurons. All these phenomena are mediated translocation nuclear kappa-B (NF-κB) enhanced reactive oxygen species (ROS). To date, drugs treat mainly aimed at relieving clinical symptoms there no disease-modifying options reverse or stop progression. review outlines role TLR/NLRP3/Cas-1 pathway PD-related dysfunction, also focusing on specific therapeutic that might be used since early stages counteract dysfunction.

Language: Английский

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NETosis: an emerging therapeutic target in renal diseases

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

Published: Sept. 8, 2023

Introduction Neutrophil extracellular traps (NETs) are web-like structures composed of nuclear and granular components. The primary role NETS is to prevent the dissemination microbes facilitate their elimination. However, this process accompanied by collateral proinflammatory adverse effects when NET release becomes uncontrollable, or clearance impaired. Although NET-induced organ damage conducted primarily indirectly via immune complexes subsequent cytokines, direct on cells also remarkable. NETosis plays a critical pathogenic in several renal disorders, such as early phase acute tubular necrosis, anti-neutrophil cytoplasmic antibody-mediated vasculitis, lupus nephritis, thrombotic microangiopathies, anti-glomerular basement membrane disease, diabetic nephropathy. Their substantial contribution course these disorders makes them desirable target therapeutic armamentarium. This article gives an in-depth review heterogeneous pathogenesis physiological regulations its pivotal diseases. Based pathogenesis, outlines current options possible molecular targets treatment NET-related disorders. Methods We carried out thorough literature research published PubMed Google Scholar, including comprehensive analysis classification, pathomechanisms, broad spectrum kidney Conclusions certain It initiates maintains inflammatory autoimmune thus making it for improving patient outcomes. Better understanding clinical translation crucial aspects treatment, patient,

Language: Английский

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Emerging treatments for myelodysplastic syndromes: Biological rationales and clinical translation

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(2), P. 100940 - 100940

Published: Feb. 1, 2023

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by myeloid dysplasia, peripheral blood cytopenias, and increased risk progression to acute leukemia (AML). The standard care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, nearly 50% have no response the treatment. Patients in whom HMA therapy has failed dismal prognosis approved second-line options, so enrollment clinical trials experimental agents represents these patients' only chance improved outcomes. A better understanding molecular biological mechanisms underpinning pathogenesis enabled development new that target alterations, death regulators, signaling pathways, immune regulatory proteins MDS. Here, we review novel therapies failed, an emphasis on rationale therapies' development.

Language: Английский

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Interplay of Chemokines Receptors, Toll-like Receptors, and Host Immunological Pathways

Biomedicines, Journal Year: 2023, Volume and Issue: 11(9), P. 2384 - 2384

Published: Aug. 25, 2023

A comprehensive framework has been established for understanding immunological pathways, which can be categorized into eradicated and tolerable immune responses. Toll-like receptors (TLRs) are associated with specific TH1 immunity is related to TLR7, TLR8, TLR9, while TH2 TLR1, TLR2, TLR6. TH22 linked TLR4, TLR5, THαβ (Tr1) TLR3, TLR9. The chemokine receptor CXCR5 a marker of follicular helper T cells, other also classified within based on host pathways. On the basis literature review chemokines following associations were identified: CCR5 responses, CCR1 TH1-like CCR4 (basophils) CCR3 (eosinophils) TH9 CCR10 CCR6 TH17 CXCR3 CCR8 regulatory cells (Treg), CCR2 TH3 These findings contribute identification biomarkers provide insights Understanding system crucial comprehending function innate system, as well adaptive

Language: Английский

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Effects of quercetin in preclinical models of Parkinson's disease: A systematic review

Basic & Clinical Pharmacology & Toxicology, Journal Year: 2024, Volume and Issue: 135(1), P. 3 - 22

Published: April 29, 2024

Abstract Parkinson's disease (PD) is a neurodegenerative that affects dopaminergic neurons, thus impairing signalling. Quercetin (QUE) has antioxidant and neuroprotective properties are promising for the treatment of PD. This systematic review aimed to investigate therapeutic effects QUE against PD in preclinical models. The search was performed PubMed, Scopus Web Science. At final screening stage, 26 articles were selected according pre‐established criteria. Selected studies used different methods induction, as well animal Most rats (73.08%) mice (23.08%), with 6‐OHDA main strategy induction (38.6%), followed by rotenone (30.8%). tested immersed oil, nanosystems or free formulations, varied routes administration doses, ranging from 10 400 mg/kg 5 200 oral intraperitoneal administrations, respectively. Overall, evidence published data suggests potential use PD, mainly through inhibition oxidative stress, neuroinflammatory response apoptotic pathways.

Language: Английский

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