Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy DOI Creative Commons
Haitao Liu, Nadezda A. Stepicheva, Sayan Ghosh

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 13, 2022

Abstract The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause blindness worldwide. Here we set out to explore Akt2 signaling—integral both RPE homeostasis and glucose metabolism—to DR. Using human tissue genetically manipulated mice (including RPE-specific conditional knockout (cKO) knock-in (KI) mice), investigate whether Akts influences DR models eye disease. We found that Akt1 activities were reciprocally regulated donor mice. cKO attenuated diabetes-induced abnormalities through compensatory upregulation phospho-Akt1 inhibition vascular injury, inflammatory cytokine release, infiltration immune cells mediated by GSK3β/NF-κB signaling pathway; overexpression has no effect. propose targeting activity may be novel therapy for treating

Language: Английский

Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging DOI Creative Commons

Yi Mou,

Yu Du, Lixing Zhou

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: April 7, 2022

It has been noticed in recent years that the unfavorable effects of gut microbiota could exhaust host vigor and life, yet knowledge theory are just beginning to be established. Increasing documentation suggests microbiota–gut–brain axis not only impacts brain cognition psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s (PD), multiple sclerosis (MS). How blood–brain barrier (BBB), a machinery protecting central nervous system (CNS) from systemic circulation, allows risky factors derived translocated into seems paradoxical. For unique anatomical, histological, immunological properties underpinning its permeable dynamics, BBB regarded biomarker associated with neural pathogenesis. The permeability mice rats caused by GM dysbiosis raises question how metabolites change causes pathophysiology neuroinflammation neurodegeneration (NF&ND) aging, pivotal multidisciplinary field tightly immune chronic inflammation. If all, microbiota-induced inflammation (GM-SCI) mainly refers excessive mucosal immunity dysregulation, which is often influenced dietary components age, produced at interface intestinal (IB) or exacerbated after IB disruption, initiates various common diseases along dispersal routes, eventually impairs integrity cause NF&ND aging. To illustrate roles affected inflammatory “leaky” resulting their metabolites, we reviewed selected publications, including role barrier, influences on permeability, NF&ND, add depth bridging inflammation, plausible mechanism indispensable for corruption was highlighted; namely, maintenance cues cytokines, may help understand play major

Language: Английский

Citations

226
GSK-3β: An exuberating neuroinflammatory mediator in Parkinson's disease DOI Creative Commons
Sabiya Samim Khan,

Sushmita Janrao,

Saurabh Srivastava

et al.

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 210, P. 115496 - 115496

Published: March 11, 2023

Neuroinflammation is a critical degradative condition affecting neurons in the brain. Progressive neurodegenerative conditions such as Alzheimer's disease and Parkinson's (PD) have been strongly linked to neuroinflammation. The trigger point for inflammatory cells body physiological immune system. response mediated by glial astrocytes can rectify alterations occurring cell time being but prolonged activation leads pathological progression. proteins mediating an response, per available literature, are undoubtedly GSK-3β, NLRP3, TNF, PPARγ, NF-κB, along with few other mediatory proteins. NLRP3 inflammasome undeniably principal instigator of neuroinflammatory regulatory pathways controlling its still unclear, besides less clarity interplay between different Recent reports suggested involvement GSK-3β regulating activation, exact mechanistic pathway remains vague. In current review, we attempt provide elaborate description crosstalk markers neuroinflammation progression, linking it transcription factors posttranslational modification recent clinical therapeutic advances targeting these also discussed parallel comprehensive view progress made PD management lacunas existing field.

Language: Английский

Citations

42
Emerging Targets in Amyotrophic lateral sclerosis (ALS): The Promise of ATP-Binding Cassette (ABC) transporter Modulation DOI
Maneesh Mohan, Ashi Mannan,

Aayush Nauriyal

et al.

Behavioural Brain Research, Journal Year: 2024, Volume and Issue: 476, P. 115242 - 115242

Published: Sept. 6, 2024

Language: Английский

Citations

11
Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis DOI Creative Commons

In‐Woon Baek,

Jung Woo Rhim,

Kyungsu Park

et al.

Arthritis Research & Therapy, Journal Year: 2025, Volume and Issue: 27(1)

Published: Feb. 8, 2025

Systemic juvenile idiopathic arthritis (sJIA) is the most severe subtype of JIA, with a combination diverse clinical manifestations and variable course. A comprehensive understanding molecular signatures at systems level discovery subtypes are initial steps toward personalized medicine in sJIA. blood transcriptomic dataset was collected from patients systemic JIA (n = 168), polyarticular 254), oligoarticular 96), enthesitis-related 40), healthy controls 220). Gene expression profiles were filtered for differentially expressed genes unsupervised clustering, gene set enrichment, network-based centrality analyses. The three novel sJIA subgroups (designated as C1, C2, C3) investigated, focusing on their distinct features treatment responses. Neutrophil degranulation IL-1 signaling pathway shared key processes subgroups. Proinflammatory signals, including TNF, IL-6, TLR, G-CSF pathways, identified variation across C1 inflammatory subset high-risk profile macrophage activation syndrome. C2 had activated IL-18 pathways. C3 have higher levels interferon-stimulated signatures. In canakinumab-treated dataset, response correlated IL1B NF-κB pathway, neutrophil activation-associated effectively suppressed good responder group. GSK3B p38 MAPK inhibitors showed significant counteracting effect perturbed feature active scheme enables formulation precision strategies

Language: Английский

Citations

1
Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites DOI Creative Commons
Ricarda Cortés-Vieyra,

Octavio Silva-García,

Anel Gómez‐García

et al.

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: May 4, 2021

Knowledge of glycogen synthase kinase 3β (GSK3β) activity and the molecules identified that regulate its function in infections caused by pathogenic microorganisms is crucial to understanding how intensity inflammatory response can be controlled course infections. In recent years many reports have described small molecular weight synthetic natural compounds, proteins, interference RNA with potential GSK3β reduce deleterious effects response. Our goal this review summarize most advances on role bacteria, bacterial virulence factors (i.e. LPS others), viruses, parasites regulation activity, mainly inhibition different type molecules, modulates inflammation.

Language: Английский

Citations

46
Lithium carbonate alleviates colon inflammation through modulating gut microbiota and Treg cells in a GPR43-dependent manner DOI

Shengjie Huang,

Shiping Hu, Shuang Liu

et al.

Pharmacological Research, Journal Year: 2021, Volume and Issue: 175, P. 105992 - 105992

Published: Nov. 18, 2021

Language: Английский

Citations

46
Calpain Inhibitors as Potential Therapeutic Modulators in Neurodegenerative Diseases DOI
Heena Khan, Nikhil Garg, Thakur Gurjeet Singh

et al.

Neurochemical Research, Journal Year: 2022, Volume and Issue: 47(5), P. 1125 - 1149

Published: Jan. 4, 2022

Language: Английский

Citations

35
Regulation of Autophagy by the Glycogen Synthase Kinase-3 (GSK-3) Signaling Pathway DOI Open Access

Hsuan-Yeh Pan,

Mallika Valapala

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1709 - 1709

Published: Feb. 1, 2022

Autophagy is a vital cellular mechanism that benefits maintenance and survival during cell stress. It can eliminate damaged or long-lived organelles improperly folded proteins to maintain homeostasis, development, differentiation. Impaired autophagy associated with several diseases such as cancer, neurodegenerative diseases, age-related macular degeneration (AMD). Several signaling pathways are the regulation of pathway. The glycogen synthase kinase-3 pathway was reported regulate In this review, we will discuss mechanisms by which GSK-3 regulates autophagy. lysosomal function regulated transcription factor EB (TFEB). shown be involved in TFEB nuclear expression an mTORC1-dependent manner. addition mTORC1, GSK-3β also via protein kinase C (PKC) eukaryotic translation initiation 4A-3 (eIF4A3) pathways. TFEB, modulating other molecules inducers including, AKT ULK1. summary, review provides comprehensive understanding role

Language: Английский

Citations

34
Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases DOI
Teresa Gianferrara,

Eleonora Cescon,

Ilenia Grieco

et al.

Current Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 29(27), P. 4631 - 4697

Published: Feb. 16, 2022

GSK-3β activity has been strictly related to neuroinflammation and neurodegeneration. Alzheimer's disease is the most studied neurodegenerative disease, but seems be involved in almost all diseases, including Parkinson's amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's autoimmune multiple sclerosis.This review aims help researchers both working on this research topic or not have a comprehensive overview of context neurodegeneration.Literature searched using PubMed SciFinder databases by inserting specific keywords. A total more than 500 articles discussed.First all, structure regulation kinase were briefly discussed, then, implications diseases illustrated with figures, conclude important multitarget inhibitors. The IC50 values at target reported for discussed compounds.GSK-3β several signaling pathways neurons, glial cells immune cells. fine interconnection these are base rationale use GSK-β inhibitors Some compounds now under clinical trials. Despite this, compounds' pharmacodynamic ADME/Tox profiles often fully characterized which deleterious such complex system.

Language: Английский

Citations

30
How many kinases are druggable? A review of our current understanding DOI Creative Commons
Brian Anderson,

Peter Rosston,

Han Wee Ong

et al.

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(16), P. 1331 - 1363

Published: Aug. 29, 2023

There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible discover a drug each individual kinase? For every kinase, we gathered data on their citation count, availability of chemical probes, approved investigational drugs, PDB structures, biochemical cellular assays. Analysis these factors highlights which kinase groups have wealth information available, still room progress. The suggest disproportionate focus the more well characterized while much kinome remains comparatively understudied. It noteworthy that tool compounds understudied already been developed, there untapped potential further development this space. Finally, review discusses different strategies employed generate selectivity between kinases. Given large volume available progress made past 20 years when comes drugging kinases, believe develop compound kinase. We hope will prove be both useful resource as inspire discovery

Language: Английский

Citations

21