Pyroptosis for osteoarthritis treatment: insights into cellular and molecular interactions inflammatory

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 1, 2025

Osteoarthritis (OA) is a widely prevalent chronic degenerative disease often associated with significant pain and disability. It characterized by the deterioration of cartilage extracellular matrix (ECM), synovial inflammation, subchondral bone remodeling. Recent studies have highlighted pyroptosis-a form programmed cell death triggered inflammasome-as key factor in sustaining inflammation. Central to this process are inflammatory cytokines interleukin-1β (IL-1β) interleukin-18 (IL-18), which play crucial roles mediating intra-articular pyroptosis through NOD-like receptor protein 3 (NLRP3) inflammasome. This paper investigates role pathway perpetuating diseases its linkage OA. Furthermore, it explores mechanisms pyroptosis, mediated nuclear κB (NF-κB), purinergic P2X ligand-gated ion channel 7 (P2X7R), adenosine monophosphate (AMP)-activated kinase (AMPK), hypoxia-inducible factor-1α (HIF-1α). Additionally, examines interactions among various cellular components context These insights indicate that targeting regulation presents promising therapeutic approach for prevention treatment OA, offering valuable theoretical perspectives effective management.

Language: Английский

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Neuroprotective mechanisms of microglia in ischemic stroke: a review focused on mitochondria

Molecular Biology Reports, Journal Year: 2025, Volume and Issue: 52(1)

Published: April 1, 2025

Language: Английский

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Manual acupuncture enhanced therapeutic efficacy in vascular dementia rat model: systematic review and network meta-analysis

Systematic Reviews, Journal Year: 2025, Volume and Issue: 14(1)

Published: April 5, 2025

This study aimed to systematically evaluate the efficacy of electroacupuncture and manual acupuncture for treating vascular dementia determine optimal point combination scheme efficacy. The PubMed, Embase, Web Science, Cochrane, CNKI, VIP, Wanfang electronic databases were searched up July 2024 identify relevant randomized controlled trials. RevMan 5.4 software Addis used assess risk bias each study, subgroup classifications, conduct meta-analyses. A total 29 RCTs involving 659 animals ultimately included. meta-analysis results revealed that treatment had a significant effect compared with model group [mean difference (MD) = - 21.68, 95% confidence interval (CI) (- 25.77, 17.59), P < 0.00001]. Manual demonstrated better than did [MD 0.42, CI 12.72, 12.27)]. Among different combinations, Baihui (GV20) + Dazhui (GV14) yielded best 23.03, 30.02, 16.04), Compared other protocols, experiment conducted by Caiyu Peng et al. exhibited superior 24.96, 92.68, 40.76)]. Acupuncture significantly improves cognitive function in rats dementia. is more effective electroacupuncture. at GV20 GV14 yields results. was observed when two-vessel occlusion (2VO) 230 ± 10 g SD rats; Mingmen (GV4), (GV14), Fengfu (GV16), (GV20), Shenting (GV24), Shuigou (GV26), Neiguan (PC6), Dalin (PC7), Laogong (PC8) acupoints selected; reinforcing reducing methods 30 min per day 14 days. PROSPERO CRD42024551402.

Language: Английский

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CMPK2 promotes microglial activation through the cGAS-STING pathway in the neuroinflammatory mechanism

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 7, 2025

The activation of microglia and the resulting neuroinflammation play crucial regulatory roles in pathogenesis progression neurological diseases, although specific mechanisms remain incompletely understood. Cytidine monophosphate kinase 2 (CMPK2) is a key mitochondrial nucleotide involved cellular energy metabolism synthesis. Recent studies suggest that CMPK2 plays role microglial-mediated neuroinflammation; however, its impact on microglial remains unclear. In this study, we hypothesize promotes by activating cGAS-STING signaling pathway. To investigate mechanism, employed lipopolysaccharide (LPS)-treated cells to detailed which regulates neuroinflammation. Our experimental results indicate BV2 mouse primary model, both protein transcript levels were significantly elevated, accompanied phenotypes such as increased cell size, shortened processes, transformation round or rod-like shapes, elevated CD40 expression. Concurrently, there was an increase pro-inflammatory cytokine decrease anti-inflammatory levels. Further investigation revealed microglial, expression cGAS STING along with oxidative products inflammatory responses. CMA stimulation further intensified these changes, while knockdown mitigated them. Finally, demonstrated inhibited stress, activation-related neuroinflammatory responses induced overexpression model. Molecular docking experiments showed stably binds at level. These findings pathway mediates CMPK2-induced activation. summary, our study demonstrates LPS-induced overactivity through

Language: Английский

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Dehydroabietic acid protects against cerebral ischaemia–reperfusion injury by modulating microglia‐mediated neuroinflammation via targeting PKCδ

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Abstract Background and Purpose Cerebral ischaemia–reperfusion injury (CIRI) is a major contributor to global morbidity mortality, although its underlying mechanisms remain only partly understood. Emerging evidence indicates that inhibiting microglia‐mediated neuroinflammation would be an effective therapeutic approach for CIRI, pharmacological interventions targeting this pathway hold significant promise. This study aimed identify potent anti‐inflammatory drug from natural compound library as potential treatment CIRI. Experimental Approach We used oxygen–glucose deprivation/reperfusion (OGD/R) middle cerebral artery occlusion in male C57BL/6 mice evaluate the efficacy of DHA neurological deficits effects. Using BV2 cells murine brain tissue, liquid chromatography–tandem mass spectrometry was molecular targets DHA, followed by bio‐layer interferometry, docking, dynamics simulations cellular thermal shift assays validate DHA's binding interactions with protein kinase C delta (PKCδ). Key Results decreased production pro‐inflammatory cytokines following OGD/R, thereby protect neurons reducing infarct size improving outcomes. Mechanistically, directly bound PKCδ, phosphorylation downstream NF‐κB signalling. interaction involved TRP 55 LEU 106 on confirmed docking other biophysical techniques. Conclusion Implications specifically interacts preventing induced injury. These results suggest novel inhibitor PKCδ provide solid experimental foundations using treating neuroinflammation‐related conditions, such

Language: Английский

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LincRNA-p21/AIF-1/CMPK2/NLRP3 pathway promoted inflammation, autophagy and apoptosis of human tubular epithelial cell induced by urate via exosomes

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 5, 2024

Urate nephropathy, a common complication of hyperuricemia, has garnered increasing attention worldwide. However, the exact pathogenesis this condition remains unclear. Currently, inflammation is widely accepted as key factor in urate nephropathy. Therefore, aim study was to elucidate interaction lincRNA-p21/AIF-1/CMPK2/NLRP3 via exosomes This evaluated effect using clinical data collected from patients with nephropathy and human renal tubular epithelial cells (HK2) cultured different concentrations urate. In research section, level lincRNA-p21/AIF-1 urine hyperuricemia or found be increased, particularly vitro exosomes, inflammation, autophagy, apoptosis increased HK2 induced by Additionally, expression lincRNA-p21, AIF-1, CMPK2, NLRP3 upregulated cells. Furthermore, manipulating activity through overexpression interference vectors regulated conclusion, pathway contributed cell exosomes. specific might serve novel biomarkers for

Language: Английский

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CircFndc3b Mediates Exercise‐Induced Neuroprotection by Mitigating Microglial/Macrophage Pyroptosis via the ENO1/KLF2 Axis in Stroke Mice

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 28, 2024

Circular RNA (circRNA) plays a pivotal role in regulating neurological damage post-ischemic stroke. Previous researches demonstrated that exercise mitigates dysfunction after ischemic stroke, yet the specific contributions of circRNAs to exercise-induced neuroprotection remain unclear. This study reveals mmu_circ_0001113 (circFndc3b) is markedly downregulated penumbral cortex mouse model subjected middle cerebral artery occlusion (MCAO). However, increased circFndc3b expression microglia/macrophages, alleviating pyroptosis, reducing infarct volume, and enhancing recovery MCAO mice. Mechanistically, interacted with Enolase 1 (ENO1), facilitating ENO1's binding 3' Untranslated Region (3'UTR) Krüppel-like Factor 2 (Klf2) mRNA, thereby stabilizing Klf2 mRNA increasing its protein expression, which suppressed NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated microglial/macrophage pyroptosis. Additionally, enhanced interaction 3'UTR Fused Sarcoma (FUS) leading FUS levels promoting cyclization. These results suggest mediates anti-pyroptotic effects via ENO1/Klf2 axis, circFndc3b/ENO1/FUS positive feedback loop may potentiate exercise's neuroprotective effects. unveils novel mechanism underlying stroke positions as promising therapeutic target for management, mimicking beneficial exercise.

Language: Английский

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Nordihydroguaiaretic acid suppresses ferroptosis and mitigates intervertebral disc degeneration through the NRF2/GPX4 axis

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 143, P. 113590 - 113590

Published: Nov. 15, 2024

Language: Английский

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Discovery of Balasubramide Derivative with Tissue‐Specific Anti‐Inflammatory Activity Against Acute Lung Injury by Targeting VDAC1

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Abstract Macrophage‐mediated inflammatory responses including pyroptosis are involved in the pathogenesis of sepsis and acute lung injury (ALI), for which there currently no effective therapeutic treatments. The natural product (+)‐Balasubramide is an eight‐membered lactam compound extracted from leaves Sri Lanka plant Clausena Indica has shown anti‐inflammatory activities, but its poor pharmacokinetic properties limit further application ALI. In this study, a (+)3C‐20 discovered with improved both activity series derivatives. exhibits markedly enhanced inhibitory effect against LPS‐induced expressions pro‐inflammatory factors mouse macrophages human PBMCs ALI patients shows preferable tissue distribution mice. remarkably attenuates through tissue‐specific actions. Mechanistically, chemical proteomics study that directly binds to mitochondrial VDAC1 inhibits oligomerization block mtDNA release, preventing NLRP3 inflammasome activation. These findings identify as novel inhibitor promising potential associated inflammation.

Language: Английский

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Deep Proteome Coverage of Microglia Using a Streamlined Data-Independent Acquisition-Based Proteomic Workflow: Method Consideration for a Phenotypically Diverse Cell Type

Proteomes, Journal Year: 2024, Volume and Issue: 12(4), P. 35 - 35

Published: Nov. 27, 2024

As the primary innate immune cells of brain, microglia play a key role in various homeostatic and disease-related processes. To carry out their numerous functions, adopt wide range phenotypic states. The proteomic landscape represents more accurate molecular representation these phenotypes; however, present unique challenges for analysis. This study implemented streamlined liquid- gas-phase fractionation method with data-dependent acquisition (DDA) parallel accumulation–serial fragmentation (PASEF) analysis on TIMS-TOF instrument to compile comprehensive protein library obtained from adult-derived, immortalized mouse low starting material (10 µg). empirical consisted 9140 microglial proteins was utilized identify an average 7264 proteins/run single-shot, data-independent (DIA)-based cell lysate digest (200 ng). Additionally, predicted facilitated identification 7519 same DIA data, revealing complementary coverage compared collectively increasing approximately 8000 proteins. Importantly, several microglia-relevant pathways were uniquely identified approach. Overall, we report simplified, reproducible approach address proteome complexity using sample input show importance optimization this phenotypically diverse type.

Language: Английский

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