Inflammopharmacology最新文献

Crohn's disease and ulcerative colitis (UC) are among the intestinal conditions that make up the category known as inflammatory bowel disease. Globally, UC prevalence and incidence are currently rising. There was substantial evidence that many pathways were involved in the pathophysiology of UC. Of these pathways, interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin and AMP-activated protein kinase (AMPK), Sphingosine kinase (SPHK)/ Sphingosine-1-phosphate, nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase (HO-1). While small-molecule pharmaceuticals and biologics are available to treat patients with UC, approximately one-third of people receiving treatment do not get better. To find an effective remedy for UC patients, new therapy and medication repurposing have therefore been thoroughly researched. Several medications, including rosiglitazone, amlodipine, felodipine, atorvastatin, metformin, pentoxifylline, nitazoxanide, nifuroxazide, carbocisteine, levetiracetam, topiramate, nicodamid, and vildagliptin, have been shown to have positive effects on multiple organs through their anti-inflammatory properties. Furthermore, data on gut barrier integrity, oxidative stress, and inflammatory pathways showed that these medications had a major favorable impact on these parameters in both cellular and clinical models of UC. Using the findings of in vitro, in vivo, and clinical investigations, the positive effects of these medications on UC are thoroughly outlined and examined in the present research. Having a better knowledge of these protective benefits and the basic mechanisms may make it possible for UC patients to take these medications effectively.

Rheumatoid arthritis (RA) is characterized by chronic synovitis with pannus formation and progressive joint destruction. Pannus growth relies on angiogenesis, and nitric oxide (NO) contributes to vascular and inflammatory signaling. Although Pelargonium sidoides (PS) has not been evaluated in experimental arthritis, prior work suggests that PS can modulate NO production in activated macrophages. Arthritis was induced with complete Freund's adjuvant (CFA) on day 0. On day 17, rats with ≥ 5% paw swelling were treated. From day 17 to day 27, rats received daily oral P. sidoides (100, 200, or 500 mg/kg), ibuprofen (100 mg/kg), or vehicle. Paw diameter was recorded during treatment. On day 27, tissues were collected for histopathology (inflammation, angiogenesis, granuloma formation, synovial hyperplasia) and blood was analysed for nitrite/nitrate (NOx) and oxidative/antioxidant markers (asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), superoxide dismutase (SOD), catalase, and glutathione). All doses of P. sidoides reduced paw oedema. The 200 mg/kg dose resulted in NOx levels and synovial microvessel densities that were numerically closer to healthy control values; however, these improvements did not reach statistical significance when compared directly to the vehicle group. Other oxidative markers showed no consistent changes. Plasma glutathione decreased across PS-treated groups without accompanying increases in MDA or body-weight loss, which is compatible with increased utilization during phytochemical clearance rather than overt systemic toxicity. In conclusion, P. sidoides improved macroscopic swelling in adjuvant arthritis and, at 200 mg/kg, showed numerical shifts toward control-like values in plasma NOx and synovial microvessel density, although studies with greater statistical power are needed to confirm these exploratory tissue-level signals.

Background: Osteoarthritis (OA) is a degenerative joint disease, which is accompanied by chronic pain and functional impairment, especially among the elderly population. Transdermal drug delivery offers a non-invasive option for managing OA. Our study assesses the relative effectiveness and safety of transdermal Buprenorphine compared to Diclofenac patches in the treatment of knee OA.

Research design and methods: A randomized controlled trial was performed in 152 patients with radiographically confirmed Grade I/II knee OA and with an age of 50 years and above. The participants were divided into two groups: Group A (transdermal buprenorphine) and Group B (transdermal diclofenac) as the treatment options to be used within 4 weeks. The Numeric Rating Scale (NRS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), and Lequesne Index were used to measure pain intensity, functional status, and disease severity, respectively. Network pharmacology analysis was also used to examine additional interactions such as safety, treatment compliance and molecular interactions.

Results: Both treatments reduced pain significantly as well as improved functional outcomes. Nevertheless, buprenorphine had a higher clinical efficacy with higher reductions in NRS scores (7.72 to 2.81 vs. 7.68 to 3.23), WOMAC total scores (71.5 to 31.8 vs. 74.0 to 45.6), and Lequesne Index values (17.4, to 5.87 vs. 17.3, to 8.42) than diclofenac. Network pharmacology analysis revealed that buprenorphine modulates 25 genes related to OA, while diclofenac affects 20 genes, suggesting that Buprenorphine may have a wider range of benefits. Both treatments demonstrated excellent tolerability.

Conclusions: Transdermal buprenorphine was found to have better short-term analgesic and functional advantages than transdermal diclofenac in early-stage knee OA. Its high tolerability, once-weekly topography and broad-spectrum interactions with its molecular targets justify its possible use in the treatment of a discrete group of patients, specifically older healthcare individuals or those intolerant to NSAIDs.

Psoriasis, long thought to be a chronic immune-mediated dermatological disease, is now being reclassified as a systemic inflammatory disease with substantial metabolic and hepatic complications. Psoriasis affects approximately 2-3% of global population and is associated with up to 50% risk of systemic comorbidities. This mini-review examines the evolving understanding of psoriasis pathogenesis, focusing on the interaction of immunological dysregulation, keratinocyte hyperproliferation, and systemic cytokine release. Tumour necrosis factor- alpha (TNF)-α, IL-17, IL-23, and IL-6 are pro-inflammatory mediators that cause cutaneous plaque formation and reach the systemic circulation, leading to insulin resistance, atherogenesis, and liver inflammation. The review identifies common immuno-metabolic pathways, including TNF-α/NF-κB activation, the IL-23/Th17 axis, and dysregulated PI3K/Akt/mTOR signalling, that contribute to psoriatic illness and associated disorders like metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). Epidemiological studies demonstrate that psoriasis patients have a high prevalence of obesity, type 2 diabetes, dyslipidaemia, regardless of established risk factors, supporting the updated classification of NAFLD as MASLD. These findings lend support to the idea that psoriasis is a multi-organ disease caused by chronic low-grade inflammation. Clinically, this requires a transition from skin-centred treatment to thorough systemic examination and customised, multidisciplinary management. Targeted biologic treatments, such as IL-17 and IL-23 inhibitors, offer potential for lowering both systemic inflammation and cutaneous symptoms. This review supports early screening, metabolic monitoring, and lifestyle changes as critical components of long-term psoriatic therapy. Recognising psoriasis as a systemic condition is critical for improving overall patient outcomes, lowering morbidity, and avoiding long-term consequences.

Complex progressive neurodegenerative Alzheimer's disease is characterized by cognitive decline, memory impairment, and accumulation of amyloid and tau pathologies, along with aggravation of neuroinflammatory and oxidative stress pathways. In our previous studies, the potential of azilsartan, a widely used angiotensin receptor blocker (ARB), was demonstrated to possess neuroprotective action when administered through intranasal route, improving memory and cognition through modulation of central renin-angiotensin signalling in a demented animal model. With the intranasal administration, azilsartan nanoemulgel offers the ability to bypass the BBB due to the use of the olfactory and trigeminal neural pathways, achieving direct brain targeting of the therapeutics. In the present study, the neuroprotective effect of azilsartan (5 mg/kg via intranasal route consequently for 45 days) was further validated in an AlCl₃-induced murine model of Alzheimer's dementia through investigation of mechanistic pathways. The results demonstrated that intranasal delivery of azilsartan significantly ameliorated cognitive decline when compared to standard drug donepezil, as evidenced from the behavioural tests, restored hippocampal oxidative balance (SOD, GSH, CAT), reduced lipid peroxidation (2.6-fold reduction in MDA levels compared to the AlCl₃-intoxicated group), and increased neuronal count. The biomarker study revealed suppression of inflammatory markers, reduction of Alzheimer's specific pathological markers, and significant restoration of neurotrophic pathways. To validate these findings, in silico molecular docking and dynamics simulations were conducted on the key markers TNFα, IL1β, PPARγ, BDNF, APP, and p-Tau, which showed strong and stable binding interactions with BDNF and PPARγ and moderate but persistent stabilization with APP and p-Tau, aligning with in vivo experimental outcomes. Therefore, the integrated computational and experimental evidence thus demonstrates that azilsartan exhibits neuroprotection, highlighting its potential as a therapeutic candidate for repurposing in Alzheimer's disease.

Protease-activated receptors (PARs) constitute a unique subfamily of G protein-coupled receptors comprising four members, PAR1-PAR4. PAR, which govern a broad spectrum of physiological and pathological processes. This review provides a comprehensive synthesis of the roles of PARs in mediating both metabolic dysfunction and inflammatory responses, exploring their potential as dual-function therapeutic targets. We analyze the current literature regarding PAR activation mechanisms and downstream signaling pathways, with a specific focus on their involvement in metabolic syndrome and inflammatory diseases. By evaluating experimental data from genetic ablation and pharmacological inhibition models, we demonstrate that while PAR activation often drives disease progression, targeted inhibition can successfully alleviate symptoms and delay pathogenesis. Ultimately, this review underscores the critical role of PARs in bridging metabolic and inflammatory crosstalk, suggesting that modulating these receptors offers a promising strategy for dual regulation of systemic homeostasis.

Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures, generally associated with an imbalance of neurotransmitters, neuroinflammation, and oxidative stress. Formononetin, a naturally occurring isoflavone found in several medicinal plants, has been previously explored for its anti-inflammatory and antioxidant effects in preclinical studies. These properties suggest a possible role of formononetin in modifying the pathological pathways underlying epilepsy. Pentylenetetrazol (PTZ)-induced kindling is one of the most reliable animal screening models for exploring the anti-epileptic potential of investigational natural compounds, such as formononetin, enabling its examination in reducing seizure susceptibility and severity in the mouse model. This study evaluates the anticonvulsant efficacy of formononetin by modulating neuroinflammation in a pentylenetetrazol-induced kindling mouse model. Male and female mice were divided into five groups: naïve, Negative control (PTZ-kindled), positive control (sodium valproate 200 mg/Kg), and PTZ + formononetin (10 mg/kg, 20 mg/kg, and 40 mg/kg). PTZ was administered at a dose of 40 mg/kg every alternate day, followed by assessment of seizure severity score using the Racine scale. Neuroinflammatory biomarkers (IL-1β, NF-κB) and neurotransmitter levels (GABA, Glutamate) were measured. Histopathology was performed to identify the morphological changes in the brains of mice following treatment. Formononetin exhibited dose-dependent anticonvulsant and neuroprotective effects in the PTZ-kindling mouse model, reducing seizure severity, improving motor coordination, and easing anxiety-like symptoms. It restored the glutamate-GABA balance, suppressed NF-κB and IL-1β expression, and preserved neuronal integrity, underscoring its potential as a multi-target therapeutic agent for epilepsy through modulation of neurotransmission and neuroinflammation.

Protease Activated Receptor 2 (PAR2/F2RL1) is a G protein coupled receptor, activated by proteolytic cleavage of its N-terminus tethered peptide. Its role in shaping the tumor immune microenvironment across different cancers remains poorly defined. This study presents an integrated immunogenomic and drug discovery approach to evaluate PAR2's role across 33 cancer types. Pan-cancer analysis revealed significant upregulation of PAR2 in eight tumor types, head and neck squamous cell carcinoma (HNSC) and lung adenocarcinoma (LUAD) showed high immunosuppressive signatures and poor prognostic through depletion of adaptive immune cells and enrichment of alternative checkpoint pathways. These findings suggest PAR2 as a viable target for reversing tumor immune suppression specially in PAR2 over expressing HNSC and LUAD. A structure based virtual screen of 5,954 compounds identified N-Acetyl-L-carnosine (NAC), a clinically used antioxidant not previously studied for GPCR binding as an orthosteric PAR2 binder. Molecular docking and molecular dynamics simulations showed that NAC forms a stable and energetically favourable binding with PAR2 at key residues (TYR326, ASP228), similar to the known antagonist AZ8838. NAC showed a predicted binding energy of -46.08 kcal/mol compared to -42.75 kcal/mol for the known antagonist AZ8838. MTT assay showed no toxicity with NAC treatment or in combination with the PAR2 activator SLIGKV. In wound-healing assays, NAC increased migration at higher concentrations and enhanced SLIGKV-induced motility, indicating that NAC does not inhibit PAR2 activity but may act as a context dependent modulator. Together, these results identify PAR2 as an immunotherapeutic target for cancers of HNSC and LUAD, and highlights NAC as a PAR2-binding molecule whose functional impact on PAR2 signalling requires further validation through direct receptor-signalling assays.

Rheumatoid arthritis is an autoimmune disorder characterized by cartilage destruction, joint inflammation, and systemic complications. Incomplete disease remission, adverse effects, and limited treatment availability underscore the need for novel therapeutic interventions. With this ultimate goal, the aim of the current study was to assess the anti-inflammatory and antiarthritic potential of chloroform and ethanol extracts of Celtis eriocarpa Decne. Gas chromatography coupled with mass spectrometry (GC-MS) analysis of these extracts revealed the presence of diverse bioactive compounds with well-recognized anti-inflammatory and antiarthritic activities, including phytol, neophytadiene, tocopherols, hexadecenoic acid methyl ester, squalene, and 2-tert-butylphenol derivatives. In vitro assays demonstrated significant, dose-dependent inhibition of protein denaturation by these extracts, with the activity of the chloroform fraction comparable to that of the diclofenac sodium standard. In vivo studies in a formaldehyde-induced arthritis rat model revealed significantly reduced paw edema and arthritis scores and improved mobility after oral administration of Celtis eriocarpa chloroform extracts (CE). Radiographic analysis further confirmed joint preservation in a rat model treated with CE. Histopathological assessments indicated marked reductions in synovial hyperplasia, cartilage erosion, and inflammatory cell infiltration, specifically in the high-dose CE groups. Finally, hematological and biochemical evaluations revealed normalization of inflammatory markers, downregulation of the expression levels of key proinflammatory cytokines (TNF-α, IL-6, NF-κB, IL-1β, and COX-2), and upregulation of the expression levels of anti-inflammatory cytokines (IL-4 and IL-10). Collectively, these findings demonstrate that Celtis eriocarpa extracts are enriched in bioactive phytoconstituents and hold substantial potential as therapeutic candidates for the management of rheumatoid arthritis and inflammatory disorders.