Inflammopharmacology最新文献

Gasdermin D (GSDMD) is currently considered the major effector of pyroptosis, a lytic proinflammatory programmed cell death, which mediates pathogenesis in numerous inflammatory lung diseases, such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. When the N-terminal fragment of GSDMD is cleaved by both canonical (caspase-1) and noncanonical (caspase-4/5/11) inflammasome pathways, membrane pores of the protein are formed, which in turn facilitate cell lysis and the release of IL-18 and IL-1B. These events culminate in immune cell infiltration, epithelial endothelial barrier disruption, and tissue remodelling. This is a critical review of GSDMD-mediated pyroptosis as a convergent pathological mediator in a variety of inflammatory pulmonary diseases and synthesizes the findings from the to 2000-2024 literature databases. We also analyzed the mechanism by which GSDMD activation mediates immune cell recruitment, cytokine storm syndrome, and fibrotic remodelling in preclinical disease models. In addition, we performed a systematic evaluation of emerging therapeutic interventions such as direct pore formation inhibitors (disulfiram and necrosulfonamide), upstream caspase inhibitors (VX-765), and anti-inflammatory phytochemicals (andrographolide, emodin, and baicalin). In our analysis, GSDMD was the chosen therapeutic target, allowing precise regulation of terminal pyroptotic signalling without compromising upstream recognition by the immune system. This is a major advantage compared to traditional general immunosuppressants. This review reports that GSDMD is a promising therapeutic target for acute and chronic inflammatory lung disease. This study provides new mechanistic contributions and translational approaches to augment targeted anti-inflammatory interventions in respiratory care by precise pyroptosis modulation.

Background: Traumatic brain injury (TBI) is a complex neurological condition, with accumulating evidence highlighting the critical roles of neuroinflammation and oxidative stress in its pathogenesis. In this context, the present study has been designed to evaluate the neuroprotective mechanism of syringic acid, both individually and in combination with minocycline, against trauma-induced behavioural and biochemical impairments in a rat model of experimental brain injury.

Material and methods: Male Sprague-Dawley (SD) rats were undergone traumatic brain injury by the weight dropped method. Following the induction of traumatic brain injury and a subsequent two-week recovery period with syringic acid and minocycline administered either individually or in combination, for an additional two weeks. During the treatment phase, a series of behavioural assessments, including body weight monitoring, evaluation of locomotor activity, motor coordination, anxiety-like behaviour (via the elevated plus maze), and memory performance at different time intervals, were conducted to assess functional recovery. These were followed by biochemical evaluations of oxidative and antioxidant markers, mitochondrial enzyme complexes activities, acetylcholinesterase (AChE) levels, and TNF-α were evaluated in specific brain regions.

Results: TBI significantly reduced body weight and caused marked impairment in locomotor, motor coordination, memory performance, and anxiety-like behaviour. While also inducing blood-brain barrier disruption, cerebral edema, elevated TNF-α and AchE levels, and attenuating oxidative defence mechanisms and mitochondrial enzyme complex activities in discrete areas (cortex and hippocampus) of the brain, compared to the sham group. Treatment with syringic acid (25, 50, and 100 mg/kg) and minocycline (25 mg/kg) for 14 days significantly improved the behavioural and reversed biochemical impairments as compared to control group (TBI), which was comparable to that of salicylic acid (150 mg/kg). Further, the combination of syringic acid (25 mg/kg) with minocycline (25 mg/kg) treatment for 14 days demonstrated a significant neuroprotective effect as compared to their effect per se, suggesting a potential synergistic effect.

Conclusion: The current study demonstrates the involvement of microglial inhibitory mechanisms in the neuroprotective effect of syringic acid in an experimental model of TBI. The study highlights that the syringic acid in combination with minocycline could be used effectively against traumatic brain damage.

Pulmonary fibrosis is a serious threat to global health, especially in after math of covid-19 infection, eventually results in fibrotic remodeling and organ damage. This SARS-CoV 2 induced fibrosis initiates cascade of proinflammatory responses such as cytokine release. EMT (Epithelial-mesenchymal transition) is a central event in post COVID 19 pulmonary fibrosis which is characterized by the accumulation of stimulated fibroblast and myoblast, finally epithelial morphology changed to mesenchymal traits. This transformation is marked by the loss of intercellular adhesion and polarity. A study of SARS-CoV 2 pathogenesis and EMT can provide insights to pulmonary fibrosis. Hence identification of biomarkers of EMT activation helps early diagnosis and determination of therapeutic approaches against pathogenesis. This review focusing on the mechanism of post-covid 19 pulmonary fibrosis through EMT with a special importance to TGF-β/Smad, NF-κB pathways and oxidative stress. Previous studies marked the EMT induced fibronectin, collagen deposition that can potentially disrupt lung structure and its function. SARS CoV 2 infection can trigger Hyper activation of profibrotic pathways like TGF-β/Smad, NF-κB pathways that maintain EMT via downregulation of E-Cadherin and upregulation of vimentin, fibronectin and α-SMA. SARS-CoV spike-protein binds to AEC-2 cells initiates cytokine storm followed by amplified NF-κB pathway, and oxidative stress. Elevated activation of this pathway increases Snail, Slug, Twist expression that leads to EMT. Moreover, increased ROS production creates fibrotic environment in lung. This review examined the mechanism behind the pulmonary fibrosis by analyzing interplay between the SARS-CoV 2 infection and EMT, providing effective therapeutic strategies to prevent EMT.

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by persistent joint inflammation, cartilage degradation, and systemic complications. Phytochemicals such as curcumin, resveratrol, phenolic acids, flavonoids, lignans, and organosulfur compounds have demonstrated significant disease-modifying potential through modulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and key signaling pathways (NF-κB, MAPK, PI3K/AKT/mTOR). Curcumin, for example, regulates immune homeostasis by restoring the Th17/Treg balance and inhibiting NF-κB and mTOR signaling, while resveratrol suppresses angiogenesis via VEGF inhibition and induces apoptosis in fibroblast-like synoviocytes. Despite their pharmacological promise, poor aqueous solubility, rapid metabolism, and low systemic bioavailability limit clinical translation. Advances in nanoformulation technologies-including polymeric nanoparticles, liposomes, micelles, solid lipid nanoparticles, and stimuli-responsive carriers-have markedly improved phytochemical stability, pharmacokinetics, targeted delivery, and therapeutic efficacy. Analytical characterization methods such as dynamic light scattering, zeta potential analysis, FTIR, HPLC, and TEM facilitate precise formulation optimization and evaluation of biological interactions. Preclinical studies reveal that nano-curcumin can achieve efficacy comparable to methotrexate, while resveratrol-loaded gold nanoparticles enhance anti-inflammatory effects and joint-specific accumulation. This review integrates mechanistic insights, formulation strategies, and analytical approaches, highlighting the opportunities and regulatory considerations for translating nano-phytochemicals into clinically viable RA therapies.

Rheumatoid arthritis is a chronic systemic inflammatory disease that predominantly affects synovial joints, resulting in progressive joint damage, disability, and systemic effects. There are still unanswered questions regarding the origin and pathophysiological complexities of the disease despite advances in treatment. A systematic review of the complex molecular pathways involved in RA pathophysiology is presented. Among the molecular processes involved in RA pathophysiology are oxidative stress, activation of fibroblast-like synoviocytes, aberrant innate and adaptive immunity, and dysregulated cytokine signalling. Important inflammatory signalling pathways related to the inflammation and destruction of joints including NF-κB, JAK/STAT, and RANK will be detailed. We will discuss the molecular components of the disease and the genetic and epigenetic predispositions such as HLA-DRB1 alleles, non-HLA loci, and regulation of miRNA and DNA methylation. We will highlight environmental and lifestyle related risk factors including smoking, infections, gut dysbiosis, and hormones contributing to disease manifestation and maintenance. We will describe the autoantibodies, rheumatoid factor and anti-citrullinated protein antibodies, as diagnostic and prognostic RA biomarkers. This review will summarize studies from in vivo animal models and translational studies to illustrate contemporary treatment strategies and drug development based on lessons from molecular knowledge of RA studies. Furthermore, progressive paradigms such as personalized medicine and multi-omics methodologies are discussed as potential future strategies to advance prediction, monitoring, and management of RA. This review seeks to provide an updated, broader view of the molecular biology and risk factors for RA, ultimately supporting better clinical outcomes and precision therapy.

Background: Oxidative stress, neuroinflammation, and cellular senescence interact to drive Alzheimer's disease (AD) progression. SRS11-92 is a redox-active small molecule with reported cytoprotective effects. This study sought to determine whether SRS11-92 mitigates Aβ-evoked oxidative stress and cellular senescence, and to delineate the underlying mechanism.

Methods: SH-SY5Y cells were challenged with Aβ_25-35 and pretreated with SRS11-92. Oxidative stress (ROS, MDA, SOD activity, and GSH), inflammatory mediators (TNF-α, IL-1β, and IL-6), senescence markers (SA-β-gal, p53, p16, and p21), and Nrf2/HO-1/NF-κB proteins were quantified. Pathway dependence was assessed using the selective Nrf2 inhibitor ML385. 3xTg-AD mice received SRS11-92 for 6 weeks; cognitive function was assessed by novel object recognition, cortical neuronal integrity was assessed by Nissl staining, and cellular senescence in the hippocampus was evaluated by SA-β-gal.

Results: SRS11-92 attenuated Aβ_25-35-induced cytotoxicity in a dose-dependent manner in SH-SY5Y cells, reduced ROS and MDA, and restored SOD activity and GSH. It suppressed TNF-α, IL-1β, and IL-6, decreased the percentage of SA-β-gal-positive cells, and downregulated p53, p16, and p21. Mechanistically, SRS11-92 increased total and nuclear Nrf2 and upregulated HO-1, while restricting NF-κB p65 nuclear translocation. ML385 abrogated these molecular and phenotypic benefits, confirming that SRS11-92 acts via the Nrf2 pathway in vitro. In 3xTg-AD mice, SRS11-92 improved cognitive function, partially rescued cortical Nissl-positive neurons, and reduced the hippocampal SA-β-gal-positive burden.

Conclusions: SRS11-92 exerts significant neuroprotective effects, attributable to reducing stress-induced senescence via activating Nrf2/HO-1 and constraining NF-κB signalling.

Crassula species are traditionally used and possess anti-inflammatory properties, but Crassula tetragona L. remains largely unexplored. This study intended to characterize C. tetragona aerial parts' phytoconstituents and assess its anti-ulcerative potential via the PPARγ/SIRT1 pathway. Aerial parts of C. tetragona were extracted using n-hexane (CT1) and 70% aqueous methanol (CT2). Phytoconstituents were profiled by HPLC-ESI-MS/MS (negative ion mode), and phenolics were quantified by MRM-LC-ESI-MS/MS. Column chromatography and NMR were used to separate and identify the compounds. Ulcerative colitis (UC) was induced in rats by intrarectal acetic acid (AA). Animals were assigned into six groups: control group: orally received vehicle for 7 days, UC control group: orally received vehicle for 7 days, and a rectal infusion of 2 mL AA (4% v/v in saline) on the 8th day, 4 treated groups: received CT1 (200 and 400 mg/kg/day), or received CT2 (200 and 400 mg/kg/day), once daily for 7 days by oral gavage and 2 mL AA (4% v/v in saline) on the 8th day. HPLC-ESI-MS/MS identified 66 constituents, including 37 novel compounds, with CT2 exhibiting higher phenolic content. Naringenin, gallic acid, and quercetin were predominant. Five phenolic compounds were isolated from the bioactive extract CT2. Both CT1 and CT2 reduced AA-induced tissue damage, lowered inflammatory markers (calprotectin, CRP, TNF-α, IL-6), improved oxidative stress (reduced MDA, increased GSH, SOD), and upregulated SIRT1 and PPARγ. These results suggest C. tetragona attenuates UC via the SIRT1/PPARγ pathway, indicating its therapeutic potential.

Polymorphonuclear neutrophils (PMNs) contribute to the pathogenesis of arthritis by releasing excessive reactive oxygen species (ROS) and proteolytic enzymes, leading to joint damage. Targeting PMNs activation represents a promising therapeutic approach. This study aimed to evaluate the immunomodulatory and anti-arthritic effects of clove essential oil (CEO) and its main constituent, eugenol, through in vitro, in vivo, and in silico approaches. CEO chemical composition was determined by GC-MS. In vitro assays assessed PMNs degranulation (lysozyme release) and oxidative burst (NBT reduction), along with antioxidant, anti-hemolytic, and antiplatelet activities. Arthritis was induced in mice by CFA injection, and therapeutic efficacy was evaluated by paw edema, histopathology, and body weight monitoring. Molecular docking was conducted to predict interactions with inflammatory targets (COX-1, COX-2, TNF-α). GC-MS revealed 77.67% eugenol in CEO. Both CEO and eugenol significantly inhibited PMN degranulation (52.81% and 57.54%) and oxidative burst (41.85% and 75.41%; p < 0.001). CEO and eugenol also displayed strong antioxidant and anti-hemolytic activities, and reduced collagen-induced platelet aggregation. In vivo, treatment markedly reduced paw edema and histopathological damage without hepatic toxicity. Docking analysis suggested potential inhibitory interactions with COX-2 and TNF-α. CEO and eugenol exert potent anti-inflammatory and immunomodulatory effects by modulating PMNs activity, preventing oxidative stress, and alleviating arthritis symptoms. These findings highlight their therapeutic potential as natural candidates for managing arthritis and related inflammatory conditions.