Inflammopharmacology最新文献

Protein Kinase C (PKC), a zinc-dependent signaling enzyme pivotal for neuronal survival and synaptic plasticity, has emerged as a central player in the pathogenesis of Alzheimer's disease (AD). Dysregulated PKC activity contributes to amyloid-β accumulation, tau-driven neurofibrillary tangles, and chronic neuroinflammation, mediated through key molecular cascades such as NF-κB, GSK-3β, and MAPK. Notably, conditions such as osteoporosis and rheumatoid arthritis further illustrate how chronic cytokine release can link systemic inflammation to PKC dysregulation and subsequent neurodegeneration. Although mechanistic insights into these pathways have expanded, AD remains a therapeutic enigma with no disease-modifying interventions available. Interestingly, traditional Indian medical texts like the Charaka-Samhita documented herbal and metallic remedies, including gold-based formulations such as Swarna Prashana, reputed for enhancing cognition. Translating this ancient wisdom into modern medicine, aurothioglucose, an FDA-approved agent for rheumatoid arthritis, has demonstrated potent anti-inflammatory properties through PKC modulation. Emerging preclinical evidence now positions aurothioglucose as a promising neuroprotective candidate, capable of mitigating oxidative stress, dampening neuroinflammation, and preserving synaptic integrity via PKC-linked pathways. This review underscores the evolving role of aurothioglucose in AD, highlighting its potential to bridge traditional knowledge with contemporary therapeutics, while emphasizing the pressing need for translational studies to confirm its disease-modifying efficacy, as supported by evidences from current state of art.

Reactive oxygen species (ROS) and nitrogen-derived oxidants, such as nitric oxide (NO), are produced by immune cells through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and nitric oxide synthases (NOS), respectively. These pro-oxidants disrupt physiological homeostasis, contributing to hyperalgesia, the excessive release of inflammatory markers and oxidative stress during ulcerative colitis (UC). Consequently, diphenyleneiodonium chloride (DPI), an inhibitor of NOXs and NOS, could be effective in alleviating visceral pain and UC. This study examines the antioxidant and analgesic properties of DPI, as well as its ability to modulate oxidative stress and pro-inflammatory responses in UC. The antioxidant properties of DPI and its ability to bind free iron were determined using ABTS and DPPH tests, as well as a ferrous iron chelating capacity assay. DPI's analgesic activity was investigated using a 0.6% acetic acid (AA) mouse model of hyperalgesia, and its preventive effects against UC were determined using a 3% AA rat model of UC. Our results demonstrate that DPI limits free radicals, chelates ferrous iron and reduces writhing number (Wn) by p < 0.001, confirming its analgesic activity. Furthermore, intraperitoneal administration of DPI (100 ng/kg) protected rats from UC by repairing large-scale colonic damage, lowering oxidative stress by decreasing NO levels and restoring antioxidant enzymatic activities in colonic tissue. DPI also lowers plasmatic C-reactive protein (C-RP), NO content, lactate dehydrogenase (LDH) and γ-glutamyl transferase (γ-GT) activity during colitis. Therefore, targeting NOXs and NOS with DPI could be a promising strategy for treating inflammatory diseases such as colitis.

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.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to global effects. COVID-19 causes pulmonary and extra-pulmonary manifestations. One of the most common extra-pulmonary manifestations is gastrointestinal (GI) manifestation. Enteric COVID-19 triggers changes in the diversity of gut microbiota (dysbiosis). Dysbiosis of gut flora increases gut permeability, resulting in secondary bacterial infections, systemic inflammation, and injury of the peripheral organs. Dysbiosis may affect the immune system and pulmonary response to the SARS-CoV-2 invasion, suggesting a link between the lungs and gut through the gut-lung axis. Intestinal inflammation caused by SARS-CoV-2 infection induces leaky gut with subsequent transmission of toxins and antigens to the systemic circulation, causing further worsening of the septic condition in COVID-19 patients. Therefore, the anti-inflammatory agents' interruption of the gut-lung axis may reduce respiratory complications due to intestinal inflammation in COVID-19. Rifaximin (RXM) is a semi-synthetic antibacterial drug derived from natural rifamycin that acts locally within GI by inhibiting bacterial RNA polymerase and reducing the bacterial population and associated intestinal inflammation. RXM inhibits bacterial adherence to the intestinal epithelial lining and translocation across this GI lining. RXM has anti-inflammatory effects by inhibiting the release of pro-inflammatory cytokines and modulating the gut pregnane X receptor (PXR). RXM acts as a prebiotic in maintaining the growth of gut microbiota and may prevent the development of COVID-19-induced dysbiosis. Therefore, RXM could be effective in managing COVID-19 and associated inflammatory complications. Therefore, this review aims to discuss the potential role of RXM in managing COVID-19.

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.

Among the chronic and progressive autoimmune disorders that primarily affect joints in the hands, wrists, and knees, rheumatoid arthritis (RA) is a highly prevalent one. A significant number of patients develop severe adverse events, display weak responses, or cannot afford long-term use of the current RA medications, requiring more efficient and safer curative alternatives. increasing evidence recommends the application of mesenchymal stem cells (MSCs)-based therapy for mitigating chronic inflammation and boosting tissue renewal in intractable disorders. Moreover, sodium hydrosulphide (NaHS) has recently been found to have anti-inflammatory effects. Therefore, this study compared the therapeutic outcomes of four approaches; bone marrow-derived mesenchymal stem cells (BM-MSCs), their conditioned media (CM), BM-MSCs pre-conditioned with NaHS, and their conditioned media in a rat model of adjuvant-induced polyarthritis. The process involved the isolation of MSCs from rat bone marrow, propagation, and characterization of the isolated cells. polyarthritis was induced in male Wistar rats via intradermal injection of type II collagen on day 0 and day 21. Affected rats were treated with naproxen, BM-MSCs, BM-MSCs-CM, NaHS, BM-MSCs preconditioned with NaHS, or BM-MSCs preconditioned with NaHS-CM. The results indicated that the administered cells homed to the bone marrow and bone trabeculae of the knee joint tissue of the afflicted rats. The proposed treatments brought about significant down-regulation of peptidyl arginine deiminase 2 (PAD2) and chemokine ligand 13 (CXCL13) genes as well as angiopoietin-1 (Ang-1) protein expression, along with substantial upregulation of the galectin-1 (GAL-1) gene and osteoprotegerin (OPG) protein expression. Compared with BM-MSCs therapy, the treatment with BM-MSCs preconditioned with NaHS and their CM exhibited superior effect, with values close to those of the controls. In addition, treatment with the CM of BM-MSCs offered a lesser effect compared to BM-MSCs therapy alone. In conclusion, NaHS has the potential to improve the therapeutic capability of BM-MSCs for RA in rats by enhancing their anti-inflammatory, immunomodulatory, and regenerative capacity.

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disorder with complex pathophysiology. Disease cycle involves immune/inflammatory cells (macrophages, CD4 + , T, and B-cells) that directly/indirectly augment NF- κB mediated inflammation/oxidative stress and vice-versa creating a vicious loop that worsens disease. Inhibition of NF-κB signalling has emerged as a target for RA alleviation thus, this study evaluates the capability of Cassia fistula leaf extracts in supressing NF-κB signalling and contribution of sennoside B in extract efficacy.

Methods: Extracts were prepared and its anti-inflammatory (IL-1β, TNF-α, IL-6, IL-17a), anti-oxidant (NO, MDA, catalase, reduced glutathione), NF-κB inhibition potential, and its effect on joint microstructure was evaluated on collagen-induced arthritis. Extracts were characterized using LC-MS and effect of sennoside B (anthraquinone glycoside detected in extracts) on NF-κB signalling was evaluated on LPS stimulated peritoneal macrophages.

Results: Ethanolic extract of C. fistula leaf significantly inhibited NF-κB signalling (transcriptional/translational level), which led to significant reduction of inflammatory mediators (IL-1β, TNF-α, IL-6, IL-17a), and restored redox imbalance (NO, MDA, catalase, and reduced glutathione). Reduced NF-κB activity supressed tissue remodelling and osteoclastogenesis markers (MMP-2, MMP-9, MMP-13, and RANKL) which resulted in joint microstructure safe-guarding, also reflected as reduced paw swelling, paw volume and disease score significantly. Sennoside B showed strong anti-inflammatory and NF-κB inhibition against LPS-stimulated peritoneal macrophages.

Conclusion: Ethanolic extract of C. fistula leaves alleviate RA by modulating NF-κB mediated inflammation and oxidative stress and disrupts the disease worsening feedback cycle. Sennoside B's capability to suppress NF-κB production/activation also plays an important role in increasing extract efficacy.

Several disrupted metabolic pathways contributed to the development of Parkinson's disease (PD). Progressive death of dopamine (DA) neurons in the substantia nigra pars compacta, abnormal aggregation of α-synuclein fibrils, and inflammation of the neural system are the hallmarks of PD. The kynurenine pathway (KP) becomes disrupted, and excitotoxic branches are activated by elevated levels of central inflammatory regulators in PD. This leads to a significant reduction in the neural protective metabolite, kynurenic acid (KYNA), and an increase in the neurotoxic metabolite, quinolinic acid (QUIN), which together promote overstimulation and heightened immune responses, both closely related to the progression and onset of PD. KP enzyme modulators, precursor-based therapies, and KYNA analogs may provide a novel way to treat PD. KP components may also serve as new prognostic indicators and therapeutic targets for PD. Finding precise biomarkers for early screening, involving preclinical and prodromal stages, is essential for improving therapeutic intervention and care at the onset of PD. The current review provides an updated analysis of KP study results related to PD. Additionally, the review highlights the need for expanded biomarker research, which could help establish new therapeutic approaches for PD.