Fibromyalgia is a syndrome characterised by widespread chronic pain, often accompanied by comorbidities such as fatigue, anxiety, and depression. Pharmacological treatments offer only partial relief of symptoms and can cause significant adverse effects. Therefore, finding new treatments is crucial. Psychotria nemorosa, a species rich in indole alkaloids, has garnered interest due to its acute antinociceptive properties observed in vivo and its effects on monoamine oxidase A and B in in vitro assays. Additionally, alkaloids are recognised for their antinociceptive effects, as well as their anxiolytic and antidepressant properties. Therefore, we examined the effects of the alkaloid fraction of P. nemorosa in a model that simulates fibromyalgia symptoms in male Swiss. Initially, the antinociceptive effects of the fraction (3, 10, and 30 mg/kg, administered orally) were tested in capsaicin- and formalin-induced nociception, and potential adverse effects on locomotion and body temperature were evaluated. Next, the 30 mg/kg dose was tested in the reserpine-induced fibromyalgia model for mechanical, cold, and heat sensitivity, muscle strength, and behaviours resembling depression and anxiety. The P. nemorosa alkaloid fraction (30 mg/kg) decreased capsaicin- and formalin-induced nociception without affecting locomotion or body temperature. It also alleviated mechanical and cold allodynia, thermal hyperalgesia, muscle fatigue, and anxiety-like behaviour caused by reserpine, although it did not show an antidepressant-like effect. These results suggest that the P. nemorosa alkaloid fraction has therapeutic potential for treating fibromyalgia pain and related conditions such as fatigue and anxiety. They also emphasise the need for further research into its mechanisms and its long-term safety.

Parkinson's disease is a progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons, resulting in tremor, rigidity, bradykinesia and poor motor coordination. The present study was aimed to evaluate anti-Parkinsonian activity and neuroprotective potential of cardamonin in reserpine and haloperidol induced experimental models of Parkinsonism in mice. Cardamonin is a naturally occurring chalcone that has been reported to possess antioxidant and anti-inflammatory activities and may modulate biological processes associated with oxidative stress and neuroinflammation. Motor and cognitive functions were assessed using behavioral tests including open-field, pole-climbing, catalepsy and novel object recognition tests. Biochemical estimations of lipid peroxidation and endogenous antioxidants status were performed. Further, the tissue levels of dopamine were estimated. Brain tissues were subjected to routine histopathological investigation. Results showed that cardamonin significantly improved motor activity, decreased oxidative stress, enhanced the status of endogenous antioxidants and increased tissue levels of dopamine. Histopathological examination showed attenuation of general histological changes in treated animals. To summarize, the results support the anti-Parkinsonian activity and neuroprotective potential of cardamonin under the experimental conditions. However, direct preservation of dopaminergic neurons was not demonstrated because dopaminergic neuron-specific markers were not evaluated.

Arthritis, particularly rheumatoid arthritis (RA) and osteoarthritis (OA), is a multifactorial musculoskeletal disorder characterized by chronic inflammation, oxidative stress, immune dysregulation, mitochondrial dysfunction, extracellular matrix degradation and progressive cartilage and bone destruction. Although conventional therapies, including disease-modifying antirheumatic drugs, biologics and JAK inhibitors, have improved disease management, their long-term use is frequently associated with adverse effects, therapeutic resistance and incomplete prevention of irreversible joint degeneration, necessitating safer multitarget therapeutic strategies. Capsicum species contain diverse bioactive constituents, including capsanthin, capsorubin, capsaicin, dihydrocapsaicin, β-carotene and zeaxanthin. Among these, capsanthin, found in Capsicum species, has attracted considerable interest because of its potent antioxidant, anti-inflammatory, immunomodulatory, and metabolic regulatory properties. This review comprehensively evaluates the potential anti-arthritic activity of capsanthin, with particular emphasis on signaling networks implicated in joint inflammation, oxidative stress, immune dysregulation, and extracellular matrix degradation, including CB2, NF-κB, Nrf2/HO-1, MAPK, PI3K/Akt, and JAK/STAT pathways. The available evidence is critically distinguished according to capsanthin-specific findings, arthritis-related mechanisms, and supportive evidence from other carotenoids or disease models. Additionally, modulation of matrix metalloproteinases (MMPs) and ADAMTS aggrecanases involved in cartilage degradation and extracellular matrix remodeling is critically discussed. Current preclinical evidence indicates that capsanthin suppresses pro-inflammatory cytokine production, restores cellular redox homeostasis, attenuates oxidative stress-mediated signaling, and preserves cartilage integrity through coordinated regulation of interconnected molecular networks. Emerging computational approaches, including network pharmacology, molecular docking, molecular dynamics simulations, artificial intelligence-assisted drug discovery, and multi-omics technologies, are also highlighted to accelerate target identification, mechanism and future clinical translation.

Pseudobombax simplicifolium A. Robyns is traditionally used to treat pain, inflammation, and fever, although its chemical composition and pharmacological properties remain poorly investigated. This study characterized the aqueous bark extract of P. simplicifolium (EAPS) and evaluated its antioxidant, antinociceptive, anti-inflammatory, and antipyretic activities. HPLC-DAD analysis identified catechin and epicatechin, and the total phenolic and flavonoid contents were 335.2 ± 0.21 mg GAE/g and 116.0 ± 0.14 mg QE/g, respectively. EAPS exhibited antioxidant activity in the DPPH and ABTS assays, with IC50 values of 58.1 ± 0.17 and 99.6 ± 0.15 µg/mL, respectively. In the acetic acid-induced writhing test, EAPS significantly reduced the nociceptive response in a dose-related manner, with inhibitions of 29.64, 39.43, and 62.10% at 25, 50, and 100 mg/kg, respectively (p < 0.001). In the formalin test, EAPS significantly reduced paw-licking time at 25, 50, and 100 mg/kg in both the first phase (30.37, 47.48, and 50.50%, respectively) and the second phase (34.21, 46.74, and 55.01%, respectively; p < 0.0001). Naloxone and atropine markedly reversed the antinociceptive effect of EAPS, supporting the involvement of opioidergic and muscarinic cholinergic pathways. EAPS also significantly reduced carrageenan-induced paw edema and decreased total leukocyte and neutrophil recruitment by up to 44.8 and 44.7%, respectively (p < 0.001). At 100 mg/kg, EAPS reduced TNF-α concentrations from 185.6 ± 12.4 to 91.3 ± 8.8 pg/mL and IL-1β concentrations from 165.3 ± 11.6 to 93.7 ± 6.1 pg/mL (p < 0.001). In the yeast-induced pyrexia model, 50 and 100 mg/kg EAPS significantly reduced rectal temperature from 30 min onward, with the most pronounced and sustained effect observed at 100 mg/kg (p < 0.001). Overall, these findings demonstrate that EAPS exhibits in vitro antioxidant, antinociceptive, anti-inflammatory, and antipyretic activities, supporting the traditional use of P. simplicifolium and its potential as a source of bioactive compounds.

Alzheimer's disease (AD) is a progressive neurological condition that has manifestations of cognitive decline, accumulation of neurofibrillary tau pathology, amyloid-β (Aβ), synaptic dysfunction, neuroinflammation, oxidative stress, and cerebrovascular abnormalities. Evidence is growing that epigenetic dysfunction is involved in the development of AD. The coactivator-associated arginine methyltransferase 1 (CARM1), also known as protein arginine methyltransferase 4 (PRMT4), is an epigenetic enzyme that functions in transcriptional control, chromatin remodeling, maintenance of cellular homeostasis, and neuronal functions. CARM1-mediated histone H3 arginine 17 methylation (H3R17me2a) and NF-κB-dependent transcription provide a link to inflammatory gene regulation; however, a direct role for CARM1 in AD-associated neuroinflammation remains unconfirmed. Findings from cultured hippocampal neurons implicate CARM1 in dendritic maturation and synaptic organization, although these effects have not established therapeutic benefits in AD models. Evidence from female 3xTg-AD mice indicates that pharmacological CARM1 inhibition can improve selected cerebrovascular parameters, including nitric oxide synthase coupling and cerebral blood flow. CARM1 phosphorylation may also influence its enzymatic activity and localization, but its involvement in AD-related neuronal pathology remains hypothetical. The aim of this study is to put together in a comprehensive manner the role of CARM1 in the molecular and cellular mechanisms involved in AD pathology and its potential as a therapeutic target. Future studies should focus on brain penetrants and selective CARM1 modulators, cell-specific functions, long-term safety, target engagement, and clinical translation. In conclusion, CARM1 may be a potential AD therapeutic target that is still in the preclinical phase.

Despite being defined pathologically by amyloid-β plaques, chronic neuroinflammation and neurofibrillary tangles, the drugs that target these processes directly (lecanemab and donanemab) have only modest effects on the clinical course of Alzheimer's disease (AD) and significant safety concerns have been identified, so there is renewed interest in upstream, systemic contributors to disease. This review aims to provide a synthesis of the latest mechanistic and clinical evidence that gut microbiota dysbiosis is associated with Alzheimer's disease with a specifically immunopharmacological focus. We will explore how the gut-brain axis pathways (vagal, immune, endocrine and microbial-metabolite signaling) converge to trigger microglial and astrocytic activation via toll-like receptor 4/NF-κB and complement-primed NLRP3 inflammasome signaling, which is also directly activated by amyloid-β and tau. Then we review the immunopharmacological interventions intended to break this axis - probiotic supplementation (some consistent benefit - although mild) and sodium oligomannate, with strong preclinical and case report signals that need human trials (in 2026) and polyphenols and GLP-1 receptor agonists, which have a persistent disconnect between mechanistic promise and clinical efficacy, including a definitive null result for semaglutide in 2026. Translative directions are addressed to nanotechnology-based delivery systems for improving bioavailability and blood-brain barrier penetration, as well as emerging precision-medicine, AI-driven approaches in the selection of treatments based on microbiome information. It is our opinion that because the gut-brain-immune axis is a mechanistically supported and potentially highly scalable therapeutic target, complementary to amyloid and tau therapies, the development of future therapies should match the inflammatory, metabolic and microbial phenotypes.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, driven by immune dysregulation, oxidative stress, and the release of pro-inflammatory cytokines. Histamine, an important mediator in gut inflammation, has immunomodulatory properties. Ebastine, a second-generation histamine H1-receptor antagonist, is primarily used for allergic conditions, but its potential role in managing IBD has not been fully explored. This study aimed to evaluate whether ebastine could prevent colitis induced by dextran sodium sulfate (DSS) in mice. The severity of the condition was assessed using the disease activity index (DAI), body weight loss, stool consistency, and rectal hemorrhage. Immune modulation was investigated by measuring serum IgE levels and inflammatory biomarkers like C-reactive protein (CRP). The study also examined the impact of ebastine on oxidative stress markers and pro-inflammatory cytokines (TNF-α, IL-6), alongside histopathological analysis of colon tissue. Swiss albino mice were induced with experimental colitis using 3% DSS and divided into five groups, including a normal control, DSS control, standard treatment (sulfasalazine), and two ebastine-treated groups (2 mg/kg and 10 mg/kg). Clinical, histopathological, and molecular markers were analyzed. Ebastine significantly improved clinical parameters, reduced DAI, inhibited oxidative stress, and lowered TNF-α and IL-6 levels. The high dose showed more potent anti-inflammatory effects, while the low dose demonstrated better antioxidant activity. Ebastine offers protection against DSS-induced colitis by modulating inflammation and oxidative stress, suggesting its potential as an adjunctive treatment for IBD.

Cycas revoluta Thunb. has traditionally been used for the management of gastrointestinal and inflammatory disorders, but its bioactive constituents and anti-inflammatory potential remain insufficiently characterized. This study aimed to optimize the extraction of phenolic-rich compounds from C. revoluta leaves and evaluate the anti-inflammatory and coloprotective effects of the optimized extract against experimental ulcerative colitis (UC). Four extraction techniques, namely Soxhlet extraction, maceration, ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE), were compared based on extraction yield, total phenolic content (TPC), total flavonoid content (TFC), antioxidant, and antibacterial activities. The most effective method was subsequently optimized using response surface methodology (RSM) using a Box-Behnken design (BBD), followed by phytochemical investigation and biological evaluation in rats with acetic acid-induced UC. Maceration showed the best performance, yielding the highest TPC (44.21 mg GAE g[-1] DM), TFC (33.77 mg RE g[-1] DM), DPPH inhibition (82.2%; IC50 = 37.61 μg mL[-1]), and antibacterial activity. RSM optimization further enhanced the recovery of bioactive constituents. Phytochemical investigation led to the isolation and structural identification of naringenin (1), 2,3-dihydrohinokiflavone (2), and amentoflavone (3). In the UC model, the optimized extract significantly improved colon length, disease activity index, and histopathological alterations. Moreover, it reduced TNF-α, nitric oxide, and VEGF levels while increasing HO-1 expression. Hence, the optimized C. revoluta extract exhibited promising coloprotective and anti-inflammatory effects, associated with modulation of inflammatory and oxidative stress-related responses, providing experimental support for its traditional gastrointestinal applications and its potential as a source of bioactive compounds for further development against inflammatory bowel diseases.

Current disease-modifying therapies for multiple sclerosis (MS) primarily target adaptive immunity but often fail to halt neurodegeneration or promote myelin repair. Leukotriene pathway inhibitors, established in the management of asthma, possess anti-inflammatory and potentially neuroprotective properties. Following the PRISMA 2020 recommendations, a systematic search was conducted in PubMed, Web of Science, and Scopus. Eligible studies included preclinical investigations of leukotriene inhibitors in MS animal models and risk of bias was assessed using SYRCLE's risk of bias tool for animal studies. Five studies met the inclusion criteria, reported that inhibition of leukotriene B4 (LTB4) or cysteinyl leukotriene receptor 1 (CysLT1) attenuated clinical severity in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination models. Mechanistically, the included preclinical studies suggest that leukotriene inhibitors may influence several pathways potentially relevant to MS pathophysiology, including T helper 17 (Th17) cell differentiation, M1-like microglial polarization, and oligodendrocyte precursor cell (OPC) differentiation. In addition, targeted central nervous system (CNS) delivery using engineered exosomes appeared to enhance the observed remyelination effects. Leukotriene inhibition may exert pleiotropic effects across both peripheral immune responses and the CNS microenvironment. Although these mechanistic observations provide biological plausibility for further investigation of these agents as potential repurposed therapies for MS, particularly in the context of remyelination and neuroinflammation, they remain based on preclinical evidence and should therefore be considered hypothesis-generating. Well-designed clinical studies are required to determine whether these experimental effects translate into clinically meaningful therapeutic benefits in patients with MS.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation, epithelial barrier dysfunction, immune dysregulation, and aberrant extracellular matrix (ECM) remodeling. Matrix metalloproteinase-2 (MMP-2), a zinc-dependent gelatinase, has emerged as a critical regulator of intestinal homeostasis owing to its dual role in tissue repair and inflammatory tissue destruction. Unlike several inducible matrix metalloproteinases, MMP-2 is constitutively expressed and tightly regulated through interactions with membrane-type MMPs, tissue inhibitors of metalloproteinases (TIMPs), cytokines, redox signalling, and microbial factors. Dysregulated MMP-2 activity contributes to epithelial barrier disruption, leukocyte infiltration, chronic inflammation, fibrosis, and disease progression in IBD. This review summarizes the current understanding of MMP-2 biology, activation mechanisms, and immunopharmacological functions in intestinal inflammation, while critically evaluating therapeutic strategies aimed at its modulation. Particular emphasis is placed on natural and synthetic MMP-2 modulators, including animal-derived peptides and endogenous inhibitors, plant-derived polyphenols, flavonoids, alkaloids, terpenoids, and rationally designed small-molecule and peptidomimetic inhibitors. Emerging nanocarrier-based and targeted delivery systems are also discussed as approaches to enhance selectivity and minimize systemic toxicity. Furthermore, the review highlights the limitations of broad-spectrum MMP inhibition and underscores the need for site-specific modulation that preserves physiological tissue remodeling while suppressing pathological activity. Advances in precision medicine, single-cell and spatial transcriptomics, organoid-based disease models, and microbiome-informed therapeutic strategies are expected to facilitate the development of next-generation MMP-2-targeted interventions. Collectively, MMP-2 represents a promising yet complex therapeutic target whose successful modulation may improve long-term outcomes in IBD.