Interleukin-1β (IL-1β) plays a central role in driving vascular inflammation and endothelial dysfunction, key processes in the development of atherosclerosis. While biologic therapies targeting IL-1β have shown clinical benefit, their high cost, injectable nature, and potential side effects limit their broader use. Therefore, there is a need to explore more accessible alternatives. In this study, we aimed to identify repurposed small-molecule inhibitors that can effectively modulate IL-1β signaling and protect endothelial function. We used an integrated strategy combining computational and experimental approaches. Virtual screening, molecular docking, molecular dynamics simulations, and MM-PBSA analyses were performed to identify potential inhibitors targeting IL-1R1. The most promising candidates were then evaluated in vitro using endothelial cell models (HUVEC and EA.hy.926). Their effects were assessed through functional assays, including transendothelial electrical resistance (TEER), VE-cadherin immunofluorescence, and cell viability measurements. Two FDA-approved drugs, radotinib and lomitapide, emerged as strong candidates with high binding affinity and stability toward IL-1R1, outperforming the reference inhibitor anakinra in computational analyses. Experimental validation showed that both compounds effectively reduced IL-1β-induced endothelial dysfunction. They restored barrier integrity, improved TEER values, and maintained VE-cadherin expression and localization. Importantly, both compounds exhibited low cytotoxicity and mitigated IL-1β-driven increases in endothelial permeability. Our findings highlight radotinib and lomitapide as promising repurposed small-molecule inhibitors of IL-1β signaling. By preserving endothelial integrity and dampening inflammatory responses, these compounds may serve as cost-effective and orally available alternatives to current biologic therapies. Further in vivo and mechanistic studies are needed to advance their potential clinical application.
暂无摘要（点击查看详情）
Alnus hirsuta (Siberian alder), a member of the family Betulaceae, is a medicinally significant species that has yet to be the subject of a comprehensive review. This article summarizes phytochemical constituents, and pharmacological activities of A. hirsuta. Phytochemical studies have identified a diverse range of secondary metabolites, including diarylheptanoids, terpenoids, flavonoids, and phenolic compounds, many of which exhibit strong bioactivities. Pharmacological investigations have revealed anti-inflammatory, anticancer, antioxidant, anti-melanogenesis, hepatoprotective, lipid-regulating, and hair growth effects with diarylheptanoids frequently implicated as major bioactive constituents. Mechanistically, these compounds especially diarylheptanoids modulate inflammation by inhibiting NF-κB and MAPK pathways, suppressing pro-inflammatory mediators such as COX-2, iNOS, and cytokines, while simultaneously enhancing antioxidant defenses. Thus, by integrating chemical and biological evidence, to our knowledge, this review presents the first comprehensive account of A. hirsuta, emphasizing the potential of this species as a valuable source of natural products for drug discovery.
RA is a chronic autoimmune disease characterized by synovial inflammation, cartilage destruction, and ultimately bone erosion that affects approximately 0.5-1% of the global population, with significant disability. Conventional therapies comprising NSAIDs, corticosteroids, and DMARDs frequently demonstrate systemic toxicity, gastrointestinal complications, and poor patient compliance. This manuscript discusses the role of nanoparticle-based dot-matrix transdermal drug delivery systems as a novel, non-invasive strategy for enhancing targeted, controlled, and localized drug delivery in the management of RA. The current literature on RA pathophysiology, existing pharmacological treatments, routes of administration, and the evolution of nanotechnology is integrated into the manuscript. Special attention is paid to nanoparticles based on chitosan due to their biocompatibility, biodegradability, and penetration-enhancing properties, and they were incorporated into dot matrix patch technology fitted with micro-depots for optimized skin permeation, sustained release, and reduced skin irritation. Traditional transdermal systems exhibit limitations in permeation through the stratum corneum, particularly for hydrophilic or high-molecular-weight substances. Incorporation of nanoparticles (size < 200 nm) improves solubility, stability, shelf life, bioavailability, and enables targeted delivery of therapeutic agents into arthritic joints. This approach facilitates rapid onset of action followed by sustained and controlled drug release, allows individualized dosing, reduces skin irritation, and enhances patient compliance. Importantly, nanoparticle-mediated transdermal systems can effectively deliver conventional drugs such as methotrexate, NSAIDs, and herbal anti-inflammatory agents, as well as disease-modifying antirheumatic drugs (DMARDs), including both conventional synthetic DMARDs and targeted synthetic agents. Additionally, this strategy bypasses first-pass hepatic metabolism, thereby improving systemic availability while potentially reducing systemic adverse effects. The dot-matrix nanoscale transdermal drug delivery platform has great potential for treating RA, offering controlled, localized drug delivery with improved efficacy and reduced toxicity. In addition to the difficulties with scalability and commercial availability, the technology also requires further studies of its long-term safety profile before it can be developed.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and systemic immune dysregulation. Although biologic therapies targeting inflammatory cytokines have improved disease outcomes, many patients fail to achieve sustained remission, highlighting the need for alternative therapeutic strategies. Increasing evidence suggests that RA represents not only excessive inflammatory signaling but also a failure of endogenous regulatory mechanisms that normally restrain immune activation. Central to RA pathogenesis is the activation of inflammatory signaling cascades involving transforming growth factor-β-activated kinase 1 (TAK1), nuclear factor-κB (NF-κB), and the NLRP3 inflammasome, which collectively promote cytokine production, synovial hyperplasia, and cartilage destruction. Recent studies have identified metabolic and neuroimmune pathways as important regulators of these processes. Among them, bile acid-activated signaling through the farnesoid X receptor (FXR) and neural modulation via the cholinergic anti-inflammatory pathway mediated by the α7 nicotinic acetylcholine receptor (α7-nAChR) have emerged as key endogenous mechanisms capable of suppressing inflammatory responses. FXR signaling regulates immune and metabolic pathways, inhibits NF-κB and inflammasome activation, and modulates immune cell differentiation. In parallel, α7-nAChR-mediated cholinergic signaling suppresses cytokine production and limits innate immune activation through neuroimmune communication. Notably, both pathways converge on TAK1-dependent inflammatory signaling. This review highlights the emerging roles of metabolic and neuroimmune regulatory circuits in RA and discusses their therapeutic potential, including opportunities for drug repurposing aimed at restoring endogenous anti-inflammatory pathways.
暂无摘要（点击查看详情）
Given the multifactorial pathogenesis of Alzheimer's disease (AD) and the limited efficacy of single-target drug therapy, there is a growing scientific need for combination regimens to concurrently target various AD-associated cascades. Currently, plant-derived phytoconstituents, with their intrinsic multi-target properties, represent a promising component for combination therapy, offering translational potential with enhanced neuroprotection. In this avenue, the current study aimed to explore the combined neuroprotective effects of geraniol (a monoterpenoid alcohol) and Z-guggulsterone (a phytosterol) in streptozotocin (STZ)-induced AD model of adult zebrafish (4-6 months old). Following intracerebroventricular STZ injection, zebrafish were treated with geraniol and Z-guggulsterone per se and in combination for 28 consecutive days. On day 27, a novel tank diving test and a light/dark preference test were performed to evaluate locomotive and cognitive impairments. Afterwards, the fish were evaluated for numerous blood parameters, including blood glucose and serum cholesterol levels, followed by biochemical assessment of oxidative stress markers, mitochondrial complexes, neuroinflammatory cytokines, and neurotransmitter levels. Results demonstrated that co-therapy of geraniol and Z-guggulsterone significantly ameliorated cognitive deficits, reduced anxiety-like behaviours, impeded acetylcholinesterase activity, regulated neurotransmitter levels (glutamate and acetylcholine), mitigated oxidative stress markers, and prevented mitochondrial dysfunction, compared to monotherapies. Additionally, downregulation of TNF-α was also observed, affirming suppression of detrimental neuroinflammatory processes. Collectively, these findings support the neuroprotective potential of geraniol and Z-guggulsterone co-therapy in the zebrafish model of AD; however, future research is warranted to explore the potential clinical application of this combination therapy in AD.
暂无摘要（点击查看详情）
Knee osteoarthritis (OA) is a degenerative joint disease involving progressive cartilage loss, subchondral bone remodelling, and inflammation. This systematic review and meta-analysis aimed to assess the efficacy and safety of metformin in reducing knee pain and adverse events among overweight and obese adults with symptomatic knee OA. We systematically searched PubMed, Scopus, and CENTRAL from inception to August 2025. Eligible randomised controlled trials (RCTs) compared oral metformin with placebo or standard care in adults with BMI ≥ 25 kg/m2 and symptomatic knee OA. Primary outcomes were pain reduction (standardised mean difference) and gastrointestinal (GI) adverse events (risk ratio). Risk of bias was assessed using the Cochrane ROB 2 tool, publication bias using the Doi plot and LFK index, and evidence certainty using the GRADE-pro approach. Seven studies (n = 1237) were included: six RCTs and one observational study. Meta-analysis included only RCTs. Metformin significantly reduced knee pain compared with controls (SMD: - 0.42; 95% CI: - 0.62 to - 0.21; I2 = 95%). Sensitivity analysis excluding an outlier study produced a consistent effect (SMD: - 0.54; 95% CI: - 0.74 to - 0.33; I2 = 91%). Based on GRADE assessment, the certainty of evidence for pain reduction was high. Metformin increased the risk of mild, non-serious gastrointestinal adverse events (RR: 1.97; 95% CI: 1.06-3.67; I2 = 0%), with moderate certainty due to imprecision. Metformin provides clinically meaningful pain reduction in overweight/obese adults with knee OA but increases mild, non-serious gastrointestinal adverse events. These findings support metformin as a promising disease-modifying therapy for metabolically complex OA phenotypes; longer-duration trials with structural endpoints are warranted.
Boswellia serrata is a medicinal plant traditionally used to treat inflammatory conditions and this study aimed to evaluate the efficacy of B. serrata dry extract (BSDE) in treating gastric ulcers and ulcerative colitis. Chronic gastric ulcers were induced using 80% acetic acid. For seven days, rats were given oral doses of BSDE (30, 100, or 300 mg/kg), omeprazole (40 mg/kg), or vehicle. Ulcer area, mucin content, and biochemical indicators (GSH, SOD, CAT, GST, MPO, MDA) were evaluated. The rectal administration of 8% acetic acid produced ulcerative colitis. BSDE (100 or 300 mg/kg), dexamethasone (2 mg/kg), or vehicle were given three days before and after colitis induction. Colonic damage was assessed macroscopically and microscopically, as well as mucin production and indicators of oxidative stress. Finally, computational investigations were carried out to identify potential pharmacological targets. BSDE was analyzed using ESI-MS, revealing the presence of six compounds, including α-boswellic acid and keto-boswellic acid. In the gastric ulcer model, oral administration of BSDE for seven days accelerated the ulcer healing, with the 100 mg/kg dose being the most effective. BSDE enhanced gastric mucin content and reduced oxidative stress. In the colitis model, BSDE reduced macroscopic damage, preserved crypt architecture, and decreased inflammatory infiltration. Computational investigations identified potential pharmacological targets for BSDE constituents, including COX-1 and 2, and iNOS. BSDE also demonstrated good ADME features and a favorable toxicity profile. The results suggest that BSDE exerts gastroprotective and intestinal anti-inflammatory effects through antioxidant and mucosal protective mechanisms. These findings support the traditional use of B. serrata as a viable therapeutic option for gastrointestinal diseases, highlighting its potential as a phytotherapeutic agent.
暂无摘要（点击查看详情）
暂无摘要（点击查看详情）
Osteoarthritis (OA) is a progressive degenerative joint disease characterized by chronic inflammation, cartilage degradation, and persistent pain, leading to functional disability and reduced quality of life. Current pharmacological treatments, particularly non-steroidal anti-inflammatory drugs (NSAIDs), provide symptomatic relief but are associated with significant adverse effects during long-term use. The present study evaluated the therapeutic efficacy and pharmacological synergy of a novel combination formulation, Ostizeel™, comprising palmitoylethanolamide (PEA) and Cucumis sativus extract (CSE), in a monosodium iodoacetate (MIA)-induced rat model of osteoarthritis. Forty-two female Wistar rats were randomized into seven experimental groups and treated orally with PEA, CSE, an NSAID standard, or their combinations for 28 days. Nociceptive behavior and functional recovery were assessed using movement-evoked pain scoring, Randall-Selitto mechanical hyperalgesia, von Frey allodynia testing, and dynamic weight-bearing analysis. Systemic inflammation and cartilage catabolism were evaluated by measuring serum interleukin-1β (IL-1β) and matrix metalloproteinase-13 (MMP-13) levels. Drug-drug interaction was assessed using the Bliss Independence model and a combination index derived from the Loewe additivity principle. The combination treatment significantly improved pain thresholds and limb function compared with either monotherapy (p < 0.0001). Serum IL-1β and MMP-13 levels were reduced by approximately 50%, indicating potent anti-inflammatory and chondroprotective effects. Bliss Independence analysis yielded positive synergy scores across behavioural and biochemical endpoints, suggesting that the observed combination effects exceeded predicted additive responses. Synergistic modulation of nociceptive and inflammatory pathways were demonstrated by PEA and CSE, which highlight Ostizeel™ as a promising pharmacological strategy for osteoarthritis management.
暂无摘要（点击查看详情）
Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.
Neuroinflammation is hypothesized to be a fundamental driver of epileptogenesis, potentially contributing to the transformation of the healthy brain into a state prone to spontaneous recurrent seizures. This manuscript explores the pivotal roles of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) in modulating neuronal excitability and structural plasticity. We delineate how the activation of the NLRP3 inflammasome and the P2×7 receptor pathway leads to the maturation of IL-1β, which subsequently triggers the MyD88 and PI3K/AKT/mTOR cascades. These pathways collectively enhance NMDA receptor activity and glutamate release while suppressing GABAergic inhibition, establishing a cycle of neuronal hyperexcitability. Furthermore, we examine the systemic and local impacts of IL-6 signaling mediated through the JAK/STAT3 pathway. Beyond acute synaptic effects, IL-6 contributes to chronic pathology by inducing gliosis, hindering hippocampal neurogenesis, and promoting blood-brain barrier leakage via CCL2 production. These multi-level disruptions not only facilitate seizure activity but also contribute to the cognitive and behavioral comorbidities often observed in epilepsy. By synthesizing current understanding of these signaling axes, this review highlights the therapeutic potential of targeting specific cytokine receptors, such as the IL-1 receptor antagonist, to intercept the epileptogenic process. Understanding these neuroinflammatory benchmarks is essential for developing disease-modifying treatments that move beyond symptomatic seizure control toward true prevention of epilepsy.
Breastfeeding plays a critical role in providing essential nutrients and antibodies that enhance the health of new-borns and infants, supporting their immune systems and overall growth and development. Healthcare professionals, universally recommend breastfeeding for the first six months of an infant's life, in conjunction with an appropriate complementary diet. However, the COVID-19 pandemic has understandably raised concerns among lactating mothers and pregnant women regarding the risks of infection and vaccine safety. Therefore, it is essential to carefully evaluate the potential dangers of COVID-19 transmission within this vulnerable population especially when considering vaccination for pregnant and breastfeeding women. Encouragingly, the United States Food and Drug Administration has granted approval for the use of two COVID-19 vaccines namely, Pfizer-BioNTech COVID-19 and Moderna COVID-19 to contain the spread of the COVID-19 virus. Both vaccines have been approved for administration in pregnant and breastfeeding women, providing much-needed reassurance to those with concerns about vaccine safety. It is important to recognize that the benefits of vaccination for both the mother and the infant far outweigh the risks associated with COVID-19 infection. Therefore, lactating mothers should view vaccination as a vital measure to protect themselves and their infants from the virus. In addition to elaborating on the successes of safety and effectiveness, this review is unique that it also includes current and newly updated evidence published between 2020 and 2025, comprehensively discussing on several newer vaccine platforms together with recent viral variants. Furthermore, it synthesizes information on the transfer of transplacental and a breast-milk antibody that outlines a clear evidence-gap that may direct further research within pregnant and lactating populations.
Chronic inflammatory diseases are major global health challenges driven by persistent oxidative stress and dysregulated immune signalling. Plant-derived indole alkaloids are structurally diverse metabolites found in medicinal plants, fungi and marine organisms; that exhibit potent multi-target anti-inflammatory and antioxidant activities. This review integrates current evidence on the chemistry, sources and mechanistic pathways of plant-derived indole alkaloids, emphasizing their modulation of key inflammatory axes, including NF-κB, JAK/STAT, MAPK, PI3K/AKT, NLRP3 inflammasome and AhR signalling. A thorough search of PubMed, Scopus and Google Scholar databases was conducted up to December 2025. Eligible studies included preclinical, clinical and review articles addressing the effects of indole alkaloids on inflammatory mediators, oxidative stress markers and disease endpoints. Indole alkaloids have been proven to suppress pro-inflammatory mediators; like TNF-α, IL-1β, IL-6, NO, PGE₂, COX-2 and iNOS; while enhancing antioxidant defences and cytoprotective responses. Representative scaffolds have demonstrated promising protective effects in colitis, osteoarthritis, COPD, atherosclerosis, chronic kidney disease and inflammation-driven cancers through restoration of epithelial and endothelial barriers, immune-cell reprogramming and rebalancing of organ-specific crosstalk. Monoterpenoid and tryptophan-derived indole alkaloids particularly integrated AhR and NF-κB/STAT3 pathways, supporting microbiota- and organ-selective therapeutic prospects. Plant-derived indole alkaloids emerge as promising yet underexploited multi-target scaffolds for chronic inflammatory diseases, primarily supported by preclinical evidence. Future advances in synthetic biology, metabolomics and rational hybrid design are essential to overcome translational barriers and enable clinically scalable development of this chemotype.
Pneumonia is the leading cause of morbidity and mortality especially among children and aged people, primarily caused by Klebsiella pneumoniae (K. pneumoniae). Hence 180 samples were collected from immune-compromised, cancer and respiratory tract-infected patients. Among these K. pneumoniae was isolated from twenty-three samples, and was tested against 23 locally available antibiotics. These isolates were found sensitive to 8 antibiotics and resistant to 8 antibiotics. Nine medicinal plants were also checked against K. pneumoniae isolates Zingiber officinale exhibited the highest activity with zone of inhibition (ZI) (21 ± 1.35 mm), followed by Cinnamomum zeylanicum with ZI 15.5 ± 0.2 mm and 15 ± 0.3 for aqueous extract and methanol extract, respectively. The ethanol extract of Citrus limetta (12 ± 2.13 mm), Cydonia oblonga ZI 11 ± 2.35 mm, Viola odorata, (11 ± 1.25 mm) and Papaver somniferum (11 ± 0.23 mm) also showed activity. While Piper nigrum, Curcuma zedoaria, and Ziziphus jujube showed relatively lower activities against MDR- K. pneumoniae. Fourier Transforms Infrared Spectroscopy (FTIR) analysis of the selected medicinal plants revealed that Zingiber officinale contains a high amount of phenolic and nitrogen-derivative compounds. Alkane, alkene, ether and alcoholic compound functional groups were also observed. The presence of these functional groups showed high anti-oxidant and cytotoxic activity. Similarly, FTIR analysis of Cinnamomum zeylanicum identified functional groups including alcohols, phenolic compounds, alkanes, alkenes and ethers. Phylogenetic analysis of the 16S rRNA gene sequencing of Klebsiella pneumoniae strains showed 98% similarity with Rhizobium strains RZ3 and 58% with K. pneumoniae NITW7150. The potential of the medicinal plants, as effective antimicrobial agents against MDR- K. pneumoniae, offering promising alternatives to conventional antibiotics.
The chronic inflammation and oxidative stress are the most deleterious pathogenic factors of psoriasis (PS). While gamma-aminobutyric acid (GABA) possesses well-documented immunomodulatory and antioxidant properties, its therapeutic potential is limited by bioavailability and targeting. Chitosan nanoparticles (CSNP) offer a promising drug delivery platform to overcome GABA limitations. This study aimed to augment the dermatological efficacy of GABA by encapsulation within CSNPs to overcome its skin penetration limitations, thereby creating an advanced transdermal delivery system for sustained anti-psoriatic local action. TEM revealed spherical, monodisperse GABA-CSNPs. Dynamic light scattering (DLS) confirmed a nanoscale size (57.63 nm), highly positive surface charge (+ 35.93 mV) and excellent colloidal stability. In vitro, GABA-CSNPs demonstrated superior antioxidant (using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay) and anti-inflammatory (membrane stabilization) activities compared to free GABA or blank CSNPs, beside enhanced biocompatibility (using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay). A PS-like model was induced in rats using 5% imiquimod (IMQ). Animals were divided into five groups: negative control, psoriatic control (PC) (62.5 mg of Aldara® cream) and IMQ groups treated with free GABA ( 200 mg/kg), unloaded CSNPs (100 mg/kg), or GABA-CSNPs (100 mg/kg). The GABA-CSNPs treatment group showed the most significant clinical improvement, reducing scaling and erythema. Mechanistically, therapy restored epidermal architecture, ameliorated oxidative stress by lowering malondialdehyde (MDA) and elevating superoxide dismutase (SOD) and catalase (CAT) levels, and potently suppressed key pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in skin tissue. In conclusion, GABA-CSNPs constitute a novel and highly effective antipsoriatic nanotherapeutic platform. The formulation synergizes the inherent bioactivity of GABA with the enhanced delivery and targeting capabilities of CSNPs, resulting in a potent dual-action therapy that alleviates oxidative damage and modulates the dysregulated immune response central to psoriatic pathology.