Matrix metalloproteinases (MMPs) play an essential role in the intricate process of wound healing of skin by creating a sequential inflammation, tissue generation, and remodelling. MMPs are a family of proteolytic enzymes that degrade components of the extracellular matrix (ECM) and are involved in tissue repair and regeneration. Their controlled activity is critical for maintaining the balance between ECM deposition and degradation required for wound closure and for determining whether excessive fibrosis occurs or chronic wounds form. Alterations in either direction would lead to dysfunction or improvement in wound healing, and could be the cause for chronic wounds and excessive scar formation. This review discusses the roles of MMPs at different stages of wound healing, primarily focusing on their functions during inflammatory responses, ECM remodelling, and reepithelialization. We have discussed the interplay between MMPs and their TIMPs (Tissue Inhibitors of Metalloproteinases), as well as therapeutic strategies to modulate the adverse effects of excessive MMP activity during cutaneous wound healing.
Inflammation-Responsive Drug Delivery System (IR-DDS) is proposed as a novel strategy for targeted therapy of the chronic inflammation-associated diseases: inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and sepsis. These smart systems take advantage of the characteristic pathological microenvironment in inflamed tissues-such as acidic pH (5-6.5), high levels of reactive oxygen species (ROS), overexpressed enzymes, including matrix metalloproteinases (MMPs), and reductive conditions from glutathione (GSH)-for drug-specific accumulation at the site of action and on-demand release. By capitalizing on stimulus-induced behaviors, such as pH-activated protonation and swelling, ROS-stimulated bond scission in thio-ketals or boronic esters, enzyme-cleavable peptide linkers, or GSH-triggered disulfides, IR-DDS have overcome drawbacks of traditional delivery systems, including low bioavailability, off-target effects, and systemic toxicity. The review discusses a variety of carrier systems, such as polymeric nanoparticles (PLGA, chitosan), liposomes, micelles, hydrogels, dendrimers, and hybrid nanocomposites that offer inherent biocompatibility, controllable degradation, and multiple functionalities for sustained delivery. This includes the use of muscle, pH-sensitive hydrogels for periodontitis, oxidation-responsive polypropylene sulfide nanoparticles for anti-inflammatory drug release in rheumatoid arthritis models, and enzyme-triggered gelatin complexes used to target inflamed tissue in IBD, which are striking examples. A sulfasalazine-loaded transdermal patch is shown for chronic inflammation assessment, with increased efficacy in preclinical animal models, such as rat colitis and mouse arthritis after localized delivery. Despite encouraging preclinical findings in lowering cytokine levels, joint swelling, and inflammation markers, clinical translation is hindered by disease heterogeneity, scalability, biocompatibility issues, and manufacturing complexity. Future perspectives: AI-guided green multi-stimuli systems and therapeutic drug delivery, and diagnostic imaging (such as fluorescence, MRI) using multifunctional nanoparticle hybrids for personalized precision therapy will most likely revolutionize the management of chronic inflammation.
INTRODUCTION:Inflammation and oxidative stress play important roles in the development of various chronic diseases, necessitating compounds with dual therapeutic potential. METHODS:A series of (E)-7-hydroxy-4-methyl-6-(3-(substituted phenyl)acryloyl)-2H-chromen-2-one (7a-m) were synthesized starting from 7-hydroxy-4-methyl coumarin. The synthesized compounds were evaluated for their in vitro antioxidant and anti-inflammatory activity Results: Compound 7a exhibited the most potent antioxidant activity with an IC50 value of 83.39 μM. Compound 7b was found to be nearly 1.5-fold more potent in inhibiting albumin protein denaturation than ibuprofen and diclofenac at 100 μg/ml. Compound 7b displayed the most potent inhibitory activity against TNF-α and weak inhibition against the COX-2 enzyme with an IC50 value of 4.32 and 419.04 μM, compared to standard ibuprofen (IC50 value of 5.0 μM against COX-2) and diclofenac (IC50 value of 21.0 μM against TNF-α). Molecular docking studies of compound 7b showed the highest docking score against TNF-α and COX-2 enzymes, compared to the standard celecoxib. DISCUSSION:It was found that chloro at the 2nd position or methoxy at the 3rd position led to promising anti-inflammatory activity. Removal of the chloro group led to a decrease in COX-2 and TNF-α inhibitory activity. In the molecular docking studies, compound 7b shows a similar binding interaction against TNF-α and COX-2 as the standard celecoxib. The DFT studies showed favorable interactions, good stability, and moderate reactivity within the biological targets. CONCLUSION:Based on the results of the present study, it is suggested that coumarin-chalcone derivatives may act as a lead for the synthesis of more potent antioxidants and anti-inflammatory compounds.
INTRODUCTION:Rutin (quercetin-3-O-rutinoside) is a naturally occurring flavonol glycoside widely distributed in fruits, vegetables, and medicinal plants. Increasing evidence suggests that rutin possesses anti-inflammatory and anti-allergic properties through modulation of oxidative stress and immune signaling pathways. This review aimed to critically evaluate the molecular mechanisms, pharmacological activities, and therapeutic potential of rutin in inflammatory and allergic disorders. METHODS:A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar for studies published up to January 2025. Relevant in vitro, in vivo, and clinical studies investigating the anti-inflammatory and anti-allergic effects of rutin were selected according to predefined inclusion and exclusion criteria and systematically analyzed. RESULTS:The reviewed studies demonstrated that rutin exerts anti-inflammatory effects by inhibiting Nuclear Factor-Kappa B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, thereby reducing the production of pro-inflammatory mediators, including Tumor Necrosis Factor-Alpha (TNF-α), Interleukin-1 beta (IL-1β), and Interleukin-6 (IL-6). Rutin also activates the nuclear factor erythroid 2-related factor 2/Heme Oxygenase-1 (Nrf2/HO-1) pathway, enhancing antioxidant defenses and reducing oxidative stress. In allergic conditions, rutin stabilizes mast cells, suppresses histamine release, decreases Immunoglobulin E (IgE)-mediated responses, and modulates immune-cell activation. DISCUSSION:Although substantial preclinical evidence supports the therapeutic potential of rutin, limitations such as poor bioavailability, variability among experimental studies, and limited clinical validation remain significant challenges. CONCLUSION:Rutin exhibits promising anti-inflammatory and anti-allergic activities through multitarget modulation of inflammatory, oxidative stress, and immune pathways. Further well-designed clinical studies and advanced drug-delivery strategies are required to facilitate its translation into clinical practice.
Osteoarthritis (OA) is a clinical problem that remains difficult to treat because few therapeutic options can support sustained cartilage repair. Hyaluronic acid (HA) hydrogels have been advanced as multifunctional drug delivery systems and tissue engineering scaffolds because they are biocompatible and can be designed to possess specific physicochemical properties. This review article makes four major contributions. First, it proposes a framework for classifying HA crosslinking techniques, including covalent, click/enzymatic, and supramolecular chemistry. Second, it proposes a chemistry-to-function framework that shows how HA structure is related to critical properties, such as drug release, chondrogenesis, and immunomodulation. Third, this article synthesizes preclinical studies that illustrate how multifunctional HA hydrogels can support cartilage repair. Fourth, this article proposes a framework for translating HA hydrogels to the clinic that considers issues, such as manufacturing scale-up and emerging technologies, such as 3D printing and AI. Despite such advancements, there are several hurdles to be overcome for translation. These hurdles include a lack of standardization in cross-linking and characterization, an incomplete understanding of long-term immune response, and difficulties with reproducibility in manufacturing. These hurdles need to be addressed to bridge the gap between preclinical and clinical success. The review aims to provide an overview for the rational design and translation of HA-based hydrogels for OA therapy.
Pentacyclic Triterpenoids (PTs) such as oleanolic acid, ursolic acid, and betulinic acid are a large family of natural products with considerable diversity and have excellent therapeutic potential in the treatment of inflammatory and metabolic diseases. PTs have substantial efficacy against both critical pathways in inflammation and glucose regulation. The anti-inflammatory effects are mainly achieved by inhibiting nuclear factor-κB (NF-κB) activation, downregulating pro-inflammatory cytokines, and attenuating oxidative stress. At the same time, the anti-diabetic effects are related to the regulation/modulation of insulin signaling, activation of AMP-activated protein kinase (AMPK), modulation of peroxisome proliferator-activated receptor-gamma (PPAR-γ), and improvement of glucose homeostasis. Cross-talk between inflammation and metabolism explains the dual biological effects of PTs on inflammation and on patients with metabolic disorders. The Structure-Activity Relationship (SAR) studies show that certain structural modifications could improve each activity, indicating potential for rational drug design. The clinical translation of these agents, although supported by encouraging data in preclinical models, has been limited by issues regarding bioavailability, standardization, and the full assessment of safety. This review discusses the role of PTs in distinct pathological conditions (inflammation, diabetes, and cancer) and the integrated examination of inflammation-metabolism crosstalk via common molecular mediators (e.g., NF-κB, Nrf2, PPAR-γ, and PTP1B). This analysis bridges Structure-Activity Relationship (SAR) trends with translational and clinical insights. The resulting framework provides a mechanistically unified, forward-looking perspective designed to guide targeted therapeutic development. In contrast to single-target synthetic drugs, PTs simultaneously drive complexity in multifactorial diseases, including diabetes, metabolic syndrome, and inflammation-associated cancer, by modulating inflammatory, metabolic, and oxidative pathways.
INTRODUCTION:Allergic inflammation has become an important public health issue. If left uncontrolled, it can lead to serious health problems. Mast cells and the drugs that regulate the endosomal compartments in these cells have become central to addressing these problems. The aim of this project was to build a biological model capable of regulating the intracellular delivery of anti-allergic corticosteroids. METHODS:The nanocarrier was designed based on micellar swelling and pH-responsive acid-sensitive linkers. The model's functionality was evaluated through a range of physicochemical characterization and in silico tests. Mathematical modeling was incorporated to simulate the nanocarrier's behavior and diffusion control. Models representing mucosal and mast cell-relevant environments were used to evaluate the designed system in a simulated microenvironment. RESULTS:The nanocarriers showed clear micellar swelling and a pronounced positive surface charge, with high drug encapsulation efficiency, and displayed both pH- and time-dependent behavior, as supported by physicochemical characterization and computational modeling. Mathematical modeling showed that charge dissolution was controlled and that drug release was governed by the rate of proton-dependent drug degradation. The system exhibited minimal drug release under physiological pH conditions, ensuring stability, while enabling controlled and enhanced drug release under acidic conditions relevant to mast cell-associated microenvironments. The system has low hemolysis, low cellular epithelial cytotoxicity, prolonged drug diffusive release, and favorable diffusive release. DISCUSSION:The collected data confirm that the design enables both time- and space-controlled release of the drug from the nanocarrier system within endolysosomal compartments associated with the allergic inflammatory response. The noted control of mast cell secretions illustrates immunomodulation and the control of side effects from systemic/extended use of corticosteroids. CONCLUSION:This study demonstrates that the system is not only safe and effective for the delivery of drugs into cells but also capable of targeting cells involved in the allergic inflammatory pathway. The emerging pH-sensitive nanocarriers have strong therapeutic potential.
INTRODUCTION:Rising resistance to conventional antifungal agents, along with concerns over toxicity and environmental safety, has intensified the search for more sustainable and safer alternatives. Natural oils, particularly essential oils and certain fixed oils, have drawn attention for their broad-spectrum antifungal properties and favourable safety profiles. This review aims to provide a comprehensive overview of the antifungal potential of natural oils, exploring their mechanisms of action, practical applications, and recent advances in formulation strategies. METHODS:To ensure transparency and reproducibility, this review followed a systematic literature search strategy covering peer-reviewed studies published between 2021 and 2025. The selection focused on research exploring the chemistry, biological activity, and translational applications of natural oils with antifungal potential. Eligible studies were critically analyzed, and findings were narratively synthesized to identify key trends and evidence gaps. Particular emphasis was placed on understanding the effects of these oils on fungal cell structures and functions, as well as their potential applications in healthcare, agriculture, and food preservation. RESULTS:Natural oils exhibit multiple mechanisms of antifungal action, including disruption of fungal cell membranes and walls, inhibition of biofilm formation, interference with virulence factors, and modulation of cellular processes like efflux pump activity and mitochondrial function. DISCUSSION:The use of natural oils extends across topical medical treatments, crop protection, food preservation, and industrial systems. Innovations in nanotechnology and synergistic formulations have further enhanced their efficacy. However, challenges remain in standardization, stability, and delivery optimization, including limited clinical trials demonstrating real-world efficacy against resistant strains like Candida albicans biofilms. CONCLUSION:Natural oils hold significant promise as effective antifungal agents within integrated approaches to human health, agriculture, and food safety. Continued research and technological innovation are essential to fully harness their potential and address current limitations in formulation and application, such as regulatory hurdles in clinical translation.
OBJECTIVE:Conventional topical antifungal therapies often exhibit limited efficacy, poor patient adherence, and inadequate stability. To address these challenges, a microwave-assisted clove oil-based organogel of sertaconazole nitrate was developed to enhance antifungal activity, sustain drug release, and improve long-term stability. METHODS:Organogels were prepared using sertaconazole nitrate, clove oil, Carbopol 934, and polyethylene glycol 400. Physicochemical parameters, including pH, viscosity, spreadability, and drug content, were evaluated, followed by in vitro drug release and ex vivo skin permeation studies using Franz diffusion cells. Antifungal activity was tested against Candida albicans and Trichophyton rubrum, while in vivo therapeutic efficacy and skin irritation were assessed in a dermatophytosis rat model. The long-term stability of the formulation was monitored for 24 months. RESULTS:The optimized formulation (F12) showed excellent performance, with a drug content of 99.96%, viscosity of 41.45 Pa.s, and spreadability of 26.81 g.cm/sec. Drug release reached 99.5% within 24 hours, following zero-order kinetics with a non-Fickian release mechanism. Ex vivo permeation was significantly higher (99.2%) than that of the marketed cream (81.7%). Enhanced antifungal activity was observed, with inhibition zones of 1.82 cm (Candida albicans) and 2.01 cm (Trichophyton rubrum). In vivo studies confirmed effective therapeutic action without signs of skin irritation. Notably, the formulation maintained its physicochemical integrity and antifungal potency throughout 24 months of storage. DISCUSSION:The microwave-assisted technique proved to be a simple, reproducible, and efficient approach for organogel fabrication. The inclusion of clove oil contributed to improved antifungal performance and enhanced skin permeation, thereby strengthening the formulation's therapeutic potential. CONCLUSION:The developed sertaconazole nitrate organogel demonstrated a safe, effective, and stable topical delivery system with superior antifungal efficacy and long-term stability, representing a promising alternative to conventional antifungal therapies.
INTRODUCTION:Acne vulgaris is a common and complex skin condition characterised by excess oil production, blocked pores, and inflammatory lesions, such as papules and nodules. While hormonal factors and sebum overproduction are key contributors, the bacterium Staphylococcus aureus has also been recognised as a contributing pathogen. Phloretin, a flavonoid present in plants, like apples, is a promising new compound for acne treatment. Its potential rests in a variety of biological activities beyond merely acting as an antioxidant. Phloretin displays anti-inflammatory and antibacterial properties, which could directly target both the inflammatory response and the bacterial component of acne. These multiple mechanisms of action indicate that a phloretin-based gel could offer a comprehensive solution for managing the condition. MATERIALS AND METHODS:Antiacne gels containing varying concentrations of Carbopol and phloretin were prepared and evaluated. Key parameters included physical appearance, viscosity, pH, drug content, in vitro drug release, and antimicrobial activity against Staphylococcus epidermidis. RESULTS:The optimized hydrogel (F4) exhibited a pH of 6.68, viscosity of 35.9 cP, and drug content of 80.9%. In vitro release studies showed a maximum drug release of 75% over 120 minutes. The formulation displayed strong antimicrobial activity with an inhibition zone of 11 mm, comparable to the marketed benzoyl peroxide gel. The gel was also well tolerated, with no signs of skin irritancy. DISCUSSION:Antiacne gel containing phloretin can be regarded as a more effective treatment for acne. The optimized formulation consisted of phloretin, Carbopol, ethanol, sodium benzoate, PEG 400, propylene glycol, and triethanolamine, showing better results in terms of antimicrobial activity. CONCLUSION:Phloretin-based gel demonstrated promising antiacne potential, achieving effective drug release and significant antibacterial activity against Staphylococcus epidermidis, while maintaining acceptable physicochemical and dermatological properties.
INTRODUCTION:The Mitogen-Activated Protein Kinase (MAPK) is an intricately linked signaling cascade that frequently contributes to drug resistance in neurodegenerative diseases. This study presents an integrated approach combining in silico molecular docking, ADMET-based screening, and evaluation to identify novel N-substituted heterocyclic compounds as MAPK inhibitors for neuroinflammation. METHODS:The molecular docking of the designed 135 nitrogen-substituted 5-, 6-, and 7- membered derivatives was carried out using Flare GUI software, docked into the MAPK (p38, ERK, JNK) binding site with PDB code 3LN1. The interaction was evaluated based on the reranked score comparison between the designed derivatives and the co-crystallized ligand. Trametinib was used as the reference, and 8 selected compounds were evaluated for their ADMET profiling using Swiss ADME, Molinspiration, OSIRIS, and Protox II. The molecules were filtered for their drug-like properties. RESULTS:The docking results showed that more than 6% of the designed compounds displayed a good binding score compared with the reference Trametinib. The three targets used for screening are P38-alpha MAP kinase (2BAL), mitogen-activated protein kinase 1 ERK (3I5Z), and JNK-interacting protein 1 (7NYK). A maximum binding score of -8 kcal/mol was found for P38-alpha MAP kinase (2BAL). DISCUSSION:ADMET screening gave 13 selected compounds that displayed affirmative pharmacokinetic and pharmacodynamic profiles, paving the way for many new drugs for development. CONCLUSION:There is a large scope for the optimization of the core, suggesting that the screened 8 molecules might be promising targets as inhibitors of P38-alpha MAP kinase in the MAPK pathway and are feasible to be synthesized.
The chronic neuroinflammatory and neurodegenerative disease known as Multiple Sclerosis (MS) is characterized by mitochondrial dysfunction and ongoing microglial activation. Developments in nanomedicine have enabled the design of immunomodulatory nanocarriers that target mitochondria and microglia simultaneously, thereby addressing two key pathogenic characteristics. By delivering antioxidants and anti-inflammatory drugs straight to microglia and their mitochondria, these systems increase the effectiveness and specificity of treatment. This review summarizes preclinical research on nanocarriers for delivery to the central nervous system, including liposomes, polymeric nanoparticles, dendrimers, amphiphilic polymer nanoparticles, and modified exosomes, for the years 2020-2025. Functionalized liposomes containing microglia-specific peptides or Toll-like receptor 4 ligands can boost microglial uptake by up to five times, which causes cells to adopt anti-inflammatory characteristics. By incorporating antioxidants such as coenzyme Q₁₀ and N-acetylcysteine, and by using polymeric nanoparticles with mitochondrial- targeting groups, such as triphenyl phosphonium, these nanoparticles improve blood-brain barrier penetration and restore mitochondrial function. Dendrimers and exosomes facilitate effective intracellular and mitochondrial transport, reducing oxidative stress and inflammatory signaling, whereas amphiphilic polymer nanoparticles target scavenger receptors to decrease protein aggregation and neuroinflammation. In MS models, dual-targeting nanocarriers that combine mitochondrial repair and microglial modulation exhibit synergistic neuroprotective effects. Even with promising preclinical findings, there are still obstacles to overcome to achieve clinical translation, scale up production, and ensure long-term safety. Early microglial modulator experiments using sophisticated delivery devices show promise. Finally, dual-targeting immunomodulatory nanocarriers present a new precision neurotherapy strategy for multiple sclerosis. Sustained improvement of clinical pathways, safety, and pharmacokinetics may revolutionize therapeutic approaches and enhance patient outcomes.
Polythiophene-based nanocomposites have emerged as a promising class of functional materials due to their tunable electrical conductivity, optical responsiveness, environmental stability, and structural versatility. This review presents a comprehensive analysis of the sustainable synthesis approaches and multifunctional characteristics of polythiophene nanocomposites, emphasizing their potential in smart and environmentally responsive material systems. Various synthesis strategies, including in-situ polymerization, electrochemical deposition, and green chemical oxidation methods, are discussed in the context of enhancing material performance while minimizing ecological impact. The incorporation of nanofillers such as carbon nanotubes, graphene, metal oxides, and layered silicates significantly influences the physicochemical properties of polythiophene matrices, improving conductivity, mechanical strength, thermal resistance, and morphological control. These enhanced features have positioned polythiophene-based nanocomposites as viable candidates for applications in energy storage devices (supercapacitors and batteries), chemical and biosensors, environmental remediation technologies, and biomedical interfaces. Moreover, the review highlights current challenges in scalability, cost-effectiveness, structural stability under operational conditions, and biocompatibility. Limitations related to process control, environmental toxicity of precursors, and long-term material degradation are also acknowledged. Future research directions are proposed to address these barriers, including the development of low-toxicity dopants, recyclable synthesis routes, and computational modelling for material optimization. In summary, polythiophene-based nanocomposites represent a key advancement in smart material development, combining sustainability with multifunctionality. With continued innovation in design and synthesis, they hold significant promise for widespread deployment in industrial and biomedical sectors as part of a greener technological future.
INTRODUCTION:Debregeasia longifolia has been used traditionally in treating inflammatory and oxidative stress-associated disorders, but the potential of this herb in redox modulation has not been fully defined. Lipid peroxidation in biological substrates sensitive to oxygen acts as a good biomarker to determine antioxidant potential. The objective of this paper was to assess the antioxidant and anti-inflammatory properties of D. longifolia root extracts and to determine the connection between those properties and the levels of polyphenols and flavonoids. METHODS:The roots of D. longifolia that were collected in Meghalaya, India, were authentic and extracted sequentially with increased polarity of the solvents. The antioxidant activity was determined by the inhibition of lipid peroxidation of brain lipid substrates by the Fe2+/H2O2 (Fenton reaction)- induced lipid peroxidation through the TBARS technique. Anti-inflammatory activity was assessed through carrageenan-induced swelling of paws in rats and protein denaturation inhibition. The polyphenols and flavonoids were totaled, and correlation analysis was conducted. RESULTS:The lipid peroxidation inhibition of the ethanol extract was the highest (49.55%) and followed by the hydroalcoholic extract (45.17%). Antioxidant activity had strong positive relations with polyphenol (r = 0.9784) and flavonoid (r = 0.9624) contents. Extracts at 250 mg/kg were both found to be effective in reducing carrageenan-induced paw edema and as effective as indomethacin. Phytochemical analysis was performed, identifying compounds such as 2-propylphenol, quercetin glycosides, and atrazine-desethyl. DISCUSSION:The ability to exert strong antioxidant and anti-inflammatory effects is probably due to the high content of polyphenols and flavonoids, which could be mediated by COX-2 and 5-LOX inhibitors. CONCLUSION:This paper confirms the traditional application of D. longifolia and demonstrates ethanolic root extracts as potential natural antioxidants and anti-inflammatory agents with therapeutic benefits.
Pongamia pinnata (L.) has long been used in both the Ayurvedic and Siddha systems of medicine. It belongs to the leguminous family and shows significant potential for antiinflammatory activity, further supported by growing pharmacological and mechanistic evidence. This paper discusses recent advances in the study of its phytochemistry and the molecular mechanisms underlying its anti-inflammatory effects. Flavonoids, furanoflavonoids, terpenoids, and sterols are the main bioactive compounds, which modulate key inflammatory pathways such as NF- κB, COX-2, iNOS, and the expression of proinflammatory cytokines. Antioxidant, immunomodulatory, and membrane-stabilising activities help reduce oxidative stress and inflammation. Diseasespecific evidence highlights potential roles in arthritis, metabolic inflammation, neurodegeneration, and skin disorders. Emerging formulation approaches, including nanoparticles, ethosomes, and hydrogels, have improved the bioavailability, stability, and targeted delivery of various constituents of P. pinnata. Although preclinical studies have demonstrated a favourable safety profile, inadequate clinical validation and the need for standardised formulations remain two major barriers to therapeutic translation. This review aims to guide future research towards standardisation, pharmacokinetics, and formulation development to position P. pinnata as an attractive candidate for anti-inflammatory drug development.
INTRODUCTION:The historical discovery that thrombin activates Protease-Activated Receptor 4 (PAR4) has paved the way for several novel findings. Besides thrombin, the complement lectin pathway protease Mannose-Binding Lectin-Associated Serine Protease-1 (MASP-1) also binds to PAR4, albeit with lower affinity. Similar to thrombin, MASP-1 activates Ca²⁺ signaling pathways in endothelial cells. MASP-2, a homolog of MASP-1, plays an important role in complement activation; however, its direct interaction with PAR4 has not yet been elucidated. In this study, we performed structural investigations of thrombin, MASP-1, and MASP-2 to evaluate their binding affinities toward the PAR4 peptide. METHODS:We employed in silico docking, binding affinity calculations, molecular dynamics simulations, and mutagenesis studies to test our hypothesis. RESULTS:For the first time, we demonstrate that, like thrombin and MASP-1, MASP-2 binds to PAR4 with appreciable affinity and could serve as a potential agonist of the PAR4 receptor and its associated inflammatory signaling pathways. DISCUSSION:The high sequence similarity of MASP-2 with MASP-1 and thrombin is an important factor in attaining comparable binding with the PAR4 peptide. CONCLUSION:Our findings may pave the way for future investigations into the signaling mechanisms and therapeutic potential of PAR4-mediated inflammatory diseases.
This review summarizes recent advances in ligand trap therapies targeting activin type II receptors [ActRIIA/ACVR2A and ActRIIB/ACVR2B], which serve as shared receptors for members of the TGF-β family, including activins, GDF11, and myostatin [MSTN]. These receptors mediate Smad2/3 signaling and play critical roles in hematopoiesis, vascular homeostasis, and muscle regulation. Two peptide-based ligand traps have recently received clinical approval: luspatercept [ActRIIB-Fc], an erythroid maturation agent, and sotatercept [ActRIIA-Fc], a novel therapeutic agent for pulmonary arterial hypertension [PAH]. Luspatercept primarily inhibits activin B and GDF11, thereby promoting late-stage erythropoiesis and demonstrating efficacy in anemia associated with conditions such as myelodysplastic syndromes [MDS] and β-thalassemia. Sotatercept binds activins and GDFs to rebalance Smad2/3 and Smad1/5/8 signaling, thereby improving vascular remodeling in PAH. Although both agents have failed to increase skeletal muscle mass in clinical trials consistently, they represent significant advances in the treatment of hematopoietic and vascular disorders. Future studies should focus on optimal dosing strategies, long-term safety, and potential synergistic effects when combined with other therapeutic modalities.
INTRODUCTION:Phenothiazine derivatives represent an important class of heterocyclic compounds known for a wide range of pharmacological activities. Their antioxidant potential has drawn considerable interest for therapeutic applications against oxidative stress-related disorders. This study focused on synthesizing a new series of phenothiazine derivatives and evaluating their antioxidant activity. METHODS:A series of phenothiazine derivatives [5a-5h] was synthesized by conjugating phenothiazine with various aryl amines via an acetyl linker using standard organic synthesis techniques. The structures of the synthesized compounds were confirmed using spectroscopic techniques, including FT-IR, ^1H NMR, ^13C NMR, and mass spectrometry (MS). Antioxidant activity was assessed using two in vitro assays: the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method and the low-density lipoprotein (LDL) oxidation inhibition assay. RESULTS:All synthesized compounds were successfully characterized by the aforementioned spectroscopic techniques. The antioxidant assays revealed that most of the derivatives exhibited notable antioxidant activity. Among them, Compound 5e, bearing a 4-amino-2-methoxyphenol moiety, demonstrated the highest activity, surpassing the standard antioxidants Vitamin C and butylated hydroxyanisole (BHA). Conversely, compound 5h showed comparatively lower activity. DISCUSSION:The findings indicate that structural variations, particularly the presence of electrondonating groups on the phenothiazine ring, significantly influence antioxidant potential. The superior performance of Compound 5e highlights the importance of specific substituent patterns in enhancing biological activity. However, further investigation into pharmacokinetics and in vivo efficacy is necessary to support potential therapeutic use. CONCLUSION:The study successfully synthesized and characterized a novel series of phenothiazine derivatives, several of which exhibited potent antioxidant properties. Structure- activity relationship (SAR) analysis suggested that electron-donating substituents enhance activity, pointing to promising future applications in treating oxidative stress-related conditions.
Osteoarthritis (OA) is a common, chronic degenerative joint disease that leads to the progressive degeneration of articular cartilage, subchondral bone, and synovium. In short, it is characterized primarily by inflammation, cartilage breakdown, and subchondral bone remodeling leading to joint pain, stiffness, and severe functional limitations. OA pathogenesis results from complex reciprocal interactions between genetic, mechanical, and environmental factors that culminate in the activation of pro-inflammatory mediators such as Interleukin 1β (IL 1β) and Tumor Necrosis Factor alpha (TNF α), which stimulate Matrix Metalloproteinases (MMPs) and break down the cartilage extracellular matrix. Additionally, oxidative stress, mitochondrial dysfunction, and chondrocyte senescence play crucial roles in disease progression. Consequently, adipokines have become important contributors to OA pathophysiology, with special emphasis on visfatin. These molecules released from adipose tissue also represent a systemic proinflammatory signal, found at higher concentrations in OA synovial fluid, and contribute to cartilage degradation and worsening of clinical symptoms. Visfatin participates in various signaling pathways to further amplify inflammatory cascades and cartilage destruction. In this review, we explore the role of visfatin and its possible mechanisms contributing to the progression of OA.
The global increase in allergic diseases, such as atopic dermatitis, allergic rhinitis, asthma, and food allergies, has become a major public health issue. These diseases typically involve immune dysregulation, including a Th1/Th2 imbalance, increased IgE levels, regulatory T cell (Treg) dysfunction, and epithelial barrier dysfunction. New research has recognised an important role for the gut and mucosal microbiome in regulating immune responses and has prompted interest in the therapeutic utility of probiotics. Probiotics are live microbes that, when given in adequate amounts, confer health benefits, generally such as immunomodulation or restoration of gut barrier function. Traditional probiotics (i.e., Lactobacillus and Bifidobacterium species) reduce allergic inflammation through promotion of Treg differentiation, increases in antiinflammatory cytokines (e.g., IL-10), suppression of Th2 cytokines (e.g., IL-4), and modification of IFNγ. Traditional probiotics also support mucosal barrier function and restore microbial composition by producing short-chain fatty acids (SCFAs), like butyrate, which act directly on Gprotein- coupled receptors and histone deacetylases to suppress inflammation. Next-generation probiotics (NGPs), such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Bacteroides fragilis, and some clusters of Clostridia, can provide more targeted effects. These NGPs can secrete anti-inflammatory metabolite compounds, such as polysaccharide A (PSA), which modulate dendritic cells and increase Treg activity, and can promote mucin production to improve gut barrier function. Overall, there are key issues with strain specificity, dose, safety in immunocompromised individuals, and possible regulatory classification issues. Future opportunities may include precision microbiome profiling, synthetic biology, and artificial intelligence-driven strain discovery to develop personalised approaches to allergy immunotherapy.
