Anti-inflammatory Research Articles

A case of acute idiopathic maculopathy in both eyes with peripheral vascular occlusion

BackgroundThis study aimed to present a case of bilateral symmetric onset of acute idiopathic maculopathy after high fever with peripheral vascular occlusion.Case presentationA 54-year-old yellow female experienced acute binocular visual acuity decrease after 1 day of high fever, and binocular visual acuity decreased to index or anterior. OCT in the external hospital showed dome-shaped cortical detachment in the symmetrical macular area of both eyes with subretinal fluid, discontinuity in the ellipsoid zone and the chimera. The patient autonomously administered antibiotics and non-steroidal anti-inflammatory agents, including amoxicillin and ibuprofen. Following a three-day period, the patient’s visual acuity demonstrated significant improvement. Additionally, macular edema demonstrated a notable reduction as indicated by optical coherence tomography, while the presence of peripheral retinal vascular occlusions was also observed on fluorescein fundus angiography. At the onset of 6 days, oral hormone therapy was given in the outside hospital, with no significant improvement in visual acuity.23 days after the onset of the disease, the patient was admitted to our hospital, and was finally diagnosed as acute idiopathic maculopathy combined with the imaging findings of FFA, ICGA and OCT. During the follow-up, the visual acuity of both eyes improved spontaneously.ConclusionsThis case is a rare acute idiopathic macular lesion with bilateral involvement, accompanied by highly symmetrical peripheral retinal vascular occlusion in both eyes, which deepens our understanding of acute idiopathic maculopathy with a view to providing guidance for subsequent clinical practice.

Isolation, Identification, Phytochemical Characterization, and In Vitro Anti-Inflammatory Property of an Endophytic Trametes Versicolor CL-1 Isolated from Rosa Roxburghii.

This study explores the anti-inflammatory potential of an endophytic fungus, Trametes versicolor CL-1, isolated from the fruit tissues of Rosa roxburghii. Morphological and molecular analyses confirmed the identity of CL-1. An ethyl acetate extract (CL-E) from its fermentation broth was subjected to UPLC-HRMS and GNPS molecular networking. The analysis revealed a diverse array of secondary metabolites, including 11 terpenes, 7 flavonoids, 10 cinnamic acid derivatives, 6 oligopeptides, and 9 fatty acids, as verified by LC-MS/MS. Notably, CL-E exhibited significant in vitro anti-inflammatory activity in RAW264.7 cells. Furthermore, molecular docking studies predicted favorable binding interactions of key compounds 1 within CL-E with the NLRP3 inflammasome (PDB ID: 6NPY). These findings suggest T. versicolor CL-1 as a promising source of natural anti-inflammatory agents and unveil R. roxburghii as a potential reservoir for discovering novel bioactive metabolites.

Synthesis and Biological Evaluation of Isoaurone Derivatives as Anti-inflammatory Agents.

Twenty-eight isoaurone derivatives with 1,2,4-triazole moieties were synthesized using a fragment-based design strategy, and their anti-inflammatory activity was investigated. The anti-inflammatory effect of the most active derivative, 14e (41.82 %), was dose-dependent and higher than the values for celecoxib (31.82 %). Compound 14e was almost non-toxic and inhibited different concentrations of nitric oxide (NO). The western blotting results demonstrated that cyclooxygenase-2 (COX-2) expression was elevated when the macrophages were exclusively treated with LPS. However, compound 14e effectively suppressed the LPS-induced COX-2 upregulation. Subsequent investigation revealed that 14e is a promising compound capable of inhibiting the downstream signaling of COX-2. With the above interesting biological profile, molecular 14e could be a promising lead to develop novel anti-inflammatory agents.

Freund’s adjuvant is a classic of vaccine adjuvants and the basis of experimental immunology

Background. The invention of vaccines is rightfully considered one of the triumphs of medical research and one of the most remarkable achievements in public health in the history of humanity. According to the World Health Organization, vaccination saves 5 lives every minute and has saved over 25 million lives from 2011 to 2020. The effectiveness of a vaccine depends not only on the components of the antigen but also on the adjuvants, which are often used for more effective stimulation of the immune system. Purpose – to characterize the modern understanding of vaccine adjuvants, particularly Freund’s adjuvant, as a foundation of experimental immunology based on open source information. Materials and Methods. The selection of publications was conducted using databases such as PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection, and others, which provided information on vaccine adjuvants, particularly Freund’s adjuvant. In the first stage, a search for literature sources was performed using keywords: vaccine adjuvants, complete Freund’s adjuvant, alum, adjuvant arthritis, experimental immunology. In the second stage, the abstracts of the articles were reviewed, and publications that did not meet the research criteria were excluded. In the third stage, the full texts of the selected articles were examined for compliance with the inclusion criteria and relevance of the studies. Results. In 1924, G. Ramon demonstrated that the co-administration of the diphtheria anatoxin he had recently developed with other compounds such as tapioca, lecithin, agar, starch oil, saponin, and others enhances antitoxin reactions to diphtheria. In 1942, J. Freund developed a potent adjuvant in the form of a water-in-oil emulsion using mineral oil that contained heat-killed mycobacteria (Mycobacterium tuberculosis), which was named complete Freund’s adjuvant. However, over time, Freund’s adjuvant was banned for use in vaccines for humans due to its toxicity. Despite numerous studies, until 2009, aluminum salts dominated the use of adjuvants in licensed vaccines. Beginning in 2010, the demand for the development of new adjuvants noticeably increased, especially following several pandemics such as Ebola, Zika, and COVID-19. It is known that adjuvants enhance the adaptive immunity of vaccines by activating innate immune cells. The main concept of their effect is that adjuvants promote the production of antigen presentation signals and costimulatory signals by activating antigen-presenting cells. The model of adjuvant arthritis induced by complete Freund’s adjuvant was created to study the pathogenesis of arthritis, including rheumatoid arthritis, gout, and osteoarthritis, as well as to evaluate the effectiveness of certain anti-arthritis and anti-inflammatory drugs. Conclusions. Vaccine adjuvants encompass a wide range of chemical compounds and substances that enhance immune responses through physical or chemical binding with antigens. The most significant influences on the formation of the modern understanding of vaccine antigens and immunology in the 20th century were Gaston Ramon (1886–1963), Alexander Glenny (1882–1965), and Jules Freund (1890–1960). Complete Freund’s adjuvant has historically been and remains one of the most useful tools for immunologists. The use of antigenic mixtures from biological tissue extracts along with complete Freund’s adjuvant allows for the reproduction of various organ-specific autoimmune diseases in laboratory animals (such as autoimmune arthritis, myocarditis, hepatitis, thyroiditis, encephalomyelitis, etc.), facilitating preclinical studies on the effectiveness of potential immunomodulating and symptomatic therapeutic agents.

Repurposing of erythropoietin as a neuroprotective agent against methotrexate-induced neurotoxicity in rats.

Methotrexate (MTX) is a cytotoxic drug that can trigger neurotoxicity via enhancing oxidative stress, apoptosis, and inflammation. On the other hand, erythropoietin (EPO) functions as an antioxidant, anti-apoptotic, and anti-inflammatory agent, in addition to its hematopoietic effects. The present study was developed to examine the neuroprotective impact of EPO against MTX-provoked neurotoxicity in rats. Chemo fog was elicited in Wistar rats via injection of one dosage of MTX (20 mg/kg, i.p) on the sixth day of the study. EPO was injected at 500 IU/kg/day, i.p for 10 successive days. MTX triggered memory and learning impairment as evidenced by Morris water maze, passive avoidance, and Y-maze cognitive tests. In addition, MTX induced oxidative stress as evident from the decline in hippocampal Nrf2 and HO-1 levels. MTX brought about apoptosis, as demonstrated by the elevation in p53, caspase-3, and Bax levels, as well as the decrease in Bcl2 levels. MTX also decreased Beclin-1, an autophagy-related marker, and increased P62 expression. In addition, MTX downregulated Sirt-1/AKT/FoxO3a pathway and increased miRNA-34a gene expression. Moreover, MTX increased acetylcholinesterase activity and reduced neurogenesis. EPO administration remarkably counteracted MTX-induced molecular and behavioral disorders in rat hippocampi. Our findings impart preclinical indication for repurposing of EPO as a promising neuroprotective agent through modulating miRNA-34a, autophagy, and the Sirt-1/FoxO3a signaling pathway.

Emerging role of microglia in the developing dopaminergic system: perturbation by early life stress.

Early life stress correlates with a higher prevalence of neurological disorders, including autism, attention-deficit/hyperactivity disorder, schizophrenia, depression, and Parkinson's disease. These conditions, primarily involving abnormal development and damage of the dopaminergic system, pose significant public health challenges. Microglia, as the primary immune cells in the brain, are crucial in regulating neuronal circuit development and survival. From the embryonic stage to adulthood, microglia exhibit stage-specific gene expression profiles, transcriptome characteristics, and functional phenotypes, enhancing the susceptibility to early life stress. However, the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood. This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia, leading to dopaminergic system disorders, along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions. Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support (e.g., insulin-like growth factor-1) and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning. Furthermore, blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission. Furthermore, inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons, inhibiting dopamine synthesis, reuptake, and receptor activity. Enhanced microglial phagocytosis inhibits dopamine axon extension. These long-lasting effects of microglial perturbations may be driven by early life stress-induced epigenetic reprogramming of microglia. Indirectly, early life stress may influence microglial function through various pathways, such as astrocytic activation, the hypothalamic-pituitary-adrenal axis, the gut-brain axis, and maternal immune signaling. Finally, various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed. These strategies include classical antidepressants and antipsychotics, antibiotics and anti-inflammatory agents, and herbal-derived medicine. Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.

Formulation and Evaluation of Herbal Footcream

Skin diseases are numerous and a frequently occurring health problem affecting all ages from the neonates to the elderly and cause harm in number of ways. If the cracks in the heels are deep, they can be painful, hurting when a person stands up, and they may sometimes bleed. Some wild plants and their parts are frequently used to treat these diseases. Herbal crack cream contains the extracts of the plantconsists of five ingredients viz., extract of Daruharida (Berberisaristata DC.), Pashanbheda (Bergenialigulata (Wall.) Engl.), Jivanti (Leptadeniareticulata W. & A.), kampilak (Mallotusphilippensis Muell.-Arg.), Manjistha (Rubiacordifolia Linn.) were used to prepare Herbal crack cream. The main objective of the research work was to prepare and evaluate Herbal crack cream and the results showed that Herbal crack cream passeall Parameters related to cream and TLC of formulated cream and extract showed that the tannins, flavonoids and alkaloids were found to be present in mentioned medicinal plants. These days, skin conditions are a major cause of illness for people of all ages. If someone has a crack in their foot's heel, it hurts and is quite uncomfortable. Environmental factors contribute to the growth of germs and fungi on human skin. This factor is taken into account when creating HERBALFOOTCREAM. That cream's function is to hydrate the heel, and its emulsion is w/o type (cold cream). Cold cream works by producing an oily coating on the skin that aids in reducing water loss from the skin to the environment. Water serves to hydrate and refresh the skin while beeswax and cocoa butter work as emollients, which aid to soften and smooth the skin. The key ingredient in these formulations is argan oil, which has vitamin E and is healthy for the skin since it hydrates. Neem extract also has antibacterial and antifungal properties. Lemongrass essential oil is used in fragrances. This cream is homogeneous, spread sreadily, and is naturally fatty. This is W/O emulsion and with anacidic pH (within the range of skin pH). There was no phase separation in this cream. • The main aim of our research was to develop on anti-cracked heels cream formulation consisting of hedychium spicatum, aleo bar, badensis azodirachta indica for the treatment of cracked heels. Skin diseases are numerous and frequently occurring health problem affecting all age from neonate to the elderly and cause harm in number of ways. • The skin is external exposure of the body. The ageing is most visible on the skin. Nowadays, premature ageing is a big complication in the world because of the changes in an environment. Feet is important part of body; they suffer from many frictions. The lack of oil gland in the feet skin which results into very dry skin. External penetration of dirt, fungus, bacteria cause cuts and wounds. Bacterial decomposition is also occurred in foot give bad odour. For these purpose herbal foot cream is prepared. • This herbal foot cream is prepared from Argan oil (good for dry skin), Neem extract (antibacterial & antifungal effects), Aloe vera extract (for hydration) and lemongrass oil (fragrance). Other than synthetic compound, herbs have more effective, low cost, more availability, and less side effects. Here, ARGAN OIL have good property which give protection to the skin and lemongrass oil is having a good fragrance. Argan oil contains vitamin E which is known as anti-inflammatory agent in skin and several studies proves that vit E is good in seal up the cracks caused by dryness..

OGC SO31 - Treatment of cachexia in gastric cancer: A literature review exploring the use of natural anti-inflammatory products and their derivatives

Abstract Background Gastric cancer is a major cause of global cancer-related mortality, with 5-year survival rates of 7% in advanced disease. Cancer cachexia, characterised by irreversible skeletal muscle loss driven by systemic inflammation, contributes to approximately 20% of cancer-related deaths. Cachexia differs from malnutrition in that it cannot be fully reversed with nutritional support alone. Current treatments that focus on nutritional support, psychological counselling and anti-inflammatory medication are lacking in efficacy. Natural dietary supplements and their derivatives such as fatty acids, probiotics, amino acids, curcumin, ginger and resveratrol, may offer additional therapeutic benefits in managing gastric cancer cachexia. Method A comprehensive literature review was conducted to evaluate the efficacy of natural anti-inflammatory products in managing gastric cancer cachexia. The review focused on widely studied compounds including omega-3 fatty acids, probiotics, amino acids, curcumin, fucoidan, epigallocatechin-3-gallate (EGCG), resveratrol and ginger, assessing their impact on inflammation, muscle mass preservation, and overall patient outcomes. Results Natural anti-inflammatory compounds demonstrate efficacy in mitigating cancer cachexia by reducing systemic inflammation and muscle wasting. Essential fatty acids from nuts, seeds, and fish oil decrease pro-inflammatory cytokines and improve chemotherapy tolerance. Probiotics reduce gut dysbiosis and may enhance chemotherapy tolerance. Essential amino acids may promote muscle anabolism and reduce catabolism. Curcumin, fucoidan, EGCG and ginger exhibit anti-inflammatory properties, with some improving appetite and reducing nausea. While promising, these compounds need further clinical trials to validate their efficacy and safety in cancer cachexia management. Conclusion Natural anti-inflammatory products hold promise as adjunctive therapies in management of gastric cancer cachexia. While preclinical evidence is encouraging, robust clinical trials are essential to confirm their efficacy and safety. Integrating these compounds with conventional treatments may offer a comprehensive approach to addressing the complex metabolic and inflammatory challenges of cancer cachexia, potentially improving patient outcomes. Future research should focus on understanding mechanisms, optimising dosages, and overcoming bioavailability challenges.

Inflammation-targeted delivery of Urolithin A mitigates chemical- and immune checkpoint inhibitor-induced colitis

Inflammatory bowel disease (IBD) treatment often involves systemic administration of anti-inflammatory drugs or biologics such as anti-TNF-α antibodies. However, current drug therapies suffer from limited efficacy due to unresponsiveness and adverse side effects. To address these challenges, we developed inflammation-targeting nanoparticles (ITNPs) using biopolymers derived from the gum kondagogu (Cochlospermum gossypium) plant. These ITNPs enable selective drug delivery to inflamed regions, offering improved therapeutic outcomes. We designed ITNPs that specifically bind to inflamed regions in both human and mouse intestines, facilitating more effective, uniform, and prolonged drug delivery within the inflamed tissues. Furthermore, we demonstrated that oral administration of ITNPs loaded with urolithin A (UroA), a microbial metabolite or its synthetic analogue UAS03 significantly attenuated chemical- and immune checkpoint inhibitor- induced colitis in pre-clinical models. In conclusion, ITNPs show great promise for delivering UroA or its analogues while enhancing therapeutic efficacy at lower doses and reduced frequency compared to free drug administration. This targeted approach offers a potential solution to enhance IBD treatment while minimizing systemic side effects.

Progress in the study of toxic effects of drugs on the male reproductive system

This paper provides a comprehensive summary of the toxic effects of drugs on the male reproductive system, with a special focus on the mechanisms of testicular and sperm damage caused by chemotherapeutic agents, antibiotics, and immunosuppressants. Drug-induced reproductive toxicity usually manifests through multiple pathways including direct injury, interference with hormone regulation, oxidative stress, and DNA damage. These mechanisms can lead to impaired spermatogenesis, decreased testicular function, and long-term infertility, thereby seriously affecting male reproductive health. Specifically, chemotherapeutic drugs, such as cisplatin and cyclophosphamide, have been widely documented to cause direct damage to the testes, leading to significant decreases in sperm quantity and quality. Antibiotics and nonsteroidal anti-inflammatory drugs also negatively affect reproductive function by affecting mitochondrial function and inducing oxidative stress in the testicular cells. Although important advances have been made in recent years in the study of drug-induced reproductive toxicity, further exploration is needed to assess the variability of individual responses to drugs and develop long-term protective measures. Future research should focus on developing accurate toxicity assessment methods, customized therapeutic regimens, and enhanced fertility protection strategies, such as the use of antioxidants and methods for the cryopreservation of testes and sperm. Interdisciplinary collaboration will provide new solutions for balancing disease treatment and fertility preservation, especially in the use of high-risk drugs, such as anticancer therapies, where achieving both efficacy and reproductive health will be an important clinical challenge.

Epigenetic regulation of the inflammatory response in stroke

Stroke is classified as ischemic or hemorrhagic, and there are few effective treatments for either type. Immunologic mechanisms play a critical role in secondary brain injury following a stroke, which manifests as cytokine release, blood–brain barrier disruption, neuronal cell death, and ultimately behavioral impairment. Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models. However, in clinical trials of anti-inflammatory agents, long-term immunosuppression has not demonstrated significant clinical benefits for patients. This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair, as well as the complex pathophysiologic inflammatory processes in stroke. Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies. Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke. Furthermore, epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management. In this review, we summarize current findings on the epigenetic regulation of the inflammatory response in stroke, focusing on key signaling pathways including nuclear factor-kappa B, Janus kinase/ signal transducer and activator of transcription, and mitogen-activated protein kinase as well as inflammasome activation. We also discuss promising molecular targets for stroke treatment. The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke, leading to improved post-stroke outcomes.

Asymptomatic parasitic worm thelazia callipaeda infection found during phacoemulsification: A case report

Introduction:We report a case of asymptomatic thelazia callipaeda infection discovered incidentally during phacoemulsification cataract surgery in March 2024. Case presentation: A 77-year-old male patient presented with complaints of blurred vision. During a slit-lamp examination, trichiasis was observed, but the patient had no foreign body sensation or itching. He was diagnosed with cataract and underwent phacoemulsification cataract surgery. During the surgery, a white, wriggling worm was discovered in the conjunctival sac and removed. It was later identified as thelazia callipaeda. The surgical eye was thoroughly washed and received anti-inflammatory medication postoperatively. No recurrence or new symptoms were reported during the 3-month follow-up period. Conclusions: Thelazia callipaeda infection can be asymptomatic and incidentally discovered. A detailed preoperative examination, such as turning over the upper and lower eyelids to check the conjunctival sac, is necessary before the surgery. When a worm is discovered during surgery, it is crucial to remove it completely and thoroughly clean and disinfect the conjunctival sac.

The Therapeutic Potential of Agarwood as an Antimicrobial and Anti-Inflammatory Agent: A Scoping Review.

Microorganisms such as bacteria, viruses, and fungi are frequently the cause of infections. Antimicrobial agents, such as antibiotics, antivirals, and antifungals, are used to target and eliminate these infectious agents. On the other hand, inflammation is a natural response of the immune system to injury, infection, or irritation. Although herbal remedies have been used to treat these conditions for centuries and can be effective in certain situations, it is crucial to use them with caution. Not all herbal remedies are supported by scientific evidence, and their safety and efficacy can vary. Thus, we conducted this review to determine the potential health benefits of agarwood as an antimicrobial and anti-inflammatory agent. Three databases (PubMed, Scopus, and Google Scholar) were used to search for original papers submitted between 2013 and 2023, using the Medical Subject Heading (MeSH) terms "agar-wood" crossed with the terms "antimicrobial" and/or "anti-inflammatory". Synonyms and relevant search terms were also searched. The most-studied agarwood for antimicrobial and anti-inflammatory agents is Aquilaria sinensis. Some studies have shown its potential application as a potent inhibitor of fungi, including Lasiodiplodia theobromae, Fusarium oxysporum, and Candida albicans. Moreover, it is capable of inhibiting Bacillus subtilis and Staphylococcus aureus activities. Several chromones detected in agarwood have been shown to inhibit NF-κB activation, LPS-induced NO production, and superoxide anion generation. In conclusion, more research is needed, particularly regarding future intervention studies, to enhance our knowledge and understanding of agarwood and its isolates. This review reveals that despite the absence of clinical trials, agarwood exhibits antimicrobial and anti-inflammatory properties.

Synthesis of arylated tetrahydrobenzo[H]quinoline-3-carbonitrile derivatives as potential hits for treatment of diabetes.

Aim: Quinoline scaffolds are serving as the core structure for numerous antifungal, analgesic, antipyretic, anti-inflammatory drugs as well as have also been investigated for their potential antidiabetic properties. Though further exploration is required in this area as the current antidiabetic agents, such as acarbose, miglitoland voglibose, are associated with several adverse side effects. In this context, arylated tetrahydrobenzo[H]quinoline-3-carbonitrile derivatives were designed and evaluated as potential antidiabetic agents.Materials & methods: A one-pot multicomponent reaction of 6-methoxy-1-tetralone with ethyl cyanoacetate, ammonium acetateand varying aldehydes yielded a range of new arylated tetrahydrobenzo[h]quinoline-3-carbonitrile molecules 1-36.Results: Compounds 2-5, 12, 13, 19 and 32-34 showed excellent inhibition against α-amylase (IC50=3.42-15.14μM) and α-glucosidase (IC50=0.65-9.23μM) enzymes in comparison to the standard acarbose (IC50=14.35μM). In addition, all compounds revealed significant to moderate DPPH radical scavenging activity (SC50=21.30-138.30μM) compared with BHT (SC50=64.40μM). Kinetic studies confirmed competitive inhibition mode, while molecular docking studies comprehend ligands'interaction with enzyme's active sitesand absorption, distribution, metabolism, and excretion analysis confirms that all synthetic derivatives are nontoxic.Conclusion: This research offers a range of lead candidates to become antidiabetic agents after further advanced study.

Identification of altered blood metabolic pathways in equines following ethyl pyruvate administration using non-targeted metabolomics

Ethyl pyruvate (EP) has emerged as a promising compound with potential therapeutic benefits attributed to its anti-inflammatory and antioxidant properties. This study aimed to understand the effects of EP on plasma metabolites and immune cells in horses, utilizing advanced liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, quantitative polymerase chain reaction (qPCR), and blood chemistry analyses. Our comprehensive analysis detected 2,366 ions, and 126 metabolites were accurately identified. Remarkably, EP administration induced significant changes in 28 metabolites at 1 h and 11 metabolites at 8 h, highlighting its time-dependent impact on metabolic pathways such as phenylalanine and arginine biosynthesis. Moreover, EP significantly lowered the expression of inflammatory markers interleukin (IL)-6 and heme oxygenase (HO)-1, indicating its potential as an anti-inflammatory agent. Blood chemistry analysis revealed notable reductions in glucose and triglyceride levels. These findings demonstrate that EP is a substance with potential effects on pathways associated with inflammation, oxidative stress, and metabolic processes.

Abstract 4122957: C-C motif chemokine receptor-2 disruption Synergizes with Phosphodiesterase Type 5 Inhibition in Ameliorating Pulmonary Hypertension in Monocrotaline-treated Rats: Proof-of-Concept Study for a Combination therapy and Potential Mechanisms

Background: Whether and how any anti-inflammatory agents and their combination with conventional pulmonary vasodilators protect against pulmonary arterial hypertension (PAH) is unknown. Hypothesis: The disruption of C-C motif chemokine receptor (CCR) -2, a receptor for CCL-2, ameliorates PAH in any models with the reversal of the associated pro-inflammatory state and vascular cell phenotypes and synergizes with any conventional pulmonary vasodilators. Methods and Results: By using Ccr2 (-/-) rats generated by CRISPR/ Cas9 , we investigated PAH in Ccr2 (+/+) or Ccr2 (-/-) rats treated with monocrotaline (MCT), SU5416/hypoxia (SuHx), and chronic hypoxia (CH). Ccr2 (-/-) decreased the right ventricular systolic pressure, right ventricular hypertrophy, and mortality rate, and reversed increased expression of inflammatory cytokines/chemokines (IL-6, TNF-α, CCL2, IL-1β, TGF-β) in MCT-treated rats, but not in SuHx or CH models. Consistently, Ccr2 (-/-) decreased indices of pulmonary vascular diseases (PVDs) and perivascular macrophage infiltration, as well as reversed impaired BMPR2 signaling, increased endothelial apoptosis, impaired NO signaling (eNOS, peNOS/eNOS) and decreased phosphodiesterase (PDE)-5 expression in lungs in MCT-treated rats. Gene expression of the receptor for prostaglandin I 2 and endothelin was not altered in MCT-treated rats by Ccr2 (-/-). In cultured pulmonary arterial smooth muscle cells (PASMCs), Ccr2 (-/-) suppressed CCL2-induced hyperproliferation and dedifferentiation as well as reversed CCL2-induced decrease in PDE5 expression. Consistently, the whole-genome RNA sequencing analysis identified differentially expressed genes in CCL2-stimulated Ccr2 (-/-) PASMCs, which are related to cellular differentiation and contraction. Based on studies in rats and cultured PASMCs, we investigated whether a PDE5 inhibitor, tadalafil, synergizes with Ccr2 (-/-). Tadalafil administration ameliorated PH and PVDs in MCT-treated Ccr2 (-/-) rats but not in Ccr2 (+/+) rats, and further improved survival in Ccr2 (-/-) rats. Conclusions: PDE5 inhibition synergized with Ccr2 disruption in protecting against PAH in MCT-treated rats, which was mechanistically related to the restoration of proinflammatory states and associated vascular cell phenotypes. These findings confer a fundamental basis supporting that CCR2 may be a therapeutic target in intractable PAH patients with a certain CCR2-related inflammatory phenotype and refractory to conventional pulmonary vasodilators.

Towards New Anti-inflammatory Agents: Design, Synthesis and Evaluation of Molecules Targeting XIAP-BIR2.

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20c. The ability of compound 20c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.

Effect of Ketorolac Administration on the Rate of Nonunion of Operatively Treated Pediatric Long-Bone Fractures

Background: Nonunion is a rare yet serious complication in pediatric fracture healing that can lead to patient morbidity and economic burden. The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased risk of fracture nonunion in adults, but data are lacking in the pediatric population. This study examines the relationship between postoperative ketorolac administration and nonunion in operatively managed pediatric long-bone fractures. Methods: A retrospective cohort study was conducted with use of TriNetX, a research network that encompasses data from the United States, Canada, and Western Europe. A total of 462,260 patients from 52 health-care organizations met the inclusion criteria. Patients <18 years old with operatively managed upper or lower-extremity long-bone fractures were included. The exposure of interest was ketorolac administration within 30 days postoperatively between 2003 and 2023. Nonunion was identified and verified with use of the pertinent medical codes. Absolute risks and hazard ratios (HRs) were calculated for both study groups. Significance was set at p < 0.05. Results: After propensity score matching, 48,778 patients were identified per group. The incidence of nonunion was 2.19% in the ketorolac group and 0.93% in the non-ketorolac group (HR, 2.71; 95% confidence interval [CI]: 2.46, 3.21; p < 0.0001). Subgroup analyses demonstrated a higher risk of nonunion in patients with lower-extremity fractures (HR, 3.45; 95% CI: 3.14, 3.75; p < 0.0001) than in those with upper-extremity fractures (HR, 2.11; 95% CI: 1.84, 2.32; p < 0.0001). Among the fracture location subgroups, the greatest HR for nonunion was observed in patients with femoral fractures, followed sequentially by those with tibial and/or fibular fractures, humeral fractures, and radial and/or ulnar fractures. Conclusions: To our knowledge, this is the largest study to date to explore postoperative ketorolac use and nonunion in the setting of operatively managed pediatric long-bone fractures. Nonunion in children was rare, occurring in <1% of all included patients. Ketorolac administration was associated with a 2 to 3-fold increase in nonunion risks, with pronounced implications for patients with lower-extremity fractures, particularly those with femoral fractures. Clinicians should weigh the therapeutic advantages of non-opiate analgesia with ketorolac against the risk of nonunion in order to optimize postoperative pain management and recovery. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Looking Inside of the Intestinal Permeability Regulation by Protein-Derivatives from Bovine Milk.

The prime function of the epithelium is to regulate the intestinal permeability; the latter is a quantitative parameter that refers to the measurement of the rate of passage of solutes through the epithelial monolayer. Function of epithelial monolayer depends on the expression of protein complexes known as tight junction proteins; whose function and expression can be disrupted under conditions of inflammation including irritable bowel disease (IBD), intestinal infections, and high-fat diets, among others. This manuscript is focused to outline the effects of bovine milk protein derivatives on the intestinal permeability addressed mostly in animal models in which the intestinal barrier is disrupted. At present, the properties of bovine milk protein derivatives on intestinal permeability have been scarcely documented in humans, but evidence raised from clinical trials provides promising findings of potential application of colostrum to control of the intestinal permeability in critically ill patients, users of non-steroid anti-inflammatory drugs, like athletes and militia members.

CTNI-37. INTERIM SAFETY ANALYSIS OF THE PHASE IB/II RANDOMIZED ANTI-GLUTAMATERGIC DRUG REPURPOSING TRIAL GLUGLIO IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NCT05664464)

Abstract The advent of cancer neuroscience has significantly advanced our understanding of brain tumor biology, yet the clinical implications remain largely unexplored. Glutamate, the most abundant excitatory neurotransmitter, presents a potential therapeutic target in brain tumors. Glioblastoma cells synthesize and secrete large amounts of glutamate, driving epilepsy, neuronal death, tumor growth, and invasion. Several brain-penetrating drugs, approved for other conditions, can inhibit glutamate synthesis, secretion, and signaling. These drugs include: (i) gabapentin, an anti-seizure medication that inhibits the glutamate synthesis enzyme branched-chain amino acid transaminase 1; (ii) sulfasalazine, an anti-inflammatory drug that blocks the cystine-glutamate exchanger system Xc, reducing glutamate secretion; and (iii) memantine, a cognitive enhancer that prevents glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate type glutamate receptors. The multi-center, open-label, parallel-group, two-arm, 1:1 randomized phase Ib/II trial GLUGLIO is investigating the efficacy of a daily oral anti-glutamatergic triple combination of gabapentin, sulfasalazine, and memantine until tumor progression, in conjunction with standard chemoradiotherapy, compared to chemoradiotherapy alone. The primary endpoint is progression-free survival at 6 months (PFS-6). A sample size of 120 patients was determined to detect an increase in PFS-6 from 50% to 70%, with 80% power, using exploratory hypothesis testing at a one-sided significance level of 10%. Secondary endpoints include overall survival, seizure-free survival, response rate, quality of life for patients and caregivers, symptom burden, cognitive functioning, tumor glutamate levels (measured by magnetic resonance spectroscopy), and the use of anti-convulsants and steroids. Each drug is dosed up to the maximum approved amount. Results from the phase Ib part of the trial, including an interim safety analysis, will be presented at the conference.