Inflammatory Disorders Research Articles

Identification and validation of efferocytosis-related biomarkers for the diagnosis of metabolic dysfunction-associated steatohepatitis based on bioinformatics analysis and machine learning.

Metabolic dysfunction-associated steatohepatitis (MASH) is a highly prevalent liver disease globally, with a significant risk of progressing to cirrhosis and even liver cancer. Efferocytosis, a process implicated in a broad spectrum of chronic inflammatory disorders, has been reported to be associated with the pathogenesis of MASH; however, its precise role remains obscure. Thus, we aimed to identify and validate efferocytosis linked signatures for detection of MASH. We retrieved gene expression patterns of MASH from the GEO database and then focused on assessing the differential expression of efferocytosis-related genes (EFRGs) between MASH and control groups. This analysis was followed by a series of in-depth investigations, including protein-protein interaction (PPI), correlation analysis, and functional enrichment analysis, to uncover the molecular interactions and pathways at play. To screen for biomarkers for diagnosis, we applied machine learning algorithm to identify hub genes and constructed a clinical predictive model. Additionally, we conducted immune infiltration and single-cell transcriptome analyses in both MASH and control samples, providing insights into the immune cell landscape and cellular heterogeneity in these conditions. This research pinpointed 39 genes exhibiting a robust correlation with efferocytosis in MASH. Among these, five potential diagnostic biomarkers-TREM2, TIMD4, STAB1, C1QC, and DYNLT1-were screened using two distinct machine learning models. Subsequent external validation and animal experimentation validated the upregulation of TREM2 and downregulation of TIMD4 in MASH samples. Notably, both TREM2 and TIMD4 demonstrated area under the curve (AUC) values exceeding 0.9, underscoring their significant potential in facilitating the diagnosis of MASH. Our study comprehensively elucidated the relationship between MASH and efferocytosis, constructing a favorable diagnostic model. Furthermore, we identified potential therapeutic targets for MASH treatment and offered novel insights into unraveling the underlying mechanisms of this disease.

Antioxidative and Anti-Atopic Dermatitis Effects of Peptides Derived from Hydrolyzed Sebastes schlegelii Tail By-Products.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with significant morbidity, including pruritus, recurrent skin lesions, and immune dysregulation. This study aimed to investigate the antioxidative and anti-AD effects of peptides derived from hydrolyzed Sebastes schlegelii (Korea rockfish) tail by-products. Hydrolysates were prepared using various enzymes, including Alcalase, Flavourzyme, Neutrase, and Protamex. Among them, Protamex hydrolysates demonstrated the highest ABTS radical scavenging activity with an RC50 value of 69.69 ± 0.41 µg/mL. Peptides were further isolated from the Protamex hydrolysate using dialysis, fast protein liquid chromatography (FPLC), and high-performance liquid chromatography (HPLC). The most active peptide, STPO-B-II, exhibited a single peak and was identified as a sequence of Glu-Leu-Ala-Lys-Thr-Trp-His-Asp-Met-Lys, designated as MP003. In vivo experiments were conducted using a 2,4-dinitrochlorbenzene (DNCB)-induced AD model in NC/Nga mice. The isolated peptide, MP003, showed significantly reduced AD symptoms, including erythema, lichenification, and collagen deposition. Additionally, MP003 decreased epidermal and dermal thickness, eosinophil, and mast cell infiltration and downregulated the expression of pro-inflammatory cytokines IL-1β, IL-6, and IgE in serum and skin tissues. These findings suggest that peptides derived from Sebastes schlegelii tail by-products may serve as potential therapeutic agents for AD.

OS RISCOS DO USO DE ANTI-INFLAMATÓRIOS NÃO ESTERÓIDES PELO PACIENTE DIABÉTICO NO BRASIL

Introduction: Diabetes mellitus (DM) is a chronic non-communicable disease characterized by hyperglycemia. The types of diabetes have different symptoms and treatments and can cause various chronic complications. Diabetic nephropathy and cardiovascular diseases stand out in this article. Anti-inflammatories are divided into two classifications: steroids and non-steroids (NSAIDs). NSAIDs can treat inflammation, pain, edema, osteoarthritis, rheumatoid arthritis, and musculoskeletal disorders. Still, they cause side effects, some of which can cause problems in the renal system and cardiovascular systems, systems that may already be at risk of suffering complications in diabetic patients. Despite these effects, some NSAIDs are Over-the-Counter Medications (OTC) and this facilitates self-medication and irrational use of these medications. Objective: To analyze the risks related to the use of NSAIDs by diabetics in Brazil. Methodology: The method was descriptive and quantitative research through a bibliographic review. Conclusion: Due to the prevalence of diabetics in Brazil and the common use of non-prescription NSAIDs, diabetics must avoid self-medication and be made aware and guided by health professionals.

Epigenetic programming of obesity in early life through modulation of the kynurenine pathway.

Childhood obesity is a global health concern that has its origins before birth. Although genetics plays a crucial role, increasing evidence suggests that epigenetic modifications during fetal life could also influence its incidence. In this model, during the fetal period, interactions between genetic makeup, intrauterine factors, and environmental conditions, increase the risk of childhood obesity. This is in accordance with the Developmental Origins of Health and Disease (DOHaD) hypothesis, in which specific intrauterine environments can have long-lasting effects on the immune system's essential functions during crucial stages of fetal growth, resulting in permanent changes to the immune function of the offspring. Consequently, dysfunction can consequently make the offspring more prone to inflammatory and immune-related disorders later in life. In this review, we examine how maternal inflammation could influence the risk of childhood obesity. We propose that during pregnancy, modification of the expression of critical genes in metabolic and signaling pathways, such as the kynurenine (Kyn) pathway, occurs due to increased levels of maternal inflammation. We also propose that such expression differences are mediated by epigenetic changes. Furthermore, we also hypothesize that the Kyn pathway produces metabolites that have immunoregulatory effects and may play a crucial role in regulating inflammation during pregnancy. As a result, interventions aimed at improving maternal inflammation may be able to help alleviate the risk of childhood obesity.

NLRP10 maintains epidermal homeostasis by promoting keratinocyte survival and P63-dependent differentiation and barrier function

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by disrupted epidermal barrier function and aberrant immune responses. Despite recent developments in new therapeutics for AD, there is still a large unmet medical need for disease management due to the complex and multifactorial nature of AD. Recent genome-wide association studies (GWAS) have identified NLRP10 as a susceptible gene for AD but the physiological role of NLRP10 in skin homeostasis and AD remains unknown. Here we show that NLRP10 is downregulated in AD skin samples. Using an air-lift human skin equivalent culture, we demonstrate that NLRP10 promotes keratinocyte survival and is required for epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of caspase-8 to the death inducing signaling complex (DISC) and by inhibiting its subsequent activation. NLRP10 also stabilizes p63, the master regulator of keratinocyte differentiation, to drive proper keratinocyte differentiation and to reinforce the barrier function. Our findings underscore NLRP10 as a key player in atopic dermatitis pathogenesis, highlighting NLRP10 as a potential target for therapeutic intervention to restore skin barrier function and homeostasis in AD.

Ghrelin in Depression: A Promising Therapeutic Target.

Depression is a widespread disease affecting over 300 million individuals of various ethnicities and socioeconomic backgrounds globally. It frequently strikes early in life and becomes a chronic or recurring lifelong illness. Out of the various hypotheses for the pathophysiology of depression, the gut-brain axis and stress hypothesis are the ones that need to be researched, as psychological stress impairs one or more pathways of the brain-gut axis and is likely to cause brain-gut axis dysfunction and depression. A dysfunctional reciprocal gut-brain relationship may contribute to many diseases, including inflammatory disorders, abnormal stress responses, impaired behavior, and metabolic changes. The hormone ghrelin is a topic of interest concerning the gut-brain axis as it interacts with the gut-brain axis indirectly via the central nervous system or via crossing the blood-brain barrier. Ghrelin release is also affected by the gut microbes, which has also been discussed in the review. This review elaborates on Ghrelin's role in depression and its effect on various aspects like neurogenesis, HPA axis, and neuroinflammation. Furthermore, this review focuses on ghrelin as a potential target for alleviation of depressive symptoms.

Enhancement of Autophagy in Macrophages via the p120-Catenin-Mediated mTOR Signaling Pathway.

Autophagy serves as a critical regulator of immune responses in sepsis. Macrophages are vital constituents of both innate and adaptive immunity. In this study, we delved into the intricate role of p120-catenin (p120) in orchestrating autophagy in macrophages in response to endotoxin stimulation. Depletion of p120 effectively suppressed LPS-induced autophagy in both J774A.1 macrophages and murine bone marrow-derived macrophages. LPS not only elevated the interaction between p120 and L chain 3 (LC3) I/II but also facilitated the association of p120 with mammalian target of rapamycin (mTOR). p120 depletion in macrophages by small interfering RNA reduced LPS-induced dissociation of mTOR and Unc-51-like kinase 1 (ULK1), leading to an increase in the phosphorylation of ULK1. p120 depletion also enhanced LPS-triggered macrophage apoptosis, as evidenced by increased levels of cleaved caspase 3, 7-aminoactinomycin D staining, and TUNEL assay. Notably, inhibiting autophagy reversed the decrease in apoptosis caused by LPS stimulation in macrophages overexpressing p120. Additionally, the ablation of p120 inhibited autophagy and accentuated apoptosis in alveolar macrophages in LPS-challenged mice. Collectively, our findings strongly suggest that p120 plays a pivotal role in fostering autophagy while concurrently hindering apoptosis in macrophages, achieved through modulation of the mTOR/ULK1 signaling pathway in sepsis. This underscores the potential of targeting macrophage p120 as an innovative therapeutic avenue for treating inflammatory disorders.

Risk Factors Associated with Gastritis among Adult Patients Attending at Capital Hospital in Mogadishu- Somalia

Background: Gastritis, an inflammatory disorder affecting the lining of the stomach, is a prevalent health concern across the globe, particularly in developing regions like Somalia. This study aims to investigate the primary risk factors linked to gastritis among adults receiving care at Capital Hospital in Mogadishu.  Methods: An unmatched case-control study was executed from June 1 to July 30, 2024, involving 63 adult participants, with 21 patients diagnosed with gastritis through endoscopic procedures and 42 controls. A semi- structured questionnaire was employed to gather data on socio-demographic characteristics, dietary patterns, lifestyle habits, medical histories, and medication usage. Statistical analysis was performed using SPSS version 26.  Results: The investigation revealed a gastritis prevalence of 78.8%, with acute cases constituting 48.9% and chronic cases 29.9%. Female participants were identified as having a protective effect against gastritis (Adjusted Odds Ratio [AOR]=0.05, p=0.023), whereas the routine use of non-steroidal anti-inflammatory drugs (NSAIDs) significantly raised the risk (Crude Odds Ratio [COR]=5.03, p=0.041). Interestingly, the presence of Helicobacter pylori was associated with a reduced risk of developing gastritis (COR=0.11, p=0.032). Other lifestyle and dietary factors did not show significant correlations.  Conclusions: The results underscore the protective influence of gender and the associated risks of NSAID intake regarding gastritis among Somali adults. The unexpected finding of H. pylori infection linked to lower gastritis risk deserves further exploration. There is an urgent need for targeted public health strategies to address the effects of gastritis in Somalia.

Innovations in Nuclear Medicine Imaging for Reactive Oxygen Species: Applications and Radiopharmaceuticals.

Reactive oxygen species (ROS) are generated during normal cellular energy production and play a critical role in maintaining cellular function. However, excessive ROS can damage cells and tissues, contributing to the development of diseases such as cardiovascular, inflammatory, and neurodegenerative disorders. This review explores the potential of nuclear medicine imaging techniques for detecting ROS and evaluates various radiopharmaceuticals used in these applications. Radiopharmaceuticals, which are drugs labeled with radionuclides, can bind to specific biomarkers, facilitating their identification in vivo using nuclear medicine equipment, i.e., positron emission tomography and single photon emission computed tomography, for diagnostic purposes. This review includes a comprehensive search of PubMed, covering radiopharmaceuticals such as analogs of fluorescent probes and antioxidant vitamin C, and biomarkers targeting mitochondrial complex I or cystine/glutamate transporter.

A feasible clinical pathway of severe pyoderma gangrenosum in burn centers based on three clinical cases

ObjectiveTo establish a standardized clinical pathway for the management of severe pyoderma gangrenosum (PG) in burn centers by analyzing and integrating insights from three detailed case studies. Methods and materialsFirst, we sum up experiences about identification and recovery methods for acute and chronic PG-induced wounds by analyzing the characteristics of emergent cases. Second, we analyzed the similarities and differences in the diagnosis and treatment of the clinical cases. Then, a clinical pathway was established by integrating the diagnosis and treatment characteristics of the three cases. ResultsA clinical pathway for severe PG management was developed for use in burn centers, which comprised: (1) Initial Assessment and Potential PG Identification Criteria, (2) Steps for Confirming a PG Diagnosis, (3) Treatment Protocol, and (4) Follow-up and Monitoring. ConclusionPG, as a rapidly progressing rare inflammatory skin disorder, is often misdiagnosed and treated inappropriately. The unpredictable course and the lack of standardized treatment protocols for PG makes its management challenging. The clinical pathway established in this study comprises a timely diagnostic process and optimizes treatment strategies, ultimately enhancing the quality of care for patients with PG. Future studies are needed to validate this pathway and explore its applicability in different clinical settings.

Psoriasis management tree based on comorbidity.

Psoriasis, a common chronic inflammatory skin disorder, encompasses various subtypes, including guttate, pustular, erythrodermic, and the most common type, plaque psoriasis. Irrespective of the subtype, psoriasis can manifest with multisystemic presentations, including psoriatic arthritis, metabolic disorders, cardiovascular disease, malignancies, chronic kidney disease (CKD), psychiatric illness, and inflammatory bowel disease (IBD). Many comorbidities and concomitant conditions must be considered when selecting the most appropriate therapy for a patient (Kaushik etal., 2019 and Monks etal., 2021) . Ongoing clinical trials and the development of new therapeutic targets contribute to the continuous improvement of available treatment options. Given the dynamic landscape of therapies, particularly when managing complex patients with multiple comorbidities, dermatologists are constantly challenged with the task of adeptly tailoring treatments to each psoriasis patient. This article systematically reviews the current evidence, presenting it as an updated Psoriasis Decision Tree to assist physicians in selecting tailored treatment options.

Development of a selective COX-2 inhibitor: from synthesis to enhanced efficacy via nano-formulation.

Non-steroidal anti-inflammatory drugs NSAIDs are widely used for managing various conditions including pain, inflammation, arthritis and many musculoskeletal disorders. NSAIDs exert their biological effects by inhibiting the cyclooxygenase (COX) enzyme, which has two main isoforms COX-1 and COX-2. The COX-2 isoform is believed to be directly related to inflammation. Based on structure-activity relationship (SAR) studies of known selective COX-2 inhibitors, our aim is to design and synthesize a novel series of 2-benzamido-N-(4-substituted phenyl)thiophene-3-carboxamide derivatives. These derivatives are intended to be selective COX-2 inhibitors through structural modification of diclofenac and celecoxib. The compound 2-benzamido-5-ethyl-N-(4-fluorophenyl)thiophene-3-carboxamide VIIa demonstrated selective COX-2 inhibition with an IC50 value of 0.29 μM and a selectivity index 67.24. This is compared to celecoxib, which has an IC50 value of 0.42 μM and a selectivity index 33.8. Molecular docking studies for compound VIIa displayed high binding affinity toward COX-2. Additionally, the suppression of protein denaturation with respect to albumin was performed as an indicative measure of the potential anti-inflammatory efficacy of the novel compounds. Compound VIIa showed potent anti-inflammatory activity with 93% inhibition and an IC50 value 0.54 μM. In comparison, celecoxib achieved 94% inhibition with an IC50 value 0.89 μM. Although molecule VIIa demonstrated significant in vitro anti-inflammatory activity, adhered to Lipinski's "five rules" (RO5) and exhibited promising drug-like properties, it showed indications of poor in vivo activity. This limitation is likely due to poor aqueous solubility, which impacts its bioavailability. This issue could be addressed by incorporating the drug in niosomal nanocarrier. Niosomes were prepared using the thin-film hydration technique. These niosomes exhibited a particle size of less than 200 nm, high entrapment efficiency, and an appropriate drug loading percentage. Transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies revealed that the niosomes were spherical and demonstrated compatibility of all of its components. The drug release study indicated that the pure drug had limited practicality for in vivo use. However, incorporating the drug into niosomes significantly improved its release profile, making it more suitable for practical use.

Unveiling the therapeutic potential of azopyridine derivatives for trypsin inhibition: a DFT and In-Vitro approach

Heterocyclic azo derivatives have emerged as promising scaffolds for drug development. This study focused on the synthesis, computational analysis, and biological evaluation of a series of azopyridine derivatives (1a, 1d, 1 g, 1 h, 1 m, 1p, and 1s) as potential trypsin inhibitors. Density Functional Theory calculations indicated that derivative 1 h exhibited the lowest HOMO-LUMO energy gap 3.167 eV and was characterised as a soft molecule, suggesting strong binding capabilities. Molecular docking studies confirmed that 1 h binds favourably to the active site of trypsin with a glide score of −6.581 kcal/mol and binding energy of −29.95 kcal/mol. Along with docking studies, the stability of the trypsin-1 h complex was further analyzed using molecular dynamic simulations at 200 ns. The results showed that the ligand molecule 1 h bound strongly at the active site of trypsin. In-vitro enzyme assays determined the IC50 value of the molecule as 100 µM, demonstrating enhanced potency. These results indicate that AzPy derivatives, particularly 1 h, hold considerable promise as therapeutic agents for inflammatory disorders and cancer, paving the way for further exploration in drug development and targeted therapies. Further research is warranted to explore 1h’s efficacy, safety, and structure-activity relationships. Highlights: DFT studies were used to classify molecules based on their softness and hardness. Molecular docking, simulation, and in-vitro studies have identified potential anti-trypsin activity of candidate molecules. Experimental and computational calculations were in close agreement.

High-CBD Extract (CBD-X) in Asthma Management: Reducing Th2-Driven Cytokine Secretion and Neutrophil/Eosinophil Activity.

Asthma is a chronic inflammatory disorder of the airways affecting over 10% of the global population. It is characterized by airway inflammation, mucus hypersecretion, and bronchial hyperresponsiveness, driven predominantly by type 2 helper T cells (Th2) and type 2 innate lymphoid cells (ILC2s) in a subset of patients. However, a significant portion of asthmatic individuals present with "type 2-low" asthma that is often refractory to standard inhaled corticosteroid (ICS) therapy. Therefore, developing innovative therapeutic strategies has become essential. Recent studies have highlighted cannabidiol (CBD) as a promising anti-inflammatory agent capable of modulating immune responses. This study investigates the therapeutic potential of a high-CBD extract (CBD-X) in asthma. We evaluated the effects of CBD-X on cells involved in asthma pathogenesis using primary human Th2 cells, neutrophils, and asthma mouse model. Our findings indicate that CBD-X extract inhibits Th2 differentiation and reduces the secretion of IL-5 and IL-13, which are crucial cytokines in asthma. Additionally, CBD-X significantly reduces pro-inflammatory cytokines IL-8 and IL-6 in neutrophils and impairs their migration, a critical step in airway inflammation. In a murine asthma model, CBD-X administration led to marked downregulation of IgE and pro-asthmatic cytokines, along with reduced leukocyte, eosinophil, and neutrophil infiltration in lung tissues. These results suggest that CBD-X extract could offer a novel and complementary approach to managing both type 2-high and type 2-low asthma by targeting key inflammatory pathways and modulating immune cell behavior.

Nutritional Benefits of Lycopene and Beta‐Carotene: A Comprehensive Overview

ABSTRACTCertain carotene components, such as lycopene and beta‐carotene, are found in tomatoes, carrots, sweet potatoes, etc. and are good for human health. It gives plants their distinctive red color. A class of lipid‐soluble natural pigments known as carotenoids is the precursor of vitamin A and is vital for antioxidant defense against peroxides in cells and tissues. This review provides an overview of the current state of knowledge and research on the sources, structures, physiochemical properties, absorption and metabolism, functional advantages, and prevention of many diseases associated with lycopene and beta‐carotene. These antioxidants have been linked to a lower risk of cardiovascular disease and cancer, and they also help draw pollinators to flowers. Carrots and sweet potatoes are also rich sources of beta‐carotene, which strengthens the immune system and improves eye health. The vivid color of many plants reproductive organs, including flowers and fruits, is caused by carotenoid, a secondary metabolite that is produced in plastids. The distinctive red color and many other health advantages are attributed to lycopene. When ingested through food or supplements, lycopene and beta‐carotene help manage and prevent a number of diseases, including cancer, metabolic, inflammatory, cardiovascular, hepatic, ophthalmic, skeletal, and infertility disorders. The main point is that toxicity is uncommon, and these carotenoids are generally accepted to be safe at different doses. Including these nutrients in your diet can improve your general health and provide illness prevention.

Anti-Inflammatory Potential of Costus speciosus rhizome Bioactive Phytochemicals: A Combined GC-MS and Computational Approach Targeting TLR-4 Signaling.

Plants represent a rich reservoir of bioactive compounds with established therapeutic value in diverse diseases. Notably, the Toll-like receptor-4 (TLR-4) signaling pathway plays a pivotal role in inflammation. Upon engagement with pro-inflammatory ligands like lipopolysaccharide, TLR-4 triggers downstream cascades involving nuclear factor ĸappa B and mitogen- activated protein kinases. This signaling cascade ultimately dictates the onset and progression of inflammatory diseases. Therefore, targeting TLR-4 signaling offers a promising therapeutic approach for managing inflammatory disorders. This study investigated the potential of Costus speciosus rhizome phytocompounds, a traditional medicinal plant, as novel as modulators of TLR-4 signaling, highlighting their mechanisms of action and potential clinical applications. In the present study, 18 phytocompounds isolated from the rhizome of Costus speciosus, were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. The compounds exhibited binding affinities ranging from -4.087 to -8.93 kcal/mol with the TLR-4 protein due to the formation of multiple intermolecular interactions. Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, methyl ester (compound 7) exhibited exceptional binding energy (-8.93 kcal/mol), indicating strong affinity for the TLR-4 protein. Additionally, compound 7 displayed favorable ADMET properties, suggesting promising drug development potential. Molecular dynamics simulations confirmed the stability of the compound 7-TLR4 complex, further supporting its ability to modulate TLR-4 signaling. These findings highlight the therapeutic potential of Costus speciosus phytocompounds, particularly compound 7, as potent anti-inflammatory modulators. Further research is warranted to validate their anti-inflammatory and neuroprotective effects in pre-clinical models, paving the way for their development as novel therapeutic agents for inflammatory diseases.

Therapeutic Potential of Methanolic Stem Extract of Costus afer on Serum Uric Acid, Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6) Levels in Monosodium Urate (MSU)-Induced Gouty Arthritis in Wistar Rats

The therapeutic potential of methanolic stem extracts of Costus afer was investigated to evaluate their effects on serum uric acid, TNF-α, and IL-6 levels, which are the key biomarkers associated with inflammatory and metabolic disorders like gouty arthritis. Qualitative and quantitative phytochemical analysis of C. afer indicated the presence of flavonoids, alkaloids, phenol, anthraquinone and glycosides, these bioactive compounds have been implicated for numerous medicinal uses and as such the therapeutic potentials of the extract were investigated by administering varying doses (100 mg/kg, 200 mg/kg, and 400 mg/kg) of the extract to a Wistar rat model with induced gouty arthritis and assessing its impact compared to a control group and an untreated MSU group. The results revealed that the extracts significantly reduced ( serum uric acid levels in a dose-dependent manner, with the high dose achieving a reduction below the control level. Additionally, the extracts effectively decreased ( TNF-α and IL-6 levels, indicating potent anti-inflammatory properties. The high dose exhibited the most substantial reduction in these biomarkers, underscoring the extract’s therapeutic potential. These findings support the traditional use of C. afer and provide scientific validation for its application in managing hyperuricemia and inflammatory conditions.

Features of Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic mutation syndrome associated with the c.121A>C, p.(Met41Leu) UBA1 genetic variant: A systematic review

Abstract Introduction/Objective Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic mutation (VEXAS) syndrome was first described in 2020. VEXAS is driven by a mutation in the UBA1 gene on hematopoietic progenitor cells that encodes the E1 ubiquitin-activating protein. Loss of this protein leads to various inflammatory clinical presentations ranging from dermatological, pulmonary, rheumatologic and hematologic. Many UBA1 variants have been identified. We did a systematic review focusing on a particular UBA1 variant gene mutation underlying this disease process. Methods/Case Report Databases were searched for articles discussing VEXAS syndrome until April 2024. Only case reports and case series in the English language were included. Data on patient demographics, clinical presentation, laboratory values, bone marrow findings, dermatologic presentation and skin biopsy findings were extracted. Results (if a Case Study enter NA) 332 articles discussing VEXAS syndrome were retrieved, of which 115 were case reports or case series. These were screened for patients carrying a p.Met41Leu UBA1 gene mutation and only the 25 patients with this genetic variant were ultimately included in our study. The average age was 68 years (59-81 years). 24/25 (96%) patients reported dermatologic symptoms ranging from erythema to urticarial eruptions to erythema multiforme. Fever was the second most common presenting complaint (76%) followed by arthritis (68%), chondritis (36%) and thromboembolic disease (28%). Macrocytic anemia was a common laboratory finding (65%). MDS was seen in 52% of the patients. All patients had hematopoietic progenitor cells with vacuoles. Sweet’s syndrome was the most common initial diagnosis (52%) as skin biopsies in most patients showed dermal edema and neutrophilic dermatoses/infiltration. Conclusion The c.121A>C, p.(Met41Leu) UBA1 variant is frequently related to cutaneous manifestations. In patients with clinical features of an inflammatory disorder with dermatological and hematologic abnormalities, testing for the p.Met41Leu UBA1 mutation might lead to an earlier diagnosis and prompt initiation of effective treatment.

Anti-inflammatory Activity of 1-Substituted Glyoxal β-Carboline Derivatives

The anti-inflammatory properties of β-carbolines have been widely studied, highlighting their potential in treating inflammatory disorders. This research investigates the anti-inflammatory activity of selected 1-substituted glyoxal β-carboline derivatives, achieved through a one-step conversion of 5-hydroxy-L-tryptophan with activated glyoxal, without forming tetrahydro-β-carboline (THβC) intermediates. These derivatives (4e-g) were synthesized successfully without requiring expensive metal catalysts, prolonged reaction times, or stringent reaction conditions, and yielded moderate amounts. Our findings indicate that all the derivatives significantly inhibit xanthine oxidase (XO) activity, leading to a reduction in reactive oxygen species (ROS) and free radicals. This inhibition disrupts the inflammatory cascade and attenuates the inflammatory response.

Outer membrane barrier impairment by envC deletion reduces gut colonization of Crohn's disease pathobiont Escherichia coli.

Adherent-invasive Escherichia coli (AIEC) has been implicated in the aetiology of Crohn's disease (CD), a chronic inflammatory disorder of the gastrointestinal tract. The presence of Enterobacteriaceae, including AIEC, is heightened in the intestines of CD patients. Therefore, inhibiting AIEC colonization in the gastrointestinal tract could be a promising therapeutic intervention for CD. This study aims to assess the potential of EnvC as a novel therapeutic target, examining how disrupting EnvC activity through the deletion of the envC gene decreases AIEC gut colonization levels. EnvC serves as a catalyst for peptidoglycan (also called murein) amidases, facilitating bacterial cell division. An AIEC mutant lacking the envC gene exhibited impaired cell division. Furthermore, envC deletion led to a diminished outer membrane barrier, as seen in our finding that the envC mutant became susceptible to vancomycin. Finally, we found that the envC mutant is impaired in competitive gut colonization in a dysbiotic mouse model. The colonization defects might be attributable to reduced resistance to colonic bile acids, as evidenced by our finding that increased colonic levels of bile acids inhibited the colonization of the gastrointestinal tract by AIEC strains. The present findings suggest that targeting bacterial cell division through the inhibition of EnvC activity could represent a promising intervention for CD.