Search Results (183)

Background: Crohn’s disease-associated intestinal strictures represent a major source of morbidity and frequently require endoscopic or surgical intervention. However, patients with stricturing Crohn’s disease demonstrate substantial clinical heterogeneity regarding disease localization, penetrating complications, systemic manifestations, metabolic alterations, and treatment exposure. This study aimed to explore phenotypic heterogeneity within patients with Crohn’s disease-associated intestinal strictures. Methods: In this retrospective exploratory cohort study, 96 patients with Crohn’s disease-associated intestinal strictures treated at a tertiary referral center between 2014 and 2024 were included. Clinical, structural, metabolic, and treatment-related variables were analyzed. Univariate analyses were performed using chi-square, Fisher’s exact test, Student’s t-test, or Mann–Whitney U test as appropriate. Exploratory multivariable logistic regression models were constructed to explore relationships between different clinical phenotypes and disease-related characteristics, including extraintestinal manifestations (EIMs), smoking status, penetrating disease manifestations, hepatic steatosis, stenosis localization, and abscess formation. Given the limited sample size and event numbers in several subgroup analyses, all multivariable analyses were considered exploratory and hypothesis-generating. Results: The cohort demonstrated a heterogeneous clinical presentation with a high prevalence of perianal disease, penetrating complications, prior intestinal surgery, and biologic therapy exposure. Female sex (OR 4.63, p = 0.044), autoimmune disease (OR 23.5, p = 0.049), rectal stenosis (inverse association; OR 0.08, p = 0.041), and exposure to multiple biologic therapies (OR 20.11, p = 0.036) remained associated with EIMs after multivariable adjustment. Smoking status was associated with anastomotic stenosis (OR 3.16, p = 0.023) and inversely associated with female sex (OR 0.35, p = 0.036). Phenotype-oriented analyses further suggested clustering of penetrating disease manifestations, including associations between intestinal fistulas, perianal fistulas, and abscess formation. Hepatic steatosis demonstrated exploratory associations with intestinal fistulas, intestinal resection, and appendectomy. Several analyses demonstrated wide confidence intervals and should therefore be interpreted cautiously. Conclusions: This exploratory retrospective cohort study highlights the substantial clinical heterogeneity observed among patients with Crohn’s disease-associated intestinal strictures. Different structural, systemic, penetrating, behavioral, and metabolic disease manifestations may indicate potentially overlapping phenotypic patterns within stricturing Crohn’s disease. Given the retrospective design, limited sample size, and exploratory statistical approach, these findings should be interpreted cautiously and require validation in larger prospective studies. Full article

Background/Objectives: Bursera bipinnata (DC.) Engl. resin (locally known as “copal blanco”) is traditionally used in Mexican ethnomedicine to treat infected wounds and skin inflammation, but the bioactive constituents underlying these effects remain largely uncharacterized. This study aimed to identify the compounds responsible for the wound-healing properties of the resin through bioactivity-guided fractionation and to evaluate their anti-inflammatory and antibacterial activities as complementary mechanisms supporting tissue repair. Methods: Crude resin (1.2–5.0 mg/mL) was assayed for anti-inflammatory activity in the TPA-induced ear-edema model in BALB/c mice, for antibacterial activity (MIC) against six clinically relevant strains, and for wound-healing activity in a murine excisional model with pirfenidone (PFD) as the reference drug (n = 5 per group). Bioactivity-guided fractionation followed by spectroscopic elucidation (¹H- and ¹³C-NMR, IR, EI-MS) led to the isolation of five constituents. Stigmasterol, the most active compound, was subsequently evaluated in an LPS-induced systemic inflammation model (oral administration, 20 mg/kg/day × 3 days) to characterize its immunomodulatory profile (TNF-α, IL-1β, IL-6, IFN-γ, IL-10) and in the wound-healing model to quantify local IL-6, IL-10 and TGF-β1 in skin homogenates. Results: The crude resin (5.0 mg/mL) achieved 99.63% wound closure at day 12 and a 49.08% reduction in TPA-induced ear edema, comparable to indomethacin (55.76%). The resin displayed selective antibacterial activity against Streptococcus pyogenes (MIC 125 µg/mL) and Salmonella typhimurium (MIC 250 µg/mL). Bioactivity-guided fractionation yielded the phytosterol stigmasterol (1), three lupane-type triterpenoids (lupeol acetate (2), lupenone (3), 3-epilupeol (5)), and the sesquiterpenoid caryophyllene oxide (4). At an equimolar 1 µM concentration, stigmasterol (1) shortened the mean wound-healing time to 10.3 ± 0.4 days, comparable to pirfenidone, and was associated with attenuation of systemic TNF-α, IL-1β and IL-6 peaks and with sustained local IL-10 and TGF-β1 expression. Histological assessment confirmed accelerated re-epithelialization and improved collagen organization. The resin was non-irritant in the OECD 404 acute dermal test (Primary Irritation Index = 0.00). Conclusions: These findings provide pharmacological evidence supporting the traditional use of B. bipinnata resin for wound healing. Stigmasterol (1), together with the lupane-type triterpenoids lupenone (3) and 3-epilupeol (5), were identified as key bioactive constituents. The data are consistent with a coordinated immunomodulation, in which stigmasterol is associated with reduced systemic pro-inflammatory signalling and increased local IL-10/TGF-β1 expression, an interpretation that should be confirmed in chronic and impaired wound-healing models. Full article

Background/Objectives: Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn’s disease can be associated with other immune-mediated inflammatory diseases (IMIDs) and extraintestinal manifestations (EIM) including dermatological manifestations, ophthalmologic manifestations, musculoskeletal manifestations and neurological manifestations. The aim of this narrative review is to discuss the optimal management and treatment strategy of IBD with immune-mediated inflammatory disease and extraintestinal manifestations. Methods: This review is based on published studies searched in PubMed until 31 December 2025. Our search focused on systemic reviews, review articles, randomized trials, cohort studies, guidelines and case series. Results: In IBD, the presence of additional immune-mediated inflammatory diseases (IMIDs) should be considered a poor prognostic factor, prompting closer disease monitoring and earlier escalation to or optimization of advanced therapy. Therapeutic management requires careful consideration including a multidisciplinary approach and a selection of the most appropriate treatment option(s) based on the presence, severity of IBD and/or IMIDs and/or EIM. For patients with refractory disease affecting multiple organs, emerging strategies include dual biologic therapies. Conclusions: The optimal management of IBD with associated IMIDs/EIM should be multidisciplinary in close cooperation among specialists to align treatment goals and management plans. Full article

Background: Aging is characterized by metabolic dysfunction and neuromuscular decline, and obesogenic diets may exacerbate these processes. High-fat, high-sugar diets (HFHSD) promote adiposity, systemic metabolic dysregulation, and skeletal muscle impairments, yet their impact on motor unit integrity and neuromuscular vulnerability during aging remains unclear. Methods: In a controlled preclinical experiment, late-middle-aged (15-mo-old) female F344 rats were randomized to HFHSD (n = 6) or regular chow (n = 6) for 10 weeks. Longitudinal assessments were conducted at baseline, 6 weeks, and 10 weeks and included body composition, motor unit number estimation (MUNE), forelimb and hindlimb grip strength, gastrocnemius tetanic contractile torque, and post-intervention electrical impedance myography (EIM). Data were analyzed using a two-way mixed-effects ANOVA to assess the effects of diet and time, with statistical significance set at p < 0.05. Results: HFHSD led to significant increases in body mass and adiposity measures (e.g., abdominal circumference, skinfold thickness). Compared with controls, HFHSD rats exhibited significant reductions in hindlimb MUNE (diet effect, p = 0.007) and decreased tetanic contractile torque in both absolute and body mass-normalized values (p ≤ 0.002). Absolute forelimb grip strength increased over time (p = 0.027), though this effect did not persist after normalization to body mass, and hindlimb grip strength did not differ between groups. EIM at 50 kHz revealed elevated resistance in HFHSD rats (p = 0.0497), whereas reactance and phase angle did not differ significantly. Conclusions: This pilot study provides preliminary evidence that an HFHSD, initiated during late middle age, may accelerate neuromuscular decline in female F344 rats prior to the typical onset of age-associated motor unit loss. A 10-week HFHSD intervention was associated with reductions in estimated motor unit numbers, impairments in muscle contractility, and a dissociation between absolute and normalized forelimb grip strength outcomes, indicating a potential early vulnerability of the neuromuscular system to obesogenic dietary exposure. These findings should be interpreted within the context of a modest sample size but collectively support the concept that diet-induced metabolic dysfunction may contribute to early neuromuscular impairment during aging. Full article

Six 1,4-disubstituted pyrazoles linked to a benzenesulfonamide and a benzodioxane unit have been synthesized through a copper(I)-catalyzed formal [3+2] cycloaddition (32CA) reaction of alkynes with 3-arylsydnones. The Cu-catalyzed sydnone–alkyne cycloaddition (CuSAC) procedure has been optimized to promote the formation of the pyrazole ring and to deliver in three steps the six target compounds 5a–f, fully characterized by ¹H/¹³C-NMR and mass spectrometry (EIMS). Ten solvent conditions were evaluated. The reaction proceeded most efficiently in the presence of copper(II) sulfate pentahydrate in aqueous t-butanol in the presence sodium acetate, to reach a yield of 96%. The mechanism of the Cu(I)-catalyzed reaction has been studied within the Molecular Electron Density Theory (MEDT). This rection is a domino process that consists in a Cu(I)-catalyzed formal [3+2] cycloaddition followed of an extrusion of CO₂ yielding the final pyrazole. The capacity of heterocyclic compounds 5a–f to interact with human cyclophilin A (Cyp A), which is a host cofactor for hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1), and with the HIV-1 protein gp120-CD4 was evaluated using molecular docking. Compounds 5a,b,d,f showed a satisfactory protein binding capacity. The physicochemical and metabolic properties of the compounds were also evaluated in silico. These predictions provide important information to guide future design in this series of potential antiviral agents. Full article

Bacterial and fungal infections, together with oxidative stress-mediated damage, remain major challenges in human health and in the protection of materials, highlighting the need for new multifunctional molecules that combine antioxidant and antimicrobial properties. In this context, a new chloropyridine-based derivative, N4,N4-bis((6-chloropyridin-3-yl)methyl)-N1,N1-diethylpentane-1,4-diamine (AMZ), was synthesized via a simple, catalyst-free N-alkylation of N1,N1-diethylpentane-1,4-diamine with 2-chloro-4-(chloromethyl)pyridine in acetonitrile at 55 °C, affording a 62% yield. The structure of AMZ was confirmed by melting point determination, ¹H and ¹³C NMR spectroscopy, and EI–MS analysis. Its antioxidant activity was evaluated using DPPH and FRAP assays with BHT as a reference standard, while antibacterial and antifungal activities were assessed via disk diffusion and microdilution methods to determine inhibition zones and MIC/MBC values. In silico investigations included drug-likeness and ADMET predictions, as well as molecular docking on catalase (PDB: 2CAG) and fungal CYP51 (PDB: 1EA1). AMZ exhibited dose-dependent radical scavenging in the DPPH assay, reaching 76.88 ± 3.20% inhibition at 1000 µg/mL, with an EC₅₀ of 26.03 ± 0.21 µg/mL, close to that of BHT (23.65 ± 0.22 µg/mL). In the FRAP assay, AMZ showed a higher reducing power than BHT at a low concentration (OD₅₀ µg/mL 0.177 ± 0.023 vs. 0.134 ± 0.017), although its FRAP EC₅₀ was higher (700.48 ± 22.54 vs. 400.16 ± 8.67 µg/mL). AMZ displayed broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi, with particularly strong effects on Bacillus subtilis (44.5 ± 0.5 mm; MIC/MBC 0.008 mg/mL) and Aspergillus niger (30 mm; MIC/MBC 0.030 mg/mL), in some cases comparable or superior to streptomycin and fluconazole. In silico analysis indicated that AMZ fulfilled major drug-likeness rules, showed high predicted intestinal absorption (91.14%), and was classified as non-AMES toxic, while docking predicted favorable binding to catalase and CYP51, in agreement with the experimental antioxidant and antifungal activities. These findings highlight the potential of AMZ as a multi-target pyridine-based lead compound that warrants further structural optimization and in vivo evaluation for applications in oxidative-stress-related and infectious conditions. Full article

Background/Objectives: Cancer remains one of the most significant challenges in modern medicine, requiring the continuous development of novel molecular scaffolds with anticancer potential that act through multiple pathways. Heterocyclic compounds incorporating indole, triazole, oxadiazole, and thiadiazine motifs have attracted considerable attention due to their diverse pharmacological activities. This study aimed to design, synthesize, and evaluate new hybrid heterocyclic systems, including 1,2,4-triazole, 1,3,4-oxadiazole, and thiadiazine motifs, targeting liver and breast cancer. Methods: A series of indolyl-based heterocyclic compounds was synthesized using efficient and environmentally friendly protocols. Indolyl-triazol-thiadiazin-6-ol 5 was prepared via solvent-free fusion of esters 2 and 3 or the corresponding acid 4. Oxadiazole derivatives were produced by reacting hydrazide intermediates with carbon disulfide. Triazole derivatives were synthesized via cylization of thiosemicarbazide 9 in aqueous KOH (4.0 N). Structural characterization was performed using Fourier Transform InfraRed (FTIR), ¹H and ¹³C NMR spectroscopy, and electron impact mass spectrometry (EIMS). Cytotoxic activity was evaluated against liver and breast cancer cell lines, and VEGFR-2 kinase inhibition was assessed for selected derivatives. Results: The synthesized compounds demonstrated notable cytotoxicity activity, with compounds 4, 5, and 9 exhibiting IC₅₀ values in the low micromolar range. Enzymatic assays revealed that compounds 4 and 9 showed strong VEGFR-2 inhibition (97.9% and 96.4%, respectively), indicating apoptosis-inducing effects. Conclusions: The synthesized indolyl-based hybrid heterocycles represent a promising chemotype with in vitro cytotoxic activity and VEGFR-2 inhibitory effects, supporting further investigation, optimization, and mechanistic studies to evaluate their potential lead for anticancer drug development. Full article

Environmental hazard-induced male infertility has become a major public health issue. The concealment and accumulation of environmental hazards, and their interactions with the endogenous immune network, have long been underappreciated. As the central organ for sperm maturation and motility acquisition, the epididymis plays a vital role in male fertility, and the homeostasis of the epididymal immune microenvironment (EIM) is essential. Nevertheless, a systematic synthesis of common environmental hazards and their impact on EIM, which can lead to male infertility, remains lacking. This review comprehensively summarizes the composition, functionality, and key characteristics of the EIM and underscores its critical role in preserving male reproductive health. We further evaluate and delineate the disruption of EIM homeostasis resulting from major categories of environmental exposures—including chemical, physical, biological, and behavioral hazards—and discuss their shared pathophysiological mechanisms. By integrating evidence linking environmental insults, EIM dysregulation, and male infertility, this work aims to identify pivotal molecular mechanisms from an immunological perspective. The findings provide a mechanistic foundation for the development of targeted interventions and preventive strategies against environmental hazard-induced male infertility. Full article

Electron ionization (EI) mass spectrometry (MS) is a widely used technique for the compound identification and production of spectra. However, incomplete coverage of reference spectral libraries limits reliable analysis of newly characterized molecules. This study presents a hybrid deep learning model for predicting EI-MS spectra directly from molecular structure. The approach combines a graph neural network encoder with a residual neural network decoder, followed by refinement using cross-attention, bidirectional prediction, and probabilistic, chemistry-informed masks. Trained on the NIST14 EI-MS database (≤500 Da), the model achieves strong library matching performance (Recall@10 ≈ 80.8%) and high spectral similarity. The proposed hybrid GNN (Graph Neural Network)-ResNet (Residual Neural Network) model can generate high-quality synthetic EI-MS spectra to supplement existing libraries, potentially reducing the cost and effort of experimental spectrum acquisition. The obtained results demonstrate the potential of data-driven models to augment EI-MS libraries, while highlighting remaining challenges in generalization and spectral uniqueness. Full article

Background/Objectives: Tumor necrosis factor alpha (TNF-alpha) plays a key role in systemic inflammation in multiple disorders, including inflammatory bowel diseases (IBDs). Our purpose was to investigate the contribution of two promoter single-nucleotide polymorphisms (rs361525/–238G/A and rs1800629/–308G/A) to disease susceptibility, clinical features, and response to biologic therapy in a cohort of Romanian patients with IBDs. Methods: A total of 198 patients with IBDs, 106 with Crohn’s disease (CD) and 92 with ulcerative colitis (UC), as well as 160 healthy controls, all Caucasians of Romanian origin, were genotyped using TaqMan Allelic Discrimination Assays. Phenotypical and anti-TNF treatment characteristics of the patients with IBDs were recorded. Statistical analyses were performed using OpenEpi and PLINK v1.07 software. Results: We found a significantly higher frequency of the minor allele A of rs361525 in patients with CD than in the controls (6.6% vs. 2.2%, p = 0.01, OR = 3.16). Half of the patients with extraintestinal manifestations (EIMs) had at least one copy of the rs1800629 A allele compared with approximately 10% of patients without EIM (p = 1 × 10⁻⁴, OR 9.58 for UC and p = 9 × 10⁻⁴, OR 6.60 for CD). In the whole IBD group of patients, the carriers of the minor allele (AA+GA) for both SNPs studied (rs1800629 and rs361525) were significantly more likely to have EIM associated with IBDs (p = 3 × 10⁻⁷, OR 7.87; p = 0.03, OR 3.02, respectively). In patients with UC, the analysis according to disease extension revealed that the frequency of the minor allele of rs1800629 was significantly higher in the subgroup with the E2 phenotype compared to the E1 and E3 phenotypes (16.6% versus 5.6%, p = 0.02, OR 3.32). Conclusions: These findings highlight the role of genetic TNF-alpha variants in disease susceptibility, phenotype, and systemic involvement, supporting their potential relevance in understanding IBD heterogeneity. Full article

Inflammatory bowel diseases (IBD) are increasingly acknowledged not merely as confined gastrointestinal disorders but as systemic immunometabolic syndromes. Central to this paradigm is the gut microbiota including non-bacterial components such as the virome, whose functional disruption marked by reduced short-chain fatty acids (SCFAs), increasingly implicated in pathogenic processes extending beyond intestinal mucosa. This review outlines how these alternations compromise the epithelial barrier and immune regulation, increasing the risk of recurrent Clostridioides difficile infections to anemia, neuropsychiatric comorbidities, and extraintestinal manifestations. We critically evaluate emerging microbiota-targeted strategies, including fecal microbiota transplantation (FMT), live biotherapeutic products (LBPs), and precision postbiotics, positioning them as potential adjuncts to conventional immunosuppression. Finally, we discuss the current barriers to clinical translation, such as safety and heterogeneity, and propose a future framework for personalized, functionally integrated IBD care aimed at restoring long-term microbiota homeostasis. Full article

This article explains why the European Union has not replicated Central and Eastern Europe’s (CEE) transformation in the Western Balkans (WB6). Drawing on the original External Incentives Model (EIM) conditions, the article argues that a different political climate in the WB6 requires attention to additional contextual conditions within the EIM framework to show how the weakened linkage between compliance and rewards emerges. Geopolitical enlargement and the presence of rival powers, a stability-over-democracy approach, bilateral vetoes, and the EU’s ongoing “permacrisis” negatively impact determinacy and EU credibility, while also increasing adoption costs. At the WB6 level, reforms become partial and reversible/at-risk, and even in cases of real progress (Montenegro and Albania), institutions remain fragile. The current arrangement serves both Brussels and local elites, providing short-term stability and keeping the WB6 on the EU path at the price of tolerating domestic capture and reforms without transformation. Yet, this arrangement carries a long-term risk of eroding the EU’s transformative power, as public dissatisfaction with local elites is not met with EU support, and rival powers exploit identity ties and elite channels. Full article

With the designation of the first cohort of national parks and the continued operation of remaining pilots, China’s national park reform has entered a critical stage requiring consolidation and adaptive improvement. A key challenge lies in the ambiguous status of five pilot zones, which lack a standardized evaluation mechanism to guide decisions on future inclusion or exit. This study develops a comprehensive indicator system specifically tailored to assess the construction and development of national park pilots, thereby supporting evidence-based governance beyond initial entry criteria. Drawing on relevant theories and China’s institutional context, the framework employs Analytic Hierarchy Process, expert consultation, and fuzzy scoring to determine indicator weights and evaluation standards. The resulting system integrates three dimensions—ecological protection system, management system, and public service system. Nanshan National Park was selected as a case study, scoring 87.77 in 2024 (Class II, “Proficient”), with strong overall performance but notable weaknesses in landscape connectivity, recreational product diversity, and regional integration. These findings suggest the need for targeted improvements in ecological corridors, service enrichment, and community benefit-sharing. Overall, the proposed framework provides a replicable tool for evaluating pilot zones, offering practical insights for refining China’s national park development and enhancing governance effectiveness. Full article

Peri-implant mucositis is an inflammatory condition that affects the peri-implant mucosa, without bone involvement. Peri-implant mucositis can include erythema, swelling, and bleeding, and the mucosa can be painful even with the traditional oral hygiene procedures. Peri-implant mucositis is always a reversible condition but, if left untreated, it can degenerate into peri-implantitis. Although biofilm control is considered the gold-standard therapy, some adjunctive therapies can be employed. The aim of this study is to investigate the efficacy of postbiotics in peri-implant mucositis management. Forty patients in good systemic health with at least one implant diagnosed with peri-implant mucositis were enrolled in this case–control study. The control group received professional biofilm removal and home care instructions, while the test group was also asked to use a postbiotic gel. Clinical indices of inflammation, such as probing pocket depth (PPD), plaque index (PI), bleeding on probing (BoP), erythema, pain, suppuration and swelling, were collected at four timepoints during observation and analyzed at both the patient and site levels. After one year, clinical indices statistically significantly improved in both groups compared to baseline. The test group showed greater reductions. PPD was statistically significantly lower at the site level in the test group than in the control group. The results of this study confirm that biofilm control is an effective therapy for peri-implant mucositis. Our findings showed that postbiotics used as an adjunctive in home therapy have been effective in managing clinical indices in patients with peri-implant mucositis. Full article

Background/Objectives: Crohn’s disease (CD) is one of the most frequent causes of short bowel syndrome (SBS), a severe clinical condition with huge morbidity and social costs. SBS occurs when, following intestinal resections, the remaining small bowel in continuity is less than 200 cm in length. Intestinal failure (IF) can complicate SBS when intravenous nutritional or electrolyte supplementation is required to maintain dietary needs. The primary aim of this study was to identify clinical predictive factors of SBS in a cohort of outpatients with CD. Methods: We conducted a prospective, single-center, cohort study enrolling consecutive CD outpatients at a tertiary-level inflammatory bowel disease center. Detailed demographic and clinical features were collected. Significant factors associated with the onset of SBS in the univariate analysis were input into a multivariate logistic regression model to identify independent predictors of SBS. Results: In total, 232 CD patients (52.6% male, median age 49 years [IQR 37–60]) were included: 24.6% of them were smokers; extraintestinal manifestations (EIMs) were present in 21.6% of patients; and 67.7% of patients had at least one intestinal resection (27% of them with more than one surgical intervention). At enrollment, 96.1% of patients were on advanced therapies, and considering the course of the disease, 24.6% of patients were exposed to ≥3 different advanced therapies. A total of 18 patients had SBS and 9 had IF. In univariate analysis, the following variables were statistically associated with the risk of developing SBS: disease duration (p < 0.001), upper gastrointestinal disease localization (L4) (p < 0.001), penetrating behavior (p = 0.023), perianal disease (p = 0.036), length of first intestinal resection (p < 0.001), shorter time elapsing from CD diagnosis to start the first advanced therapy (p < 0.001), and treatment with advanced therapy after first intestinal resection (p < 0.001). In multivariate analysis, disease duration (OR 1.083, 95% C.I. 1.025–1.145, p = 0.005) and L4 (OR 20.079, 95% C.I. 2.473–163.06, p = 0.005) were independently associated with the development of SBS. Conversely, the number of different advanced therapies before the onset of SBS was independently associated with a reduced risk of developing SBS (OR 0.247, 95% C.I. 0.107–0.58, p = 0.001). Conclusions: Our data identifies several clinical features that could possibly predict the development of SBS in CD. Further studies with a larger sample size are needed to confirm our findings. Full article