Search Results (1,502)

The present study aimed to design, synthesize, and evaluate a new series of thieno[3,2-d]pyrimidin-4(3H)-one-based Schiff bases as potential antileishmanial agents against Leishmania major (L. major). A series of twenty thieno[3,2-d]pyrimidine Schiff base derivatives were synthesized and characterized using FTIR, NMR, and HRMS techniques. Their antipromastigote activities were evaluated in vitro against L. major, while cytotoxic effects were assessed on HUVECs to determine selectivity indices. The most active compound was further investigated using molecular docking against several L. major proteins. Among the tested compounds, compound 12, bearing a 2-hydroxy-5-bromophenyl moiety, exhibited the most potent activity against L. major promastigotes with an IC₅₀ value of 13.7 µM, along with a favorable selectivity index (SI = 17.5), outperforming the reference drug miltefosine (IC₅₀ = 31 µM and SI = 0.2). Docking studies demonstrated that compound 12 showed the strongest binding affinity toward phosphodiesterase B1, supported by a docking score of −9.042 kcal/mol and an MM-GBSA value of −67.21 kcal/mol. This study highlights thieno[3,2-d]pyrimidin-4(3H)-one as a promising scaffold in the context of in vitro antileishmanial screening and suggests the role of ortho-phenolic substitution in enhancing activity and selectivity. Compound 12 emerges as a promising lead, warranting further optimization and biological evaluation in future studies. Full article

Background/Objectives: Diabetes mellitus (DM) is a critical metabolic condition with escalated blood glucose levels caused by insulin resistance, restricted insulin production, and the activity of alpha-amylase and alpha-glucosidase enzymes. Methods: This current work focuses on the synthesis and evaluation of novel Pyrimidine-derived pyrazole-based thiadiazole derivatives to target DM by inhibiting α-amylase and α-glucosidase. Results: The findings exhibited that, except for three compounds, all other synthesized derivatives inhibited α-amylase and α-glucosidase enzymes with IC₅₀ values ranging from 5.17 μM to 29.84 μM on α-amylase and 7.60 μM to 31.62 μM on α-glucosidase, in comparison to the standard drug Acarbose (α-amylase IC₅₀ = 8.25 ± 0.80 μM; α-glucosidase IC₅₀ = 10.75 ± 1.10 μM). Analogs 8g, 8k, and 8b displayed superior or comparable inhibitory activity compared to the reference drug Acarbose. The inhibition potential of the derivatives can be attributed to their stable contacts with crucial amino acid residues of targeted enzymes, as shown through molecular docking analysis. Moreover, DFT-calculated HOMO–LUMO parameters and electrostatic potential (ESP) maps were used to gain complementary insight into the electronic characteristics, charge distribution, and potential interaction behavior of the synthesized derivatives, which supported the molecular docking observations. Conclusions: Experimental outcomes and in silico support display that these derivatives serve as potential leads for anti-diabetic drug development. These potent pyrimidine-derived pyrazole-based thiadiazole derivatives were comparable to an existing diabetic mellitus inhibitor, specifying potential for further therapeutic development and optimization against diabetic mellitus. Full article

A series of substituted pyrrolo[2,3-d]pyrimidines was designed, synthesized, and evaluated in vitro against two protozoan parasites: Plasmodium falciparum and Trypanosoma brucei brucei. Pharmacological studies revealed antiprotozoal activity with IC₅₀ values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new compounds was assessed using human HepG2 cells. Among them, the pyrrolopyrimidine derivative 1d emerged as the most potent antimalarial compound, exhibiting a selectivity index (SI) of 600.81 against the P. falciparum chloroquine-resistant W2 strain. For the chloroquine-sensitive 3D7 strain, the most notable selectivity index (SI) was observed for pyrrolo[2,3-d]pyrimidine 1c, with a value of approximately 123. Furthermore, compound 1b demonstrated the most interesting activity against Trypanosoma brucei brucei, with an SI of 39.52, marking it as a promising trypanocidal agent. FRET melting assays confirmed that these nitrogen-containing heterocyclic compounds bind to telomeric G-quadruplexes in P. falciparum and Trypanosoma. However, no clear correlation was found between G-quadruplex binding and antiparasitic activity or selectivity, suggesting that G-quadruplex targeting is unlikely to be the main mechanism underlying cytotoxicity. Full article

Cordyceps militaris, a medicinal and edible mushroom, is renowned for its bioactive constituents and health-promoting effects. This study investigated the effects of vacuum freeze drying (VF), vacuum drying (VD), oven drying (OV), and sun drying (SU) on the metabolite profiles and antioxidant activities of C. militaris. VF showed the highest levels of total phenolics, total carotenoids, cordycepin, and N⁶-(2-hydroxyethyl)-adenosine, whereas VD better preserved total flavonoids. VF- and VD-treated samples also exhibited stronger antioxidant capacities than those processed by OV and SU in 1,1-diphenyl-2-picrylhydrazyl radical (DPPH•), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS^•+), hydroxyl radical (•OH), and ferric reducing antioxidant power (FRAP) assays. Metabolomics analysis identified 193 significantly altered metabolites after drying treatments. VF, VD, and SU increased carbohydrates, vitamins, and phenolic acids, while leading to reductions in amino acids, nucleotides, and fatty acids. KEGG analysis revealed that drying significantly affected pathways related to purine and pyrimidine metabolism, amino acid biosynthesis, and phenylpropanoid biosynthesis. Network pharmacology further identified 8 key compounds potentially associated with antioxidant effects through interactions with 37 core targets. These findings highlight the importance of selecting appropriate drying methods to preserve the bioactive compounds and functional quality of C. militaris. Full article

All-trans retinoic acid (atRA) is known to regulate lipid metabolism, adipocyte differentiation, and the immune system in mammals and other aquatic species. However, studies on atRA in crustaceans, especially in Eriocheir sinensis, are still scarce. The present study aimed to investigate the regulatory effects of dietary or injected atRA on female crabs during the fattening period. In the dietary regulation experiment, 270 female crabs were fed diets containing different doses of atRA (0, 150, 300, 600, 1200, and 2400 mg/kg) for a total of 49 days. In the in vivo injection experiment, 90 females were divided into an experimental group (injected with a 0.3 μg/g dose of atRA) and a control group (injected with the same amount of DMSO solvent). Injections were given weekly throughout the 35-day experimental period. Results: Both dietary atRA and atRA injection promoted ovarian development, as evidenced by increased GSI, elevated serum Vg levels, decreased GIH, and upregulated expression of vg, vgr, and rxr genes. In terms of mechanism, dietary atRA promoted ovarian development via the upregulation of pyrimidine nucleotides and dehydroepiandrosterone, which supplied nucleic acid precursors and hormonal support. Furthermore, RXR was identified as a potential key target of atRA in inducing ovarian development, as molecular docking revealed that atRA could spontaneously bind to RXR. Moreover, following atRA injection, the expression of rxr, along with key genes involved in ovarian development, lipid synthesis, and lipid transport, was significantly upregulated. In addition, the atRA diet created a favorable microenvironment for ovarian development by reducing pro-inflammatory lipid levels in the ovary. Transcriptomic and metabolomic analyses revealed that atRA modulates energy and lipid metabolism by activating the AMPK pathway. In terms of the bacterial community structure, the atRA diet significantly decreased Fusobacterium abundance and enriched Parabacteroides as the signature beneficial bacterium. In terms of nutritional quality, the atRA diet markedly reduced saturated and trans-fatty acids while increasing monounsaturated fatty acids and various key essential amino acids. Conclusions: This study revealed that atRA plays a key role in promoting ovarian development, improving nutritional quality, and modulating the structure of the microbiota, thereby providing theoretical support for healthy aquaculture of female crabs during the fattening period. Full article

Severe cutaneous adverse reactions (SCARs) are rare, life-threatening drug hypersensitivity syndromes. Although pharmacovigilance can identify drugs disproportionately reported with SCARs, it does not reveal which local chemistries recur among them. To address this, we assessed whether drugs with FAERS-derived SCAR disproportionality signals share interpretable chemical motifs. We screened FAERS data from 2004Q1 to 2024Q3, identified 5523 drugs with available Simplified Molecular-Input Line-Entry System (SMILES) representations, and constructed a signal-enriched dataset of 1676 compounds with nominally significant broad-SCAR associations after excluding predefined therapeutic/supportive confounders. Compounds were assigned to positive-signal [natural logarithm of reporting odds ratio (lnROR) > 0, n = 1219] or non-positive-signal (lnROR ≤ 0, n = 457) classes and encoded with 9753 explicitly mappable atom-centered local substructure descriptors. A LightGBM signal-classification model evaluated using random repeated nested cross-validation (six-fold outer × 50 repeats) achieved moderate internal discrimination (mean area under the receiver operating characteristic curve = 0.7041 ± 0.0337). Descriptor-space cluster-based repeated nested cross-validation, designed to reduce train–test structural leakage, yielded lower but still above-chance performance (mean ROC AUC = 0.6409; permutation p = 0.001), indicating that random-split estimates should be interpreted as optimistic for structurally novel compounds. Sensitivity analyses using minimum SCAR case-count thresholds and retention of predefined therapeutic/supportive drugs showed broadly similar performance and motif rankings. SHapley Additive exPlanations (SHAP) analysis revealed a fragment-level contrast: allylamine-like, ethanolamine-related, and diaminopropane-related motifs were associated with higher positive-signal class probability, whereas phenol and pyrimidine motifs were associated with lower positive-signal class probability. These findings suggest that FAERS-derived broad-SCAR signal direction is not chemically random within the selected dataset. Overall, the proposed framework should be viewed not as a direct predictor of absolute clinical SCAR risk but as an exploratory, pharmacovigilance-driven cheminformatics approach for prioritizing compounds and motif families for further SCAR-focused evaluation. Full article

Background: CAD (Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase) is a pivotal tri-functional enzyme complex associated with the rate-limiting steps of the de novo pyrimidine biosynthetic pathway. Despite its established metabolic role, the multi-dimensional involvement of CAD in the pan-cancer landscape—specifically regarding its regulation of the metabolic–immune axis and its impact on immunotherapy response—remains to be fully elucidated. Methods: We performed a systematic pan-cancer multi-omics analysis integrating TCGA, GTEx, and DepMap datasets to evaluate CAD expression, genomic alterations, and diagnostic potential. In addition, multiple immunotherapy cohorts were integrated for meta-analysis, and metabolomic data were incorporated to explore CAD-associated metabolic features. Results: CAD was significantly upregulated in 17 cancer types, with protein-level evidence supporting this trend. CAD also showed high diagnostic accuracy in several malignancies, particularly LAML and CHOL (AUC approximately 1.0). In immunotherapy-related analyses, CAD expression was positively associated with TMB, MSI, and initial therapeutic response, but was also linked to worse long-term overall survival in pooled cohorts (HR = 1.42, 95% CI: 1.19–1.70). Integrative metabolomic analyses further suggested that high CAD expression was associated with pyrimidine metabolite accumulation and altered amino acid metabolism, indicating a potential link between CAD-related metabolic reprogramming and the tumor immune microenvironment. Conclusions: CAD may represent a promising candidate biomarker across multiple malignancies. Notably, its association with immunotherapy-related features, together with the observed discordance between response-associated signals and long-term survival, warrants further mechanistic and clinical validation. Full article

Purpose: Preclinical studies report low-intensity ultraviolet C (UVC) light to be safe and effective in treating murine bacterial keratitis, however, limbal impacts of UVC have yet to be investigated directly. This study evaluated the depth and density of UVC-induced DNA damage in the porcine and human limbus following UVC exposures of varying supratherapeutic dose. Methods: The corneoscleral junction (limbus) of full-thickness porcine corneas was exposed to supratherapeutic doses of UVC light (265 nm, 1.93 mW/cm²) for 5, 10, 15, 30, or 60 min (exposure groups) or remained unexposed for the same durations (control groups), with a sample size of 6 per group. In parallel, human corneal tissue was exposed to UVC for 1 or 5 min and processed identically. Following exposure, all tissues were frozen, dissected, and analysed using immunohistochemistry to detect cyclobutane pyrimidine dimers (CPDs) as markers of DNA damage. CPD distribution, depth, and density were subsequently evaluated. Results: CPDs were localised predominantly in the superficial corneal epithelial layers, irrespective of the UVC dose. The mean ± SD thickness of the corneal epithelium in the UVC-exposed groups was 38.9 ± 18.9 µm, and the average depth of CPD formation was 13.3 ± 8.43 µm. The proportions of cells affected by CPDs within the corneal epithelium (mean ± SD) were 47.8 ± 25.6%, 58.5 ± 16.2%, 39.9 ± 26.4%, 41.3 ± 27.3%, and 38.9 ± 28.3% for exposure durations of 5, 10, 15, 30, and 60 min, respectively (p > 0.05). Human cornea showed similarly limited penetration, with no difference in CPD proportions between the 1 and 5 min UVC exposures (p = 0.70). Conclusions: UVC-induced DNA damage in both species was confined to the superficial cellular layers of the cornea, with no detectable damage observed in deeper tissues, including those where limbal stem cells reside, even after supratherapeutic doses of up to one hour of exposure. Full article

Background/Objective: With rising per capita sugar consumption, skin glycation-related issues including dullness, homeostasis disruption and accelerated wrinkling have gained widespread attention. However, globally standardized and rigorous evaluation criteria for anti-glycation efficacy remain lacking. This study aimed to establish stage-specific glycation injury cell models and elucidate the stage-dependent molecular mechanisms of glycation-induced fibroblast damage, providing a standardized reference for anti-glycation efficacy assessment. Methods: Three glycation injury models were constructed in human foreskin fibroblasts (HFF-1): early-stage (glucose-induced), intermediate-stage (glyoxal-induced), and late-stage (advanced glycation end products (AGEs)-induced). Core biomarkers including Nε-(carboxymethyl)lysine (CML), collagen type I (Col I) and elastin (ELN) were used to optimize modeling conditions via Cell Counting Kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA). Untargeted metabolomics based on ultra-high-performance liquid chromatography (UHPLC)-Q Exactive Orbitrap was applied to identify differential metabolites and perturbed pathways, following Metabolomics Standards Initiative (MSI) Level 2 identification criteria. Results: Optimal conditions were determined as 50 mmol/L glucose for 48 h, 0.5 mmol/L glyoxal for 48 h, and 200 μg/mL AGEs for 24 h. A total of 319, 34 and 148 differential metabolites were identified in the three groups, respectively. Six key pathways were significantly perturbed. Early and intermediate models shared similar mechanisms (purine metabolism disturbance), while the late model showed distinct alterations in pyrimidine, nicotinate, arachidonic acid and steroid hormone metabolism. Conclusions: Three stable stage-specific glycation models were successfully established in HFF-1 cells. Significant differences in metabolic profiles and mechanisms exist across the three stages, providing a rational basis for model selection and theoretical support for anti-glycation efficacy evaluation. Full article

Diabetic peripheral neuropathy is an important cause of functional disability, and current therapies have limited ability to halt its progression. Uridine, a pyrimidine nucleoside essential for the synthesis of membrane phospholipids and neuronal metabolism, appears to be a potential neuroprotective agent, but its impact on motor behavior and peripheral nerve integrity in diabetes remains insufficiently investigated. Our study investigated the effects of chronic uridine supplementation on locomotor performance, neuromuscular electrophysiological manifestations, and morphological changes in the sciatic nerve in a murine model of streptozotocin-induced diabetes. We used male C57BL/6 mice (n = 8/group) that were assigned to three groups: sham (no diabetes), diabetic (streptozotocin-induced, diabetes mellitus, DM+), and diabetic treated with uridine (DM+U). We observed that uridine did not alter the metabolic status, as the HbA1c values remained comparable between diabetic groups (9.93 ± 0.57% DM+ vs. 9.71 ± 0.55% DM+U; p = 0.72), suggesting effects independent of glycemic control. The open field test revealed that diabetic mice showed a marked reduction in spontaneous locomotion, while uridine-treated mice maintained a significantly higher level of activity (longer total distance traveled 3761.7 ± 789.1 cm vs. 2477.5 ± 1017.6 cm in DM+; p = 0.023). Electrophysiological evaluation revealed near-normal sciatic nerve function in DM+U mice, including higher compound motor action potential (CMAP) amplitudes (10.21 ± 0.64 mV vs. 5.75 ± 0.72 mV; p < 0.0001) and reduced F-wave latency (6.35 ± 0.45 ms vs. 7.29 ± 0.31 ms; p < 0.0001). Histological and immunohistochemical analyses (PGP 9.5) further confirmed reduced nerve degeneration in DM+U mice. Our data suggest that chronic uridine administration may confer both functional and structural neuroprotection in diabetic neuropathy, even in the absence of improved glycemic control. Full article

Background: To investigate the effect of angiotensin-(1-7) [Ang-(1-7)] on serum metabolomics in obese type 2 diabetic (T2DM) mice. Methods: Four-week-old male C57BL/6 mice were fed a high-fat diet and intraperitoneally injected with streptozotocin (35 mg/kg) to establish an obese T2DM model. Mice were randomized into control, T2DM and T2DM+Ang-(1-7) groups (n = 6). Body weight and blood glucose were recorded weekly. At 10 weeks, blood glucose, serum inflammatory factors, lipid profiles, and pancreatic β-cell insulin secretion were detected; serum metabolite alterations were analyzed via untargeted metabolomics. Results: 1. Ang-(1-7) intervention decreased blood glucose (p < 0.05) and CRP levels (p < 0.01), and alleviated dyslipidemia (p < 0.05 or p < 0.01), as well as β-cell morphology and insulin expression in obese T2DM mice. 2. Non-targeted metabolomics analysis suggested that Ang-(1-7) may alleviate abnormal amino acid metabolic pathways by regulating levels of metabolites such as L-valine, L-proline, L-histidine, and glutamic acid. This intervention also tended to reduce multiple lipid metabolites, including Omega-3 Arachidonic Acid Ethyl Ester, phosphatidylcholine, and glycerophosphocholine, thereby participating in the modulation of lipid metabolism balance. KEGG enrichment analysis further indicated that Ang-(1-7) was involved in the regulation of protein digestion and the absorption pathway, as well as the HIF-1 signaling pathway related to oxidative stress, bile acid metabolism pathway, and other signaling pathways, and improving the insulin secretion pathway, pyrimidine metabolism, and TCA cycle energy metabolism pathway. Conclusions: Ang-(1-7) may partially improve metabolic disturbances in obese T2DM mice, which is potentially associated with the modulation of multiple metabolic processes, including amino acid metabolism, lipid metabolism, insulin secretion, and TCA cycle energy metabolism. Full article

The gut microbiota plays a crucial role in regulating fish growth. In this study, we performed 16S rRNA sequencing and metabolomics to compare the gut microbiota and metabolic profiles of fast-growing (FG) and slow-growing (SG) brass gudgeon (Coreius heterodon) from the same family, reared under identical conditions for 12 months. Our results revealed that there was no significant difference in the overall gut microbiota structure between FG and SG groups, but significant differences were observed at specific phylum and genus levels. The FG group harbored a greater abundance of potential probiotics (e.g., Prevotella, Lactobacillus, and Lachnospiraceae NK4A136_group), while opportunistic pathogens such as Klebsiella and Pseudomonas were less abundant. Metabolomics analysis identified 136 differential metabolites, among them, 61 were upregulated and 75 were downregulated in the FG group, with higher levels of phosphatidylcholine, acylcarnitine, and amino acid derivatives in the FG group. KEGG pathway analysis showed enrichment of butanoate metabolism, tryptophan metabolism, and pyrimidine metabolism in the FG group. Spearman correlation analysis indicated that specific gut microbiota was significantly correlated with metabolites involved in energy metabolism, gut homeostasis, and oxidative balance. These findings revealed associations between specific gut microbiota, gut metabolites, and growth performance in brass gudgeon. Although overall community structure did not differ significantly between groups, the compositional and metabolic shifts observed suggest that the gut microbiota–metabolite association might be linked to growth variation. This study provided new insights into the microbiota–metabolite–growth axis of brass gudgeon and offers valuable reference information for the development of specialized probiotic feeds for this species. Full article

Toxoplasma gondii (T. gondi) is a widespread zoonotic parasite that poses a significant threat to global public health, yet effective therapeutic options remain limited. In this study, we found that the flavonoid compound myricetin (MYR) can significantly inhibit the proliferation of T. gondii. This effect is associated with the inhibition of dihydroorotase (TgDHO) activity in the de novo pyrimidine biosynthesis pathway, and this inhibition can be partially reversed by exogenous supplementation with uracil. Further studies revealed that MYR treatment can induce cell cycle arrest in tachyzoites and impair bradyzoite proliferation, concurrently disrupting the UDP-GlcNAc glycosylation of the cyst wall. In mouse models, MYR demonstrated significant efficacy, achieving an 80% survival rate in acute infection and inducing morphological abnormalities in intracerebral cysts during chronic infection. Collectively, these findings elucidate the anti-Toxoplasma activity and multifaceted mechanisms of MYR, providing valuable insights for developing novel therapeutics against toxoplasmosis. Full article

A novel nitrogen-containing heterocyclic compound, 4-(6-Chloropyridin-3-yl)-6-cyclopropylpyrimidin-2-amine, was designed and synthesized using 6-chloropyridin-3-aldehyde and cyclopropyl methyl ketone as starting materials. The structure of the target compound was characterized by ¹H NMR, ¹³C NMR and HRMS, and the spectral data were consistent with the expected structure, confirming the correctness of the product. Full article

The growing problem of antibiotic resistance poses a serious threat to public health and ecosystems. New disinfection methods could help address this global issue. In this study, ultraviolet-C light-emitting diodes (UV-C LEDs) were used to inactivate Escherichia coli isolates resistant to antibiotics. These isolates were obtained from various real water sources, including seawater, surface water, and treated wastewater. Inactivation assays were performed using two wavelengths (255 nm and 265 nm), applying UV fluences ranging from 1 to 7 mJ/cm² to a phosphate-buffered saline solution inoculated with a mixture of 10 E. coli strains. Using an UV fluence of 2 mJ/cm², a log reduction of about 5 was achieved with both UV-C wavelengths tested. SEM imaging revealed no observable alterations in cell morphology after UV-C exposure. Pyrimidine dimer formation was quantified, yielding approximately 40 ng/mL of cyclobutane pyrimidine dimers after 2 mJ/cm² of exposure to both wavelengths. Additionally, water treatment was tested using ceramic silicon carbide membranes. High average rejection efficiencies (99.9%) were obtained for both total coliforms and E. coli using uncut flat sheet membranes. The combination with UV-C LEDs led to treatment of the concentrated membrane retentate (99.985% or higher), highlighting the potential of this treatment approach for effective water disinfection. Full article