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Follicular development is recognized as a highly complex biological process regulated by multiple factors. Thyroid hormone (TH) is considered one of the key regulators of female reproduction, and its dysregulation can significantly impair follicular development. Epigallocatechin gallate (EGCG), the main active component of green tea, possesses strong antioxidant properties. Numerous studies have demonstrated that EGCG positively influences reproductive function in both humans and animals. However, whether EGCG directly affects follicular development under conditions of TH dysregulation remains poorly understood. The primary objective of this study was to investigate the impact of hyperthyroidism on ovarian development, examine whether EGCG could mitigate the adverse effects of TH dysregulation, and elucidate the underlying molecular mechanisms. In the T₄-induced hyperthyroidism rat model, ovarian tissues were serially sectioned for Hematoxylin-Eosin (HE) and Masson’s trichrome staining to assess morphological changes, and follicle numbers were quantified at each developmental stage. Granulosa cell (GC) viability, proliferation, and apoptosis induced by T₃ were evaluated using CCK8, EdU, and TUNEL assays, respectively. Antioxidant enzyme activity was measured, and the expression levels of related proteins were analyzed via Western blotting. Results showed that hyperthyroidism altered ovarian structure, significantly increasing the number of atretic follicles. Levels of antioxidant enzymes, including Superoxide Dismutase (SOD), Glutathione Peroxidase (GSH-PX), and Catalase (CAT), were markedly decreased, whereas the lipid peroxidation product malondialdehyde (MDA) was significantly elevated. Furthermore, all ERS-related proteins, phosphorylated Eukaryotic Initiation Factor 2 Alpha (p-eIF2α), Activating Transcription Factor 4 (ATF4), C/EBP homologous protein (CHOP), and Caspase-3, were upregulated, accompanied by decreased glucose-regulated protein 78 (GRP78) expression. Treatment with EGCG alleviated these detrimental effects of hyperthyroidism. At the cellular level, high concentrations of T₃ reduced GC viability and proliferation while increasing apoptosis. Reactive oxygen species levels were elevated, and GRP78 expression was decreased. Notably, all T₃-induced effects were reversed by EGCG treatment. In summary, this study demonstrates that hyperthyroidism induces oxidative stress in GCs, which triggers endoplasmic reticulum stress via the eIF2α/ATF4 pathway and leads to apoptosis. EGCG mitigates apoptosis by enhancing antioxidant capacity, thereby preserving ovarian function. These findings establish EGCG as a protective agent for maintaining ovarian health and fertility. Full article

Lytic bacteriophages, viruses that attack and kill bacteria cells, can be used in food as biocontrol agents to prevent the growth of pathogenic bacteria. Meat is highly susceptible to bacterial growth, including pathogenic species, the control of which is crucial. Antibiotic use by breeders has resulted in bacterial resistance, which remains a huge problem; bacteriophages have emerged as an interesting alternative. In the literature, the influence of bacteriophages on common foodborne pathogens, such as Salmonella sp., Listeria monocytogenes, Campylobacter jejuni, Yersinia enterocolitica, Escherichia coli, and Shigella sp., has been described. Some phage preparations can show synergistic effects when used with other antimicrobial agents. However, data on the use of bacteriophages to inhibit the growth of meat spoilage bacteria are limited. Bacteriophages can also synthesize endolysins, which possess antimicrobial properties. Contrary to bacteriophages, which are active against only a narrow range of microorganisms (usually one bacterial species), endolysins show a broad spectrum of activity. Full article

Colletotrichum graminicola, the causative agent of maize anthracnose leaf blight and stalk rot, severely jeopardizes the healthy development of the maize industry. Auxiliary activity enzymes (AAs), a vital subclass of carbohydrate-active enzymes, act as beneficial accessory proteins for fungi in degrading lignocellulose. This study identified 127 AA genes from the genome of C. graminicola strain TZ-3 and further analyzed the subcellular localization, conserved motifs, and domains of the proteins encoded by these genes. The CgAA genes exhibited significant variations in gene structure, and the structural motifs within their encoded proteins also differed. Subcellular localization analysis revealed that most CgAA proteins were localized in the extracellular space. Moreover, the CgAA gene family contained abundant conserved domains, suggesting diverse functionalities and potential roles in various fungal biological processes. Multiple cis-acting regulatory elements related to stress responses and plant hormones were detected in the promoter regions of these genes. This study analyzed the expression patterns of CgAA genes during pathogen–host interactions and found that most CgAA genes were differentially expressed in the interaction between C. graminicola and maize. Coupled with GO functional analysis, it was discovered that CgAAs are deeply involved in the interaction between C. graminicola and maize, closely associated with the pathogenic mechanisms of the pathogen, and may play crucial roles in the initiation and expansion of fungal infections. These results provide valuable resources for elucidating the functions of AA genes and lay the groundwork for sustainable agricultural development through the utilization of AA genes in disease control and the breeding of stress-resistant, high-yield crop varieties. Full article

Sclerotinia sclerotiorum, a devastating phytopathogenic fungus with global distribution, exhibits a broad host range encompassing over 700 plant species. Sclerotinia stem rot caused by this pathogen poses a significant threat to sustainable oilseed rape production. Coniothyrium minitans, a mycoparasite of S. sclerotiorum, is a promising biological control agent against this devastating disease. C. minitans-based formulations have been commercially developed for field application. A transcriptomic analysis revealed significant upregulation of the chitinase-encoding gene CmCH1 in C. minitans during interaction with S. sclerotiorum. Knockout of either CmCH1 or another chitinase-encoding gene CmCH10 in C. minitans did not markedly affect the mycelial growth, development, and parasitism of S. sclerotiorum. However, knockout CmCH1 and CmCH10 simultaneously resulted in reduced growth rate, impaired protoplast release, enhanced cell wall integrity, and diminished mycoparasitic capability. These results indicate that CmCH1 and CmCH10 collectively influence remodeling of the cell wall in C. minitans and its mycoparasitic activity. Full article

Development of new sustainable pesticides represents a real challenge for researchers due to environmental issues and public health aspects. In fact, the overuse of chemical pesticides has led to environmental damage, loss of biodiversity, and pesticide-resistant pests. In a framework characterized by the necessity of new sustainable agricultural practices, this study investigates the plant Genista ulicina as a producer of bioactive compounds for potential application as eco-friendly biopesticides. First, both roots and aerial parts of G. ulicina were extracted and the main compounds in the crude extracts were identified via GC-MS. Subsequently, the crude extracts were submitted to antifungal and phytotoxic assays. In particular, the antifungal effects were evaluated on three common phytopathogenic fungi, Fusarium oxysporum, Alternaria alternata, and Botrytis cinerea, while phytotoxic activity was evaluated on two weed species: Euphorbia peplus L. and Oxalis corniculata L. Further insights were obtained on the herbicidal potential of phytochemical compounds produced by G. ulicina through in silico investigations. In particular, molecular docking analyses were performed against three key enzymes involved in essential plant metabolic pathways: acetohydroxyacid synthase (AHAS), 4-hydroxyphenylpyruvate dioxygenase (HPPD), and protoporphyrinogen oxidase (PPO). Among the compounds identified, linolelaidic acid methyl ester, 1-monolinolein, stearic acid, and palmitic acid derivatives showed promising binding affinities and favorable interaction patterns compared to reference ligands. Selected phytochemicals from G. ulicina show potential as inhibitors of key herbicide targets, suggesting their value as promising leads in the development of sustainable bio-based weed control agents. Full article

Background/Objectives: Increasing the bioavailability of poorly absorbed drugs is a continuous challenge in modern pharmaceutical technology. This is due to the problematic nature of BCS class IV active pharmaceutical ingredients: these drugs possess poor solubility and membrane permeability. Moreover, many undergo immediate efflux and/or rapid systemic metabolism after absorption. This project aimed to improve the bioavailability of BCS class IV drugs by formulating gastroretentive self-emulsifying systems using curcumin as a model drug. Methods: The base of the systems was created by melting emulsifying agents, dissolution retardants, and PEGs together. Curcumin was added after the mixture was cooled slightly. Aqueous dispersions of several compositions were characterized by dynamic light scattering. After screening these results, the viscosities of the selected formulations were evaluated. Dissolution retardants were selected and added to the most superior samples, and their dissolution profiles were compared. Gastroretention of the final formulation was achieved by dispersing air in the molten system through melt foaming; internal structure was assessed by microCT, and physicochemical properties by PXRD and DSC. Cytotoxicity was measured in Caco-2 cells using MTT and Neutral Red assays, and transcellular transport was also studied. Results: Based on these results, a homogeneous gastric floating system was developed. We observed an advantageous cytotoxic profile and increased bioavailability. Conclusions: Overall, we were able to create a self-emulsifying gastroretentive formulation displaying extended release and gastric retention with a low amount of cost-efficient excipients. Full article

Metabolic syndrome is characterized by a group of metabolic disorders that can lead to the development of cardiovascular diseases, obesity and type 2 diabetes mellitus (T2DM). Nowadays, there are several groups of drugs for the treatment of T2DM, but there is no one that would not have significant side effects and suitable for most patients. In our previous study, it was shown that the (S)-2-ethoxy-3-phenylpropanoic acid derivative containing isopimaric acid moiety exhibited pronounced antidiabetic activity. In the present study, a series of (S)-2-ethoxy-3-phenylpropanoic acid derivatives containing an isopimaric acid moiety with various aromatic substituents at position 16 were synthesized. The synthesized compounds were tested for their ability to improve glycemic control and to counter lipid abnormalities in C57BL/6^Ay mice placed on a high-fat/high-cholesterol diet. Of all tested compounds, the 2-NO₂-phenyl derivative (16d) had the most pronounced effect in decreasing blood glucose and serum triglyceride levels. All the compounds displayed a relatively safe profile in the animal studies carried out in this work. Therefore, it can be concluded that chemical modification of isopimaric acid may enhance its efficacy as an antidiabetic agent as part of the potential glitazar. Full article

Low-density lipoprotein receptor-related protein 5 (LRP5) is a multifunctional transmembrane coreceptor that plays a pivotal role in development and disease. Wnt/β-catenin signaling is the primary downstream signaling pathway activated by LRP5. Furthermore, some LRP5 functions are mediated by noncanonical pathways, such as AKT/P21 and TGF-β/Smad signaling. Pathologically, both loss-of-function and gain-of-function mutations in LRP5 produce distinct phenotypes, ranging from osteoporosis-pseudoglioma syndrome to high bone mass disorders. Beyond the skeletal system, LRP5 has emerged as a key regulator of retinal angiogenesis, vascular integrity, renal tubular function, neurodevelopment, and lipid metabolism. Its physiological functions are highlighted by its ability to influence adipocyte differentiation, insulin sensitivity, and neuronal synaptic plasticity. Moreover, LRP5 displays a dual role in development and disease progression. Although it plays a protective role in acute injuries such as myocardial infarction and acute kidney injury, LRP5 also contributes to chronic pathologies such as tubulointerstitial fibrosis, polycystic kidney disease, and atherosclerosis through fibrotic and inflammatory pathways. Recent therapeutic interest has focused on modulating LRP5 activity using agents such as anti-Dickkopf-related protein 1 antibody, sclerostin inhibitors, polyclonal antibodies, CRISPR/Cas9 knockout, and some natural products. This review discusses the current understanding of LRP5's physiological and pathological roles across organ systems and highlights its therapeutic potential, emphasizing the need for targeted approaches considering its context-dependent effects. Full article

Background/Objectives: Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) frequently coexist, contributing to worse clinical outcomes and increased risk of exacerbations. While newer glucose-lowering agents have demonstrated cardiovascular and renal benefits, their comparative efficacy on COPD exacerbations remain uncertain. Methods: We systematically searched PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov from inception to June 2025. We included randomised controlled trials (RCTs) and observational studies enrolling adults with COPD and T2DM that reported the risk of COPD exacerbations following initiation of SGLT2is, GLP-1RAs, DPP-4is, or sulfonylureas, with an active comparator group. The primary outcome was a composite of moderate-to-severe COPD exacerbations. Secondary outcomes included the individual components separately. A Bayesian random-effects network meta-analysis was performed to estimate risk ratio (RR) with 95% credible intervals (95% CIs). Results: Nine observational studies were ultimately included. No RCTs were retrieved. Compared to sulfonylureas, initiation of SGLT2is (RR 0.64, 0.59–0.69), GLP-1RAs (0.66, 0.60–0.71), and DPP-4is (0.79, 0.74–0.86) was associated with reduced risk of moderate-to-severe exacerbations. Moreover, SGLT2is (0.80, 0.75–0.86) and GLP-1RAs (0.83, 0.77–0.88) were more favourable compared to DPP4is. Consistent results were found for secondary outcomes. Sensitivity analyses confirmed the robustness of the findings for the primary outcome. Robustness was not consistently observed across all treatment comparisons for secondary outcomes. Conclusions: Among patients with COPD and T2DM, newer glucose-lowering agents, particularly SGLT2is and GLP-1RAs, were associated with significantly lower risk of moderate-to-severe exacerbations. These findings support the potential respiratory benefits of these agents and warrant confirmation through RCTs. Full article

Vitiligo is an acquired depigmentation disorder characterized by the selective destruction of melanocytes, resulting in the progressive loss of pigment in the skin and hair. This condition frequently leads to significant psychological distress. Its pathogenesis is complex and multifactorial, involving a combination of genetic susceptibility, metabolic derangement related to oxidative stress, defective melanocyte adhesion to the basal epidermis, and dysregulated innate and adaptive immune responses, ultimately converging in the targeted elimination of melanocytes. Despite the availability of several therapeutic modalities, current corrective options are often limited in efficacy and are associated with high relapse rates. There remains a pressing need for novel, safe, and more effective therapeutic strategies to improve patients’ quality of life. Growing evidence indicates that the immune system plays a pivotal role in vitiligo onset and progression, as most triggers converge on inflammatory and autoimmune pathways targeting melanocytes. However, immunosuppressive therapies alone have shown limited effectiveness in halting disease progression and achieving lasting repigmentation. Targeting only immunological processes without addressing the underlying triggers of their activation likely represents a significant limitation in restoring pigmentation. In contrast, interventions aimed at upstream events may help prevent the initiation of the immune response. Consequently, combinatorial therapeutic approaches that target multiple pathogenic pathways and incorporate diverse pharmacological agents are being explored to improve clinical outcomes. This review aims to re-evaluate the intrinsic cellular abnormalities and associated dysregulated signaling pathways in vitiligo, with the goal of identifying novel, effective, nonimmunological treatment strategies. Full article

This study investigates the scavenger activity of Polynucleotide High Purification Technology (PN HPT^TM), alone or in combination with hyaluronic acid (PN HPTTM + HA) against oxidative stress induced by hydrogen peroxide (H₂O₂). Since oxidative stress is implicated in numerous pathological conditions, identifying effective antioxidants is crucial for therapeutic development. We employed a cell-free fluorometric assay based on Calcein-AM, a fluorescence probe whose signal increases proportionally to the generation of reactive oxygen species (ROS), to evaluate the ability to neutralize ROS under varying oxidative stress conditions and determine the dose- and time-dependent effects of these compounds. PN HPT^TM, HA, and PN HPTTM + HA were tested at various concentrations over multiple time points. Our results demonstrated that all tested treatments significantly lowered ROS levels compared to the untreated control. Notably, the PN HPT^TM -based compounds exhibited robust scavenging activity, with PN HPTTM + HA displaying the strongest and most consistent ROS-neutralizing effect across all concentrations and time points. This enhanced performance suggests a synergistic interaction between PN HPT^TM and HA, potentially due to complementary mechanisms of free radical scavenging and structural stabilization. These findings highlight the potential of PN HPT^TM and PN HPTTM + HA as effective antioxidative agents, offering potential for therapeutic applications where oxidative stress is central, including wound healing and tissue regeneration. Full article

Crumb rubber used in asphalt modification can generally improve the road performance of asphalt mixture pavement while offering substantial environmental and economic benefits. This study investigates the volatile organic compound emissions from crumb rubber-modified asphalt binders via gas chromatography–mass spectrometry, focusing on the effects of crumb rubber types (e.g., activated crumb rubber, non-activated crumb rubber), contents, and additives (warm-mix agents, deodorants, styrene–butadiene–styrene (SBS)). The analysis encompasses total volatile organic compound emissions, compositional variations, secondary organic aerosol and ozone formation potentials, and carcinogenic risks. Results indicate that non-activated crumb rubber increases volatile organic compound emissions initially, peaking at a 15% content (3.99 times higher than base asphalt), dominated by trichloroethylene. The surfactant-based warm-mix additive significantly reduces emissions by 73%, whereas deodorants exhibited limited efficacy. At equivalent contents, activated crumb rubber-modified asphalt emits more volatile organic compounds than non-activated crumb rubber-modified asphalt and leads to a higher ozone formation potential. Activated crumb rubber/SBS-modified asphalt blends reduce emissions by 69%–81% due to synergistic effects. In contrast, non-activated crumb rubber/SBS blends increase emissions, likely due to phase separation. All samples contain carcinogens, primarily trichloroethylene (20%–79%) and benzene (0.1%–9%). These findings underscore the critical importance of crumb rubber activation status and SBS addition in controlling volatile organic compound diffusion. The activated crumb rubber/SBS combination achieves a synergistic reduction exceeding the sum of individual effects (“1 + 1 > 2”). These findings provide valuable insights for designing eco-friendly asphalt. Full article

Background/Objective: The present study reports the design, synthesis, and biological evaluation of novel imidazo-triazole derivatives as potential antidiabetic agents. Methods: The novel series was synthesized by treating amino-triazole bearing carboxylic acid with substituted 2-bromo acetophenone and was biologically compared with acarbose under in vitro analysis. Results: Structure–activity relationship (SAR) analysis revealed that among these compounds, remarkable activity was shown by compound 5 (having three hydroxyl substituents) with IC₅₀ value of 6.80 ± 0.10 and 7.10 ± 0.20 µM for α-amylase and α-glucosidase in comparison to reference drug acarbose. To support experimental findings, computational investigations including molecular docking, pharmacophore modeling, molecular dynamics simulations, density functional theory (DFT), and absorption distribution metabolism excretion and toxicity (ADMET) profiling were employed. These studies confirmed the stability of ligand–protein interactions and provided insights into electronic and reactivity features governing enzyme inhibition. Conclusions: Collectively, the integration of in vitro and in silico approaches underscores the potential of novel imidazo-triazole scaffolds as promising leads for the development of safer and more effective therapeutics against diabetes mellitus. Full article

Sugar amino acids (SAAs) represent a privileged class of molecular chimeras that uniquely merge the structural rigidity of carbohydrates with the functional display of amino acids. These hybrid molecules have garnered significant attention as programmable conformational constraints, offering a powerful strategy to overcome the inherent limitations of peptide-based therapeutics, such as proteolytic instability and conformational ambiguity. The strategic incorporation of SAAs into peptide backbones, particularly within cyclic frameworks, allows for the rational design of peptidomimetics with pre-organized secondary structures, enhanced metabolic stability, and improved physicochemical properties. This review provides a comprehensive analysis of the synthetic methodologies developed to access the diverse structural landscape of SAAs, with a focus on modern, stereoselective strategies that yield versatile building blocks for peptide chemistry. A critical examination of the structural impact of SAA incorporation reveals their profound ability to induce and stabilize specific secondary structures, such as β- and γ-turns. Furthermore, a comparative analysis positions SAAs in the context of other widely used peptidomimetic scaffolds, highlighting their unique advantages in combining conformational control with tunable hydrophilicity. We surveyed the application of SAA-containing cyclic peptides as therapeutic agents, with a detailed case study on gramicidin S analogs that underscores the power of SAAs in elucidating complex structure–activity relationships. Finally, this review presents a forward-looking perspective on the challenges and future directions of the field, emphasizing the transformative potential of computational design, artificial intelligence, and advanced bioconjugation techniques to accelerate the development of next-generation SAA-based therapeutics. Full article

Background/Objectives: A series of 1-(3,5-dimethoxyphenyl)azetidine-2-ones were synthesised to evaluate their antiproliferative activity in MCF-7 breast cancer cells and HT-29 chemoresistant colon cancer cells. The 1,4-diarylazetidin-2-ones were designed by replacing the characteristic 3,4,5-trimethoxyphenyl Ring A of the antimitotic stilbene combretastatin CA-4 with a 3,5-dimethoxyphenyl substituent at N-1, together with phenyl, hydroxyl, and phenoxy substituents at C-3 of the four-membered ring. Methods: A panel of 12 novel compounds was synthesized and evaluated in estrogen receptor (ER)- and progesterone receptor (PR)-positive MCF-7 breast cancer cells followed with the more potent compounds further evaluated in HT-29 chemoresistant colon cancer cells. Cytotoxicity was determined by LDH assay. The structures of the 1-(3,5-dimethoxyphenyl)azetidine-2-ones 12i, 12k, 12o, 12p together with the 1-(3,5-dimethoxyphenyl)azetidine-2-one 12s were determined by X-ray crystallography. The trans configuration of the C-3 and C-4 substituents of the β-lactam ring was confirmed for compounds 12k and 12u. Molecular modelling and molecular dynamics studies examined the molecular interactions of the compounds with the colchicine binding site of tubulin. Results: The 1-(3,5-Dimethoxyphenyl)-4-(4-ethoxyphenyl)-3-hydroxyazetidin-2-one 12l was identified as the most potent antiproliferative compound in the series (with an IC₅₀ value of 10 nM in MCF-7 breast cancer cells and 3 nM in HT-29 colon cancer cells) and with greater potency than CA-4 in the chemoresistant HT-29 cells. Computational docking studies predicted binding conformations for 12l and the related series of compounds in the colchicine binding site of tubulin and rationalised the impact of the 3,5-dimethoxyphenyl substituent at N-1 of the azetidine-2-one on activity. Conclusions: These findings indicate that the novel 1-(3,5-dimethoxyphenyl)-2-azetidinone 12l is a suitable candidate for further investigation as a potential antiproliferative microtubule-targeting agent for breast and chemoresistant colon cancers. Full article