Search Results (2,212)

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE₂ concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE₂ levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE₂, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes. Full article

This study investigated the effects of four antioxidative substances, α-tocopherol (α-TP), phytosterols (PS), squalene (SQ), and propyl gallate (PG), on micronutrient retention and antioxidative capacity of rapeseed oil during ethanol steam deodorization (ESD, 140–220 °C). Results demonstrated that supplementation with these antioxidants increased the retention rates (percentage relative to initial content) of tocopherols, phenols, carotenoids, phytosterols, and squalene by up to 2.92%, 46.25%, 25.82%, 1.03%, and 60.15%, respectively. These improvements are attributed to the protective effects of the supplemental antioxidative substances against thermal and oxidative degradation. Moreover, α-TP and PG increased the antioxidative capacity of the oil after ESD at 180 °C for 60 min by 10.37% and 5.35%, respectively, which can be attributed to their increased concentrations and synergistic interactions with endogenous antioxidants. A model oil system of caprylic triglyceride supplemented with binary mixtures of antioxidative substances revealed synergistic behavior in blends of α-TP with PG or CE (β-carotene), and of CE with PG or PS, through complementary interactions, whereas antagonism occurred in blends of PS with PG, and of SQ at a high concentration (40.10 mg/100 g) with α-TP, PG or CE, due to unfavorable molecular interactions. Full article

The swallowing reflex is a highly coordinated process that is essential for safe bolus transit and airway protection. Although its neurophysiological framework has been extensively studied, the molecular mechanisms underlying reflex initiation remain incompletely understood, limiting targeted therapies for oropharyngeal dysphagia. Recent evidence implicates purinergic signaling as a key mediator of swallowing initiation, particularly through ATP release from taste buds and neuroendocrine cells in the hypopharyngeal and laryngeal mucosa. Experimental studies in mice demonstrate that water, acidic, and bitter chemical stimuli induce ATP release, activating purinergic receptors (P2X2, P2X3, heteromeric P2X2/P2X3, and P2Y1) on afferent sensory fibers. This receptor activation enhances input to the brainstem swallowing central pattern generator, initiating reflexive swallowing. Genetic ablation of purinergic receptor-expressing neurons or epithelial sentinel cells, as well as pharmacological antagonism of P2X or P2X3 receptors, markedly attenuates these responses. Furthermore, exogenous ATP or selective P2X3 agonists applied to swallowing-related mucosa evoke swallowing reflexes in an animal model, underscoring translational potential. While the precise upstream receptor mechanisms for water- and acid-induced ATP release, as well as species-specific differences, remain to be clarified, targeting purinergic pathways may represent a novel physiologically grounded therapeutic strategy for restoring swallowing function in patients with oropharyngeal dysphagia. Full article

Interactions between antioxidants are of interest, mainly for understanding their action in complex biological and food systems. This study aimed to evaluate interactions between the anthocyanin-rich aqueous red cabbage extract and several natural (ascorbic acid, gallic acid, and glutathione) and synthetic (Trolox and TEMPOL) antioxidants as a function of reaction time, concentration, and extract/antioxidant ratio in the ABTS^• decolorization and FRAP antioxidant activity assays. The measured interaction type showed dependence on assay type, reaction time, and the extract/antioxidant ratio, but no general dependence on the concentrations of the extract and the antioxidants over a 6-fold concentration range. In the ABTS^• decolorization assay, the interactions between the red cabbage extract and exogenous antioxidants were additive (Trolox), weakly antagonistic (ascorbic acid, gallic acid, and glutathione), and definitely antagonistic for TEMPOL. In the FRAP assay, the interactions were additive (ascorbic acid and Trolox), weakly antagonistic (gallic acid and TEMPOL), and definitely synergistic for glutathione. These results suggest the need for a series of assays covering a range of conditions to demonstrate a deviation from additivity in the interactions between antioxidants. The synergy of the interaction of glutathione with the extract in the FRAP assay indicates the possibility of a higher reactivity of this compound in Fe³⁺ reduction in complex systems than in an assay of the pure compound. Full article

Background/Objectives: The development of effective oncologic therapies with fewer adverse effects is often limited by the intrinsic and acquired resistance of tumor cells. Hybrid molecules, rationally designed to combine different pharmacophores, represent a promising strategy by providing synergistic effects, dose reduction, and a lower risk of resistance. In this study, the antitumor potential and mechanisms of action of 22 novel hybrid compounds derived from xanthene and pyran scaffolds (SJ022–SJ103) were investigated. The hybrids were initially evaluated through in vitro screening in four breast, three ovarian, and two prostate cancer cell lines, followed by the selection of T-47D, OVCAR-3, and LNCaP cells for detailed assays assessing cytotoxicity, apoptosis, cell cycle distribution, DNA damage, caspase-3/7 activity, morphology, and PI3K/AKT/mTOR pathway modulation. Methods: Cytotoxicity assays were performed in the selected cell lines, while mechanistic studies included apoptosis and cell cycle analysis by flow cytometry, γH2AX detection, Western blotting for PI3K/AKT/mTOR pathway proteins, and 3D spheroid assays. Combinatorial effects with hormone therapies (tamoxifen, fulvestrant, and letrozole) and the AKT inhibitor MK2206 were evaluated. AKT silencing by esiRNA and molecular docking was performed to confirm target engagement. Results: SJ028 demonstrated broad activity across all tested cell lines, whereas SJ064 and SJ078 exhibited higher selectivity. Treatments induced apoptosis, S/G2-M arrest, and DNA damage, accompanied by decreased phospho-AKT levels and stable PI3K and mTOR expression. In 3D models, the hybrids increased caspase-3/7 activity and necrotic core expansion. Co-administration with hormone therapies resulted in synergistic effects in breast and ovarian cancer cells, reducing IC₅₀ values by more than 50% in both parental and resistant models, while combinations with MK2206 were antagonistic across all tumor subtypes. AKT silencing abrogated cytotoxicity, and docking confirmed SJ028 binding to AKT. Conclusions: Xanthene- and pyran-based hybrids—particularly SJ028, SJ064, and SJ078—showed strong antitumor activity through apoptosis induction, cell cycle arrest, and PI3K/AKT pathway modulation. Their preserved efficacy in resistant models and synergistic interactions with hormone therapies contrasted with the antagonism observed with AKT inhibition, highlighting their potential as promising candidates for the treatment of hormone-responsive and -resistant cancers. Full article

Background: Cisplatin (CP) use is associated with testicular toxicity. Cuproptosis-related genes are associated with dysfunctional spermatogenesis. Additionally, the HMGB1/NF-κB axis has been involved in cuproptosis-mediated inflammation. The aim of the current study was to investigate the effect of CP toxicity on the HMGB1/NF-κB axis and cuproptosis in the rat testis. The effect of thymol was also explored. Methods: Four groups of male Wistar rats were used: control, thymol (60 mg/kg P.O. daily for 2 weeks), CP (8 mg/kg i.p single injection), and CP+thymol. Results: CP induced a significant decrease in serum testosterone and LH. CP-induced oxidative stress was evident by the modulation of oxidative stress markers. The expressions of IL-8, NF-κB, and HMGB1 were induced by CP treatment, accompanied by increased expression of cuproptosis genes, including SLC31A1, FDX1, and DLAT. On the other hand, thymol antagonized CP testicular injury. Thymol’s effect was associated with reduced expressions of IL-8, NF-κB, HMGB1, and cuproptosis markers. Conclusions: Collectively, this study provides evidence of the possible potential role of the HMGB1/NF-κB axis and cuproptosis in CP-induced testicular injury and illustrates the protective effects of thymol against testicular damage, which are attributed, at least in part, to blunting HMGB1 and cuproptosis-related genes expression. Full article

Integrated pharmacokinetic (PK) and pharmacodynamic (PD) models are essential for the understanding of quantitative relationship between drug exposure and response towards the identification of optimal dosing regimens in drug development and clinical therapy. This article summarizes the common PK–PD models being established in oncology, with a focus on combination therapies. Among them, the PK models include those used for practical non-compartmental and compartmental analyses, as well as those for physiologically based modeling that describe and predict exposure to various chemotherapy, targeted therapy, and immunotherapy drugs. Built on proper natural disease progression models, such as the empirical logistic growth curve, the Gompertzian growth model, and their modifications, the integrated PK–PD models recapitulate and predict antitumor drug efficacy, in which the PD models include practical indirect response model and various tumor growth inhibition models, as driven by the mechanistic actions of the drugs administered. Since anticancer drugs are usually co-administered, PK–PD modeling has been extended from monotherapy to combination therapy. However, relying on a single interaction factor or parameter to capitulate complex drug interactions, predict outcomes of different combinations, and determine possible synergism is problematic. Considering the apparent contributions from individual drugs following mutual interactions, a new PK–PD model has been developed for combination therapy, which may be integrated with proper algorism (e.g., the Combination Index method) to critically define combination effects, synergism, additivity, or antagonism. As drug combinations become more complex and individual drug actions are variable, these models should be optimized further to advance the understanding of PK–PD relationships and facilitate the development of improved therapies. Full article

The COVID-19 pandemic caused by the SARS-CoV-2 virus has exposed the urgency of research on rapid and efficient virus detection and strategies to inhibit its replication. Previous studies have mostly focused on traditional immunoassay or optical methods, but they have limitations in terms of sensitivity, timeliness, and in-depth analysis of molecular interaction mechanisms. Solid-state nanopore single-molecule detection methods, which can monitor molecular conditions in real time at the single-molecule level, bring new opportunities to solve this problem. The nucleocapsid protein (N protein) of SARS-CoV-2 was systematically investigated under different conditions, such as external drive voltage, pH, nanopore size, and N protein concentration. The translocation of the N protein through the nanopore was then analyzed. Subsequently, we analyzed the translocation characteristics of the N protein, RNA, and N protein–RNA complexes. With the aid of EMSA experiments, we conclusively confirmed that RNA binds to the N protein. Building on this finding, we further explored small molecules that could affect the nanopore translocation of N protein–RNA complexes, such as gallocatechin gallate (GCG), epigallocatechin gallate (EGCG), and the influenza A viral inhibitor Nucleozin. The results show that GCG can disrupt the liquid-phase condensation of the N protein–RNA complex and inhibit the replication of the N protein. Meanwhile, the structural isomer EGCG of GCG and the small molecule Nucleozin can also block RNA-triggered N protein liquid–liquid phase separation (LLPS). Our results confirmed that GCG, EGCG, and Nucleozin exhibit antagonistic effects on the N protein, with differences in their effective concentrations and the potency of their antagonism. Herein, using solid-state nanopore single-molecule detection technology, we developed an experimental method that can effectively detect RNA-induced changes in N protein properties and the regulatory effects of small molecules on the LLPS of N protein–RNA complexes. These findings not only provide highly valuable insights for in-depth research on the molecular interactions involved in viral replication, but also open up promising new avenues for future responses to similar viral outbreaks, the development of a rapid and effective detection method based on solid-state nanopores and single-molecule detection, and antiviral therapies targeting N protein–RNA interactions. Full article

Integrated urban–rural development is of great significance in promoting coordinated development in underdeveloped areas across provinces and advancing common prosperity. Previous studies have mostly focused on typical counties in single or developed areas, with insufficient exploration of integrated urban–rural development in underdeveloped areas. A total of 71 counties in Wuling Mountain area were taken as the research object, and a conceptual model of “element–structure–function” was constructed based on the theory of the urban–rural integration system. The entropy weight ideal point method, variation coefficient method, coupling coordination model, and obstacle model were employed to analyze the integrated urban–rural development in counties of the Wuling Mountain area during 2010 and 2023 from the five dimensions of population, economy, space, society, and ecology, and to explore their coupling coordination relationship and key obstacle factors. The research results indicate the following: (1) During the study period, the average annual growth rate of integrated urban–rural development was only 1.213%, showing a relatively low level. The spatial evolution exhibited a trend of “overall optimization–gap convergence–multipolar linkage–hot in the south and cold in the north”. (2) The comprehensive coupling coordination increased from 0.6380 in 2010 to 0.7016 in 2023, and the coupling coordination of “population–space” became the dominant mode. Nearly 60% of counties achieved a level upgrade from the transition stage to the coordination stage, and the multidimensional coordination relationship was mainly affected by the dual effects of spatial polarization and ecological constraints. (3) The obstacle of spatial integration ranked first and the mismatch of factors was severe. Land urbanization and population distribution imbalance were key obstacles, and their core contradictions were concentrated in the tripartite dilemma of “extensive land utilization–factor blockage–ecological antagonism”. It is urgent to achieve coordinated and sustainable development of urban and rural integration through market-oriented reforms of two-way factor flow. The conceptual model of “element–structure–function” constructed by the research results can provide a theoretical tool for analyzing the integrated development of urban and rural areas in counties, and can provide decision support for solving the dilemma of element mismatch. Full article

Cerebral ischemic reperfusion injury (CIRI) induces irreversible neurological dysfunction with high morbidity and mortality, yet effective clinical interventions remain limited. This study focused on ferroptosis in CIRI and explored the neuroprotective components and mechanisms of Pomelo peel essential oil (PPEO)—a product derived from Guangxi’s characteristic Shatian pomelo. Sprague-Dawley rats were used to establish two CIRI models: focal CIRI via Middle Cerebral Artery Occlusion (MCAO) and global CIRI via Cardiac Arrest/Cardiopulmonary Resuscitation (CA/CPR). Analyses were conducted using metabolomics, transcriptomics, histopathological staining, biochemical assays, RT-qPCR, Western blotting (WB), and molecular docking. Metabolomic results showed altered lipid-related metabolites in both models, predominantly unsaturated fatty acids and components of the arachidonic acid (AA) metabolic pathway. Transcriptomic analysis revealed significant upregulation of PTGS1/2 in the MCAO model. Nootkatone and β-pinene improved neuronal morphology, increased glutathione peroxidase 4 (GPX4) levels, and enhanced neurological scores. Notably, Nootkatone exhibited strong binding affinity to ALOX15, and reduced lipid metabolic disturbances in the CA/CPR model. AA metabolism varies with CIRI severity: it is inflammation-driven in focal CIRI and ferroptosis-associated in global CIRI. As a key component of PPEO, Nootkatone antagonizes ferroptosis via the ACSL4-LPCAT3-ALOX15 axis, offering a novel therapeutic target for global CIRI after CA/CPR. Full article

Oral squamous cell carcinoma (OSCC) is marked by profound differences in survival between the localized and disseminated disease, estimated to result in a 70% and less than a 40% five-year survival rate with surgical and/or radiation approaches (in localized cases) and chemotherapy (in metastatic cases), respectively. Given the suboptimal efficacy of current management options, new therapeutic approaches are needed to supplement existing chemotherapies and improve outcomes. One emerging therapeutic option is naltrexone (NTX), an opioid antagonist that has shown promising outcomes at low doses in other forms of cancer. This study sought to determine the effectiveness of intermittent dosing of naltrexone on oral cancer cell survival, either as a single agent or in combination with traditional chemotherapy. Two human OSCC lines (locally invasive SCC-25 and metastatic Detroit 562) were cultured. Cells were exposed to 1 µM and 10 µM NTX alone, using intermittent (5 h once, 5 h daily, 5 h every other day) or constant 72 h exposure. Cells were exposed to combination therapy with cisplatin or docetaxel under three NTX regimens (5 h, 24 h, and continuous). Cell viability was determined using Sulphorhodamine B (SRB) assay and Cell Counting Kit-8 (CCK-8). Differences across treatments were assessed using ANOVA (p < 0.05). The effect of low-dose NTX alone, across varying treatment regimens, did not yield significant, consistent changes in OSCC cell survival. Combination with cytotoxic drugs reduced cell viability more efficiently than chemotherapy alone at select doses, particularly through intermittent short-term pretreatment schedules, but the full dose response demonstrated antagonism between NTX and chemotherapy, independent of the dosing schedule. These results contrast with previous findings in other cancers, and, thus, further study and optimization will be needed to determine the clinical benefit and reproducibility of these findings. Full article

Needle cast (Lophodermium seditiosum Minter, Staley & Millar) in Scots pine (Pinus sylvestris L.) and European ash (Fraxinus excelsior L.) dieback (Hymenoscyphus fraxineus (T. Kowalski) Baral, Queloz & Hosoya) are among the most destructive forest and tree plantation diseases in Europe, threatening not only targeted plant species but also the whole ecosystem. While considerable research effort has focused on microbial antagonists against ash dieback, comparable investigations into needle cast biocontrol remain virtually absent from the literature. Here, isolated microbial antagonists from European ash and Scots pine were evaluated for their efficacy against respective pathogens. In vitro dual-culture assays revealed bacteria with strong inhibitory effects on pathogen growth, as well as multiple plant growth-promoting traits (PGPTs). It was found that bacteria from the genera of Pantoea, Erwinia, Priestia, and Pseudomonas inhibited the growth of H. fraxineus by ≥70%. Most significantly, our investigation revealed that bacteria isolated from Scots pine, belonging to the genera Pseudomonas, Bacillus, and Priestia, inhibited the growth of L. seditiosum by 50% to 80%, representing one of the first reported bacterial antagonisms for this neglected pathogen. All isolates were positive for at least two PGPTs, primarily due to mineralization of organic phosphate and the production of siderophores. The dual functional traits of isolated bacteria highlight their potential application in integrated forest protection strategies, particularly for the previously overlooked L. seditiosum pathosystem. Full article

Early cellular alterations in abdominal aortic aneurysm (AAA) are scarcely investigated. Aortic remodeling inflammation-related suggested the CXCR2/CXCL1/IL-8 axis as a therapeutic target. This study investigates CXCR1/CXCR2 antagonism in primary human aortic endothelial (HAOEC) and smooth muscle cells (HAOSMC) conditioned with IL-8 or serum from patients with AAA (sPT). Ladarixin (10 μM Lad or 25 μM) served as an inhibitor. Readouts included RT-qPCR for CXCL1, CXCL8, CXCR2, MMP9, NFKB1, and VEGF-A; zymography for MMP9 activity confocal microscopy for F-actin and mitochondria; NADPH/NADH diaphorase histochemistry for redox activity; and ATP assay. In HAOEC, IL-8 downregulated CXCR2, increased MMP9 activity, and induced cytoskeletal and mitochondria disorganization without altering NADH/NADPH diaphorases but increasing ATP release. At concentration of 10 μM Lad rescued cell organization and gene expression. sPT upregulated CXCL8, CXCR2, and MMP9, decreased NADH/NADPH diaphorases, and altered cytoskeleton and mitochondria organization in HAOEC. At concentration of 10 μM Lad (partially) and 25 μM Lad reverted gene upregulation and mitochondria distribution; both doses increased diaphorase and released ATP. HAOSMC were scantily susceptible to IL-8 and weakly responsive to sPT, slightly upregulating CXCR2 and VEGF-A but increasing proMMP9 gelatinolysis. Ladarixin recovered proMMP9 activity and modulated CXCL1. AAA-like vascular cell alterations involve multiple inflammatory factors and are modulable by inhibition of IL-8 receptors. The results underline careful dose calibration. Full article

The rapid global emergence of multidrug-resistant (MDR) Klebsiella pneumoniae threatens public health, as treatment options remain limited and resistance to last-line antibiotics is rising. Natural phenolic compounds emerge as promising adjuvants to restore antibiotic activity. This study pooled data from 216 in vitro assays evaluating interactions between phenolic compounds and conventional antibiotics against MDR K. pneumoniae. Fractional inhibitory concentration index (FICI) values were analyzed at the individual-test level, and structure–activity relationships were explored using a binary chemotype flagging approach. Overall, synergy was highly context-dependent, varying by both antibiotic class and phenolic chemotype. Polymyxin B combined with resveratrol demonstrated the most consistent and robust synergy (median FICI = 0.25, synergy rate = 96.2%), with no antagonism observed. For carbapenems, meropenem showed strong synergy when paired with flavonoids containing catechol or gallol motifs (e.g., quercetin, kaempferol), whereas curcumin exhibited inconsistent or antagonistic effects. Variability analysis revealed that combinations with low dispersion, such as polymyxin B + resveratrol, offer greater translational potential than high-variability pairs. These findings highlight the structural determinants of synergy and support further preclinical evaluation of select phenolic compounds as adjuvants to conventional antibiotics in the fight against MDR K. pneumoniae. Full article

In agroecosystems, bacterial antagonism is an alternative to agrochemicals, which are a threat to the environment and global health. From this perspective, a collection of environmental bacterial isolates was tested for their potential as antagonists against the phytopathogenic bacterium Xanthomonas vesicatoria, which is one of the etiological agents of bacterial spot in tomato and pepper. The isolates with the greatest in vitro antagonistic activity were selected for ex vivo assays using tomato plant leaves and further characterized for their capacity to produce hydrolytic enzymes. The results revealed promising prospects for an antagonism-based X. vesicatoria biocontrol against bacterial spot disease, thus favouring more sustainable agricultural production. Full article