Search Results (4,678)

Herpes simplex virus type 1 (HSV-1) remains a significant pathogen, particularly in immunocompromised patients. The emergence of drug-resistant strains necessitates alternative therapeutic agents. Lentinula edodes (LE), Hypsizygus marmoreus, and Pleurotus eryngii are edible mushrooms with recognized medicinal properties. However, their effects on drug-resistant HSV-1 remain unclear. This study characterized metabolites from high-temperature/high-pressure (121 °C) water extracts of fresh and dried fruiting bodies and evaluated anti-HSV-1 activities using in vitro and in silico approaches. Metabolic profiles were analyzed by electrospray ionization–quadrupole time-of-flight mass spectrometry. Antiviral activity against HSV-1 KOS (wild-type) and HSV-1 dxpiii (drug-resistant) strains was assessed by plaque assays and qPCR. Molecular docking and network pharmacology were performed on candidate compounds. LE extract from dried mushroom tended to show the highest levels of selected major bioactive constituents, along with greater antioxidant activities. All extracts significantly inhibited viral infection and gene expression in both strains. LE extract from dried mushroom modulated the expression of NFKB1 and IL6. Molecular docking analysis revealed that eritanidine showed a predicted binding affinity to HSV-1 DNA polymerase (−7.95 kcal/mol). Additionally, eritanidine, 5′-methylthioadenosine, and 3-indoleacrylic acid were predicted to interact with TNF and MAPK1. Several compounds also demonstrated favorable drug-likeness properties. Overall, these mushroom extracts are promising natural sources of antiviral agents against HSV-1, including drug-resistant variants. Full article

Metronidazole is an antibiotic used to treat Helicobacter pylori, a bacterium responsible for chronic infections in humans that cause gastric inflammation, ulcers, and cancer. However, its long-term administration is limited by toxicity and increased resistance. In the search for more effective agents against H. pylori infection, molecular hybridization has now been applied to the synthesis of the new compound 3. Its structure connects the metronidazole moiety to pectolinarigenin, the latter obtained by acid hydrolysis of glycosylated flavonoids isolated from the plant Linaria reflexa Desf. The NOE effect supported the C-7 functionalization of 3, as evidenced by the energy-minimized DFT-calculated structure. The new molecule enriches the chemical space of known metronidazole–flavonoid analogs, among which the genistein derivative 2 was reported as the most active in inhibiting bacterial strains. The computational analysis of 2 and 3 compared with metronidazole as the reference has provided favorable data for both Absorption, Distribution, Metabolism, and Excretion (ADME) predictions and the probability of anti-H. pylori activity, besides rising docking evaluation on three specific targets and dynamics simulation as inhibitors of the flavodoxin enzyme. The results are promising for further in-depth biological investigation. Full article

Background/Objectives: Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia, dyslipidemia, and oxidative stress, leading to severe systemic complications. Medicinal plants rich in polyphenolic compounds have gained increasing attention as complementary therapeutic agents. This study aimed to comparatively evaluate the chemical composition, as well as the antidiabetic, hypolipidemic, and antioxidant effects of Polygonum persicaria and Vaccinium myrtillus in a streptozotocin-induced diabetic model. Although Vaccinium myrtillus has been more extensively investigated for its antidiabetic potential, the pharmacological relevance of Polygonum persicaria in diabetes remains insufficiently characterized, particularly in direct comparison with a recognized phytotherapeutic comparator. Methods: Hydroalcoholic tinctures prepared from Polygonum persicaria L. herb and Vaccinium myrtillus L. leaves were subjected to phytochemical analysis using High-Performance Thin-Layer Chromatography (HPTLC) for the identification of flavonoids and phenolcarboxylic acids, alongside spectrophotometric determination of total polyphenol and flavonoid content. Experimental diabetes was induced in CD1 mice by streptozotocin administration. Animals were treated orally for 35 days, and glycemic parameters, lipid profile, body weight, food and water intake, and oxidative stress markers (MDA, SOD, TAC, and GPx) were evaluated. Results: HPTLC/CSS screening indicated the presence of rutin, chlorogenic acid, and caffeic acid in Polygonum persicaria, while Vaccinium myrtillus showed stronger densitometric signals for phenolcarboxylic acid-type compounds, particularly chlorogenic and caffeic acids. Total polyphenol and flavonoid content were also higher in Vaccinium myrtillus (433.89 ± 8.67 mg/L GAE; 154.38 ± 3.08 mg/L QE) compared to Polygonum persicaria (269.28 ± 5.25 mg/L GAE; 132.75 ± 2.65 mg/L QE). Functionally, Vaccinium myrtillus demonstrated a significant antihyperglycemic effect from day 14 (p = 0.009) and improved lipid parameters, while Polygonum persicaria showed a delayed glycemic effect, significant only at day 35 (p = 0.014), without significant hypolipidemic activity. In contrast, Polygonum persicaria exerted a marked antioxidant effect, significantly increasing GPx activity (p = 0.025) and reducing MDA levels (p = 0.053). Conclusions: Vaccinium myrtillus showed stronger antihyperglycemic and hypolipidemic effects, while Polygonum persicaria was mainly associated with antioxidant-related biochemical changes. These differences may be influenced by phytochemical composition, but they cannot be attributed solely to total polyphenol or flavonoid content. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality, with substantial heterogeneity that is not fully explained by genetic alterations alone. Emerging evidence positions metabolic reprogramming as a central driver of tumor behavior, integrating glycolysis, mitochondrial function, lipid and amino acid metabolism, and autophagy into coordinated networks that extend beyond cancer cells to the tumor microenvironment. Tumor–immune metabolic competition and metabolite-mediated signaling shape immune responses, often promoting immunosuppression and resistance to immunotherapy, particularly in microsatellite-stable (MSS) CRC. Systemic factors, including obesity, insulin resistance, and the diet–microbiota axis, further modulate tumor metabolism and immune function, reinforcing disease progression. Metabolic biomarkers reflecting these multi-level interactions, spanning tumor-intrinsic pathways, immune contexture, and host metabolism, offer promising opportunities for improved patient stratification and therapeutic targeting, although clinical validation remains limited. Current treatments, including chemotherapy, targeted agents, and immune checkpoint inhibitors, are effective in selected subgroups but are constrained by resistance mechanisms. In this review, we propose an integrative immunometabolic framework in which tumor, immune, and systemic metabolic processes co-evolve, defining CRC progression and treatment response. Targeting this interconnected network through combinatorial and metabolism-oriented strategies may enable precision therapies, particularly for immunotherapy-resistant MSS CRC. Full article

Chemical agents have long been used to control plant diseases, but their effects on the environment and lack of alignment with sustainable development goals are making them gradually unsuitable. One trend in green agriculture is the use of Bacillus species for the biocontrol of plant diseases. Due to their vast metabolic and genetic diversity, Bacillus spp. can contribute significantly to the soil ecosystem, while also enhancing plant resilience to biotic and abiotic stresses. Bacillus spp. are widely used in the agrobiotech industry due to their multi-functional versatility and are well-known for protecting plants from numerous plant diseases. In this review, we discussed the diversity and functions of antimicrobial compounds (AMCs) produced by Bacillus spp., along with their roles in plant growth promotion (PGP), and immunity. Furthermore, we highlighted the potential of Bacillus spp. as biopesticides in host plants, ways to enhance their biocontrol efficacy, and also addressed their possibility to cause disease in host plants. Considering the beneficial impacts of Bacillus spp. on PGP and pathogen biocontrol and their disease-causing capability, we discussed the possible solutions for a safe development of Bacillus-based biocontrol agent (BCA). Collectively, these insights can guide the selection of Bacillus strains with broad-spectrum or target-specific activity against pathogens, ensuring minimal adverse effects on the host. Full article

Chronic inflammation accelerates the aging process, and targeted clearance of senescent cells shows potential in alleviating age-related decline. PCC1, a potent senescent cell clearance agent in grape seed extract (GSE), has limited applications due to its low oral bioavailability. This study introduced a novel GSE formulation, Natural Senolytics PCC1 (NSPCC1), which significantly enhanced PCC1 absorption and metabolic characteristics. Validation in two mouse aging models demonstrated that oral administration of NSPCC1 markedly extended lifespan and promoted healthy aging. The formulation improved the capacity for hematopoietic stem/progenitor cell differentiation and reduced age-related myeloid cell bias. Comprehensive histological analysis revealed attenuated aging phenotypes in bone marrow and skin, improved peripheral blood erythroid parameters, and a partial increase in blood antioxidant capacity, alongside reduced M1 macrophage infiltration and fibrosis in liver, kidney, and lung tissues. These effects were validated through histological assessments, including H&E, Masson, F4/80, and iNOS staining. This study highlighted the pivotal role of hematopoietic stem cells in aging and established NSPCC1 as a promising natural intervention for age-related pathologies. Its enhanced efficacy lays the groundwork for deeper exploration of natural products in aging biology and provides crucial support for the development of safe and effective anti-aging therapies. Full article

Alzheimer’s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease’s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required. Full article

Melanoma is a highly aggressive and metabolically adaptable cancer that often resists conventional therapies. Targeting core bioenergetic pathways may, therefore, represent an effective strategy to improve therapeutic responses, particularly in tumors dependent on mitochondrial function. SC18 is an imidazolidine-2,4-dione compound that binds the NADH-binding pocket of voltage-dependent anion channels (VDACs), inducing mitochondrial dysfunction. VDAC expression is increased in melanoma and strongly associated with advanced disease stage and poor prognosis. In this study, we evaluated the effects of SC18 in melanoma cell lines with distinct pigmentation states, including melanin-rich melanotic human MNT-1 and mouse B16-F1, as well as low/amelanotic human SKMel28 and mouse YUMM cells. VDAC1, VDAC2 and VDAC3 were highly expressed across these melanoma lines, all of which relied on both glycolysis and mitochondrial oxidative phosphorylation for ATP production. SC18 reduced mitochondrial membrane potential and oxygen consumption rates, accompanied by declines in intracellular ATP levels and TCA cycle substrate utilization. SC18 also increased reactive oxygen species, mitochondrial superoxide, and lipid peroxidation, indicating enhanced oxidative stress. These metabolic and redox disturbances were associated with reduced cell viability and significantly impaired migration in multiple melanoma cell lines, supporting a potential anti-metastatic effect. In addition, SC18 showed synergistic cytotoxicity when combined with other chemotherapeutic agents. Overall, SC18 disrupted mitochondrial metabolism, induced oxidative stress, and impaired survival and motility pathways, with more pronounced effects in low/amelanotic than in melanotic melanoma cells. Together, these findings support the further development of SC18 as a mitochondrial metabolic disruptor that targets redox vulnerabilities in melanoma. Full article

Fatty liver disease represents a major metabolic disorder affecting domestic animals worldwide, with significant implications for animal health, welfare, and agricultural productivity. Disrupted communication between mitochondria and other organelles—particularly the endoplasmic reticulum, lipid droplets, and lysosomes—plays a critical role in disease pathogenesis. This review synthesizes knowledge on inter-organellar communication across domestic animals, with emphasis on species-specific adaptations. We address the “Dairy Cow Paradox”—periparturient dairy cows develop severe hepatic steatosis (>30% liver fat), yet under sterile conditions, they have a higher threshold for progressing to sterile steatohepatitis compared to rodents and humans. However, it is critical to note that severe fatty liver in dairy cows is indeed associated with impaired autophagy, inflammation, and liver damage, particularly when accompanied by ketosis or concurrent infections, and 39% of transition cows exhibit moderate to severe lymphocytic hepatitis. We propose that the tolerance to severe steatosis in dairy cows arises from three adaptations: (1) attenuated innate immune sensing via the cGAS-STING pathway; (2) enhanced lipid buffering from perilipin 5 (PLIN5) with a hypothesized ruminant-specific Val152 substitution that may stabilize lipid droplet–mitochondria contacts; and (3) dampened calcium signaling due to ER–mitochondria membrane lipid raft rigidity, elevated inositol 1,4,5-trisphosphate receptor 2 (IP₃R2) expression, and reduced mitochondrial calcium uniporter (MCU) conductance. We contrast this with the inflammatory steatohepatitis common in rodent models driven by calcium overload and mitochondrial DNA (mtDNA) release, and glucocorticoid-mediated mitofusin 1 (MFN1) suppression, causing mitochondrial fragmentation in poultry. We identify critical knowledge gaps, including the need to define bovine and avian mitochondria-associated endoplasmic reticulum membrane (MAM) proteomes and spatially resolve hepatic zonal communication patterns. Targeting organellar communication hubs with nutraceuticals or pharmacological agents offers promising therapeutic strategies. Full article

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent whose clinical application is limited by cardiotoxicity. In clinical settings, chemotherapy is given to tumor-bearing patients, whereas most preclinical studies of DOX-related cardiotoxicity use non-tumor-bearing animal models, potentially missing context-dependent differences. To address this, we compared DOX-induced cardiotoxicity between non-tumor-bearing and tumor-bearing mouse models. Cardiac function was assessed by echocardiography, and serum biomarkers, histopathological changes, and cardiac transcriptomic profiles were analyzed. Tumor burden exacerbated DOX-induced increases in BNP and CK-MB levels and myocardial structural damage, whereas systolic function was significantly reduced in non-tumor-bearing mice but did not further decline in tumor-bearing mice. Transcriptomic analysis revealed that DOX treatment induced 2528 and 398 differentially expressed genes (DEGs) in non-tumor-bearing and tumor-bearing mice, respectively, compared with their respective controls. A total of 206 shared DEGs were identified, most of which showed consistent directions of change under both conditions, while 16 genes exhibited opposite expression patterns. Common DEGs were mainly enriched in immune-inflammatory responses, cell adhesion, and extracellular matrix (ECM)–receptor interaction pathways. In non-tumor-bearing conditions, DOX-specific mechanisms were mainly associated with ECM remodeling, oxidative stress, metabolic dysregulation, and p53-mediated apoptosis. In contrast, tumor-bearing conditions showed predominant enrichment of immune-related pathways, including JAK-STAT, Toll-like receptor, NOD-like receptor, and chemokine signaling. These findings suggest that tumor burden may modulate the molecular mechanisms of DOX-induced cardiotoxicity, revealing context-dependent differences and offering insights for future cardioprotective strategies. Full article

Background/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM. Full article

5-Aminolevulinic acid (5-ALA) has emerged as an important theranostic agent in oncology due to its selective intracellular conversion to protoporphyrin IX (PpIX), enabling both photodynamic diagnosis (PDD) and photodynamic therapy (PDT). This narrative review summarizes current knowledge regarding the biological mechanisms underlying 5-ALA metabolism, selective tumor accumulation, and the clinical applications of 5-ALA-based approaches across multiple oncological indications. Particular emphasis is placed on glioblastoma, head and neck lesions, dermatological malignancies, urological cancers, gynecological lesions, and emerging translational applications. The review also discusses key biological and technical limitations, including tumor hypoxia, restricted light penetration, heterogeneous PpIX accumulation, resistance mechanisms, and tumor-specific variability. Recent advances in drug delivery systems, nanotechnology, sonodynamic therapy, radiodynamic strategies, and combination immunotherapeutic approaches are also highlighted. Collectively, current evidence indicates that while 5-ALA has established clinical utility in selected indications, many applications remain preclinical or early translational, underscoring the need for further well-designed clinical studies. Full article

This study aimed to isolate, characterize, and evaluate bacterial consortia capable of degrading the diamide insecticide cyantraniliprole in aqueous systems and to assess their bioremediation potential under environmentally relevant conditions. Four bacterial consortia, each comprising six isolates, demonstrated significant growth in mineral media containing cyantraniliprole as the sole carbon source, and the isolates were identified using conventional microbiological techniques in combination with MALDI-TOF-MS analysis. The bacterial consortia were enriched from pesticide-contaminated environments and systematically evaluated using microbiological, physiological, and analytical approaches to determine their degradation potential and environmental adaptability. The degradation performance of the consortia was systematically assessed under varying environmental parameters, including temperature, pH, salinity, and incubation time, with optimal degradation observed at 30–35 °C, pH 7.0–8.0, 0.5–5.0% NaCl, and 11 days of incubation at 150 rpm using an initial cyantraniliprole concentration of 50 mg/L. Biodegradation efficiency was further evaluated using DCPIP reduction assays, alongside measurements of biofilm formation and biomass production, indicating enhanced metabolic activity and adaptive responses under pesticide-induced stress. The consortia also exhibited the capacity to degrade structurally related diamide pesticides, including flubendiamide, chlorantraniliprole, cyclaniliprole, and fluchlordiniliprole, suggesting broad-spectrum biodegradation potential. Their performance was further validated in a simulated water microcosm system designed to mimic environmentally relevant contamination scenarios. In simulated contaminated water (60 mg/L cyantraniliprole), bacterial inoculants standardized to 10⁷ CFU/mL achieved substantial degradation after 20 days of incubation at 30 °C, as confirmed by HPLC analysis, with the six-strain consortium (T4), comprising Bacillus subtilis subsp. subtilis AZFS3, Bacillus pumilus AZFS5, Bacillus mojavensis AZFS15, Bacillus paramycoides AZFS18, Pseudomonas aeruginosa KZFS4, and Alcaligenes aquatilis KZFS11, demonstrating the highest removal efficiency (98.27%) and reducing the pesticide concentration to 1.00 mg/L, followed by consortium T3 (96.72%), which consisted of Bacillus subtilis Ht1, Bacillus subtilis Ht2, Bacillus mojavensis Ht3, Pseudomonas aeruginosa Ht4, Pseudomonas aeruginosa Ht5, and Pseudomonas aeruginosa Ht6. Residue analysis and predictive bioinformatic assessment further supported the biodegradation capacity of the selected bacterial communities and suggested the formation of simpler transformation products. Overall, the investigated bacterial consortia exhibited high degradation efficiency and environmental adaptability, highlighting their potential as effective and eco-friendly agents for the bioremediation of cyantraniliprole-contaminated water systems Full article

Diabetes mellitus is a complex metabolic disorder whose management has moved from glycemic control to the control of risk factors through the use of new antihyperglycemic drugs with pleiotropic effects. Despite the multiple cardio–renal benefits of sodium-glucose co-transporter 2 (SGLT2) inhibitors, their prescription is often avoided due to concerns regarding side effects. This review aims to discuss the multiple benefits of SGLT2 inhibitors in balance with one of the most concerning side effects, the risk of euglycemic diabetic ketoacidosis (EDKA). A literature search was performed to identify and select articles relevant to this topic. We accessed several databases, including PubMed, Web of Science and Scopus, using appropriate keywords. We selected and evaluated randomized controlled trials, retrospective studies, systematic reviews and meta-analysis published between 2014 and 2024 supporting the multifaceted benefits of SGLT2 inhibitors and the limitations of their recommendations and focusing on the risk of EDKA. Initially designed as antidiabetic agents, SGLT2 inhibitors have demonstrated important cardio–renal benefits, these drugs being the first-line medication in patients with established cardiovascular disease, heart failure and chronic kidney disease. SGLT2 inhibitors are associated with some potential side effects, but with contradictory data concerning their prevalence and clinical relevance. From the possible side effects, EDKA is a life-threatening metabolic emergency whose incidence and recognition has increased, in particular with the use of SGLT2 inhibitors. These drugs can cause this disorder through several mechanisms, including reduced insulin secretion and increased glucagon levels, leading to free fatty acid production, which generally occurs in the presence of some risk factors such as reduced dietary carbohydrates, intercurrent illnesses, surgical stress and alcohol consumption. Through awareness of these risk factors as well as of the clinical symptoms, this condition could be promptly avoided or managed and SGLT2 inhibitors could be safely used. Full article

Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death. Full article