Search Results (6,833)

Prostate cancer remains a major cause of cancer-related mortality, and new therapeutic strategies are needed for advanced disease. Niclosamide and related salicylanilide compounds have emerged as multitarget anticancer agents, but the molecular contexts associated with their activity remain incompletely understood. Here, we applied a phenotype-oriented integrative framework to characterize the molecular context and phenotypic activity of NSC828786, a niclosamide-like salicylanilide derivative. Cross-cohort transcriptomic analyses identified AMACR (alpha-methylacyl-CoA racemase) and HPN (hepsin) as consistently upregulated genes in independent prostate adenocarcinoma cohorts. NCI-60 profiling demonstrated broad-spectrum low-micromolar antiproliferative activity, including AR-negative prostate cancer and breast cancer cell lines spanning multiple receptor subtypes; however, quantitative ranking did not support preferential receptor subtype selectivity. CellMiner COMPARE analysis showed no significant correlation between baseline AMACR or HPN expression and NSC828786 sensitivity. Structure-based analyses supported computational compatibility of NSC828786 with predicted HPN- and AMACR-associated binding regions, while zebrafish assays showed no overt developmental abnormalities at concentrations ≤ 5 μM. These findings identify NSC828786 as a phenotypically active salicylanilide derivative and position HPN and AMACR as exploratory candidate molecular associations warranting further mechanistic and target engagement studies. Full article

Toxoplasmosis remains a major global health concern, particularly in immunocompromised individuals and pregnant women, while currently available therapies are associated with significant toxicity and limited efficacy against chronic infection. Drug repurposing represents an attractive strategy for the identification of safer and more effective anti-Toxoplasma gondii agents. This study investigated the antiparasitic potential of loratadine, a second-generation antihistamine, using an integrated in silico, in vitro, and in vivo approach. The anti-T. gondii activity of loratadine was evaluated through β-galactosidase-based proliferation assays, reversibility assays, and experiments using pretreated tachyzoites. In vivo efficacy was assessed in murine models of acute and chronic toxoplasmosis. Disease progression, survival, parasite burden, and cerebral cyst formation were analyzed following treatment. Loratadine inhibited the intracellular proliferation of T. gondii tachyzoites in a concentration-dependent manner and induced partially irreversible effects on parasite viability after drug withdrawal. Pretreatment of extracellular tachyzoites produced limited effects, suggesting that loratadine predominantly acts during the intracellular stage of infection. In the acute toxoplasmosis model, loratadine treatment delayed disease progression, prolonged animal survival, and significantly reduced the number of tachyzoites recovered from the peritoneal cavity. In the chronic infection model, treatment significantly decreased both the number and size of cerebral cysts, although these findings do not demonstrate cyst eradication or direct bradyzoite killing. Despite its measurable biological activity, loratadine exhibited a relatively low in vitro selectivity index, highlighting the need for further optimization. These exploratory findings identify loratadine as a promising lead compound (hit) for further optimization rather than an immediately translatable therapeutic candidate. Additional medicinal chemistry, pharmacokinetic, mechanistic, and confirmatory preclinical studies will be required to determine its potential for anti-T. gondii drug development. Full article

Phaeomoniella chlamydospora (Pch) is a pioneer pathogen of esca, one of the most destructive grapevine trunk diseases worldwide. A recent work suggests that acetate may act as a quorum-sensing (QS) molecule in Pch, promoting biofilm formation in a concentration-dependent manner. However, the broader influence of acetate on virulence-associated traits remains unexplored. In this study, three Pch isolates were cultured under increasing sodium acetate concentrations (0–100 mM) and assessed for pigmentation, extracellular enzyme activities (amylase, cellulase, protease, esterase, and pectinase), phenolic compound-degrading capacity, and antibacterial activity against a grapevine-associated Pseudomonas sp. isolate. Pigmentation, as well as amylase and cellulase activities, were significantly increased at low acetate supplement levels (6.25–12.5 mM), while esterase activity was unaffected. The expression of these traits decreased above 25 mM acetate supplementation. Phenolic compound degradation capacity, antibacterial efficacy, as well as protease and pectinase activities progressively suppressed at all acetate concentrations. These results indicate that acetate concentration modulates multiple virulence-associated phenotypes of Pch in vitro. Based on these patterns, we propose a hypothetical model in which acetate-dependent phenotypic changes may reflect a shift between establishment-associated activities and reduced extracellular activity at higher acetate levels. This model remains to be validated by mechanistic and in planta infection-based studies. Full article

GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance—a potential cause of neurodegenerative conditions—in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions. Full article

Apple leaf disease detection in orchards faces a unique challenge: lesion regions (foreground) are semantically important but visually less salient (weak texture, blurred boundaries), while background distractors (soil, weeds) are visually salient but semantically irrelevant. Traditional models, reliant on visual saliency, are usually misled by strong background textures. Unlike humans who first use leaf shape to locate possible lesions and then examine local textures, these models lack this semantic-guided strategy, leading to inaccurate detection. To address this problem, we propose a Semantic-Decoupled Dual Attention Network (SD-DAN). The core idea is to achieve target-distractor separation via semantic decoupling and then foreground enhancement and background suppression via dual attention. The network consists of two core modules. First, a frequency-enhanced preprocessing module adaptively fuses low- and high-frequency information to highlight lesion details and suppress redundant low-frequency information. Second, an attention-based foreground-background decoupling and enhancement module explicitly separates foreground and background with a learnable threshold, and applies a dual-attention mechanism: spatial-frequency enhancement to the foreground (active focusing) and spatial-frequency suppression to the background (active filtering), to improve discriminative features of apple disease. Experiments on the Apple Leaf Disease Dataset 9 (ALDD9) and the Apple Leaf Diseases Dataset demonstrate that SD-DAN achieves strong performance and consistently outperforms mainstream detectors across nine common apple disease detection tasks. Full article

Background/Objectives: Breast cancer (BC) remains the most frequently diagnosed malignancy among women worldwide, and patient outcome is strongly influenced by disease stage at diagnosis. Although imaging-based screening has improved early detection, its performance may be reduced in dense breast tissue and is associated with false-positive findings. In addition, tissue biopsy is invasive and unsuitable for longitudinal disease monitoring. Liquid biopsy (LB) has emerged as a minimally invasive approach for detecting tumor-derived material in peripheral blood. However, early-stage tumors typically exhibit low tumor burden and limited biomarker shedding, generating weak systemic signals that challenge reliable detection. This review examines current and emerging LB biomarkers for early BC detection. Methods: A comprehensive review of recent literature was conducted focusing on circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNAs, proteins, and other blood-based biomarkers associated with early BC. Studies addressing biomarker biology, detection technologies, clinical applications, and methodological limitations were critically evaluated. Results: ctDNA, CTCs, EVs, circulating RNAs, proteins, and additional blood-based biomarkers capture distinct aspects of tumor biology and disease evolution. ctDNA enables the analysis of tumor-specific mutations, methylation patterns, and fragmentation profiles, whereas CTCs provide direct cellular and phenotypic information despite their rarity and marked epithelial–mesenchymal plasticity. EVs offer increased molecular stability and actively participate in tumor progression, immune modulation, and metastatic niche formation. Nevertheless, low biomarker abundance, biological heterogeneity, technical variability, and background biological noise continue to limit analytical performance, particularly in early-stage disease. Current evidence further suggests that no single biomarker consistently provides sufficient sensitivity and specificity for reliable early BC detection. Conclusions: LB represents a promising strategy for non-invasive early BC detection. Future clinical implementation will likely depend on integrated multi-analyte approaches that combine complementary genomic, transcriptomic, proteomic, and cellular information, supported by multi-omics technologies and artificial intelligence-based analytical frameworks. Full article

Automated and accurate segmentation of retinal vessels in fundus images provides pivotal evidence for ophthalmologists to effectively and non-invasively diagnose prevalent ocular and systemic diseases. However, existing methods often struggle to maintain the topological continuity of fine-diameter capillaries, leading to severe vascular discontinuity and fragmented segmentation results in challenging scenarios such as complex, irregular microvascular branches, pathological lesions, and high-noise conditions. To address these limitations, we developed a novel symmetric dual-branch network with frequency-aware decomposition and prototype refinement (FDPR-DBNet). Specifically, the network initially utilizes the discrete wavelet transform (DWT) to decompose input retinal images into high-frequency and low-frequency components, which are then processed by a structurally symmetric dual-branch encoder. In the high-frequency branch, the parallel atrous convolution activation (PACA) module is designed to explore fine-grained contour and edge patterns related to vessel terminals and microvessels. Concurrently, within the low-frequency branch, the spatial-frequency characteristic activation (SFCA) unit is constructed by introducing the selective state-space model ($S6$) and Fourier transform to extract salient structural backbones. Moreover, the spatial attention residual fusion (SARF) module and cross-frequency fusion (CFF) block are designed to establish a symmetric guidance mechanism, effectively reinforcing bidirectional feature interaction and alignment across different frequency spectra to eliminate vascular fragmentation. Furthermore, by embedding global and local window self-attention into the Transformer, we formulated the cross-scale enhancement (CSE) module, comprising global semantic enhancement (GSE) and local detail enhancement (LDE), to model multi-scale contextual semantic correlations and enhance the adaptive recognition of vessel structures. Ultimately, we embedded the multi-wise prototype characteristic refinement (MPCR) component into the decoder to correct cross-scale semantic features through a dynamic calibration mechanism, while introducing a new connectivity loss to strictly enforce topological continuity. Experimental results on four publicly available retinal image datasets (DRIVE, CHASE_DB1, STARE, and IOSTAR) demonstrate that the proposed model achieves competitive performance and effectively preserves vascular integrity even in the presence of fundus lesions and noise. Full article

Chagas disease, caused by Trypanosoma cruzi, remains a neglected tropical infection with limited therapeutic options and significant drug-related toxicity. Endophytic fungi are emerging as sustainable sources of bioactive metabolites with potential antiparasitic activity. In this study, endophytic fungi isolated from the medicinal plant Lippia alba were screened for trypanocidal activity. Crude extracts from seven isolates were tested against epimastigote and amastigote forms of T. cruzi, together with cytotoxicity assays in J774A.1 murine macrophages. The crude extract of Montagnula sp. exhibited the strongest trypanocidal activity (IC₅₀ = 22.1 ± 0.5 μg/mL for epimastigotes and 29.2 ± 3.0 μg/mL for amastigotes), comparable to benznidazole, with low toxicity (CC₅₀ > 600 μg/mL) and a high selectivity index (>26). Morphological and mitochondrial analyses demonstrated preservation of host-cell integrity and mitochondrial function, in contrast to the reference drug. UHPLC-ESI-HRMS profiling identified phenolic and terpenoid compounds, including caffeic acid, ferulic acid, naringenin, apigenin, and ursolic acid, which may underlie the observed biological activity. To our knowledge, this study provides the first evidence of trypanocidal activity in an endophytic Montagnula species and highlights endophytic fungi as promising platforms for the discovery of novel anti-T. cruzi agents. Full article

Background: The human microbiota plays a crucial role in maintaining physiological homeostasis and influencing the development of chronic diseases not only in the gut but in the whole body. Material and Methods: This literature review is based on a comprehensive search of the PubMed database covering the period from 2008 to 2026. Approximately 65 key studies were included in the final analysis. Only articles published in English were included. The search included keywords such as microbiota, inflammaging, eubiosis, diet, gut diseases, cardiovascular diseases, diabetes, and osteoporosis. This narrative review explores the composition, development, and functional significance of the gut microbiota across the human lifespan, highlighting its dynamic interaction with environmental factors. Early-life microbial colonization, shaped by factors including delivery mode and breastfeeding, has long-term implications for immune system maturation and disease susceptibility. Results: A balanced gut microbiota (eubiosis) supports host health through metabolic activities, mainly by the production of short-chain fatty acids (SCFAs), which regulate intestinal barrier integrity, immune responses, and systemic inflammation. Contrarily, dysbiosis—characterized by reduced microbial diversity and an overrepresentation of pro-inflammatory species—is associated with chronic low-grade inflammation (inflammaging) and contributes to the pathogenesis of multiple diseases. Age-related changes in microbial composition are shown to activate inflammatory processes and impair immune regulation, thereby increasing disease risk. Therefore, it is important to recognize the role of microbiota alterations in key pathological conditions, including neurodegenerative diseases, cardiovascular diseases, type 2 diabetes mellitus, and osteoporosis. Conclusions: Finally, the potential of microbiome-targeted interventions, such as probiotics, prebiotics, and dietary modulation—in particular the Mediterranean diet is recognized as the most balanced—is discussed as a promising strategy to restore microbial balance and mitigate inflammaging. Further research is needed to better understand the association between microbiota and host health and to optimize therapeutic approaches for aging populations. Full article

Uncoupling protein 1 (UCP1) is a mitochondrial inner-membrane carrier classically recognized as the molecular effector of non-shivering thermogenesis in brown adipose tissue. By dissipating the proton-motive force generated by oxidative phosphorylation, UCP1 converts stored chemical energy into heat and enables adaptive thermogenesis during cold exposure. The rediscovery of metabolically active brown adipose tissue (BAT) and inducible beige adipocytes in adult humans has renewed interest in UCP1-positive thermogenic adipose tissue as a regulator of systemic metabolism and a potential target for therapeutic modulation in obesity and cardiometabolic disease. Beyond thermogenesis, accumulating evidence indicates that UCP1-positive brown/beige adipocytes and thermogenic adipose tissue are involved in lipid and glucose metabolism, mitochondrial redox homeostasis, inflammatory remodeling, organ protection, and tumor-associated metabolic adaptation, mainly through adipocyte-autonomous mechanisms and adipose–organ communication. However, UCP1 biology is complex: BAT activity measured by imaging does not directly quantify UCP1 proton conductance, non-adipose UCP1 expression is often low and technically challenging to validate, local cell-autonomous UCP1 function in non-adipose tissues remains controversial, and UCP1-independent thermogenic pathways may compensate in selected contexts. In this review, we summarize the molecular and structural basis of UCP1 function, its regulation at transcriptional and post-transcriptional levels, and its biological roles in cellular and systemic homeostasis, with explicit distinction between direct adipocyte-autonomous UCP1 functions, indirect systemic effects mediated by thermogenic adipose tissue, and preliminary or incompletely validated evidence of local UCP1 activity in non-adipose cells. We further discuss the association of UCP1-positive thermogenic adipose tissue with obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease, kidney injury, liver disease, neurological disorders, and cancer. Finally, we evaluate UCP1-related thermogenic adipose tissue activity as a biomarker and therapeutic target, highlighting current limitations, safety concerns, and future directions for precision metabolic medicine. Full article

Background: Thyroid carcinoma (THCA), especially papillary thyroid carcinoma (PTC), remains clinically challenging because recurrence and metastasis occur in a subset of patients. SMDT1 is an essential regulator of the mitochondrial calcium uniporter complex that may influence tumor progression, but its role in thyroid carcinoma is unclear. This study investigated the expression, clinical significance, and biological functions of SMDT1 in thyroid carcinoma. Methods: Public databases were used to analyze SMDT1 expression, diagnostic value, prognostic relevance, co-expression networks, functional enrichment, protein interactions, and immune infiltration. SMDT1 expression was validated in 50 paired PTC and adjacent non-tumorous tissues. In vitro SMDT1 overexpression was performed in PTC cell lines, followed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting (WB), CCK-8, colony formation, wound healing, and transwell assays. Results:SMDT1 was significantly downregulated in thyroid carcinoma tissues, PTC tissues, and PTC cell lines. Low SMDT1 expression was associated with lymph node metastasis and shorter disease-free survival. Functional analyses linked SMDT1 with mitochondrial calcium transport, oxidative phosphorylation, apoptosis, cellular senescence, and immune infiltration, including CD8⁺ T cells and activated NK cells. SMDT1 overexpression significantly suppressed PTC cell proliferation, colony formation, migration, and invasion. Conclusions:SMDT1 may function as a tumor suppressor in thyroid carcinoma and has potential diagnostic and prognostic value. Its effects may involve mitochondrial calcium homeostasis, metabolic regulation, and immune microenvironment remodeling. Full article

Background/Objectives: Natural products derived from plants, animals, and microorganisms have long been used as nutritional supplements and are increasingly recognized for their potential role in preventing and managing human diseases. This narrative review aims to summarize current evidence on the therapeutic relevance of natural products as dietary supplements across major disease categories and to highlight their mechanisms of action, clinical efficacy, and safety considerations. Methods: A narrative literature review was conducted using peer-reviewed articles, systematic reviews, and clinical studies focusing on natural products used as nutritional supplements in disease management. Relevant data were analyzed thematically, with emphasis on bioactive compounds, mechanisms of action, and evidence from preclinical and clinical research. Results: Natural products, particularly plant-derived polyphenols, flavonoids, terpenoids, omega-3 fatty acids, and probiotic-derived metabolites, exhibit diverse biological activities, including antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial effects. Evidence suggests potential benefits in cardiovascular diseases, metabolic disorders such as diabetes and obesity, neurodegenerative conditions, certain cancers, gastrointestinal disorders, and infectious diseases. However, clinical efficacy varies depending on compound type, dosage, and formulation. Key limitations include low bioavailability, variability in composition, and insufficient large-scale clinical trials. Safety concerns such as herb–drug interactions and lack of standardization remain significant challenges. Conclusions: Natural products as nutritional supplements represent a promising adjunct strategy in the prevention and management of various human diseases. While preclinical and early clinical evidence is encouraging, stronger clinical validation, improved standardization, and clearer regulatory frameworks are required to fully integrate these agents into evidence-based medical practice. Full article

Background/Objectives: Alzheimer’s Disease (AD) and vascular dementia contribute up to ~75% of dementia cases, as determined via autopsy. AD arises in part due to the buildup of aberrant proteins (amyloid beta (Aβ) and Tau); vascular dementia is caused by reduced cerebral blood flow. Each dementia mechanisms damages brain. Bobola et al. found that their low-intensity focused ultrasound (FUS) protocol applied to the brains of the 5XFAD mouse model of AD reduced Aβ by 50% through activation of microglia. Eguchi et al. found that their own FUS protocol applied to the brains of the same mouse model reduced Aβ by 15% and increased cerebral blood flow by 50% through an increase in endothelial nitric oxide synthase (eNOS). Here, we sought to test a combined version of those two FUS protocols, expecting both a decrease in Aβ burden and an increase in eNOS. Methods: Using a diagnostic ultrasound probe, we applied our combined FUS protocol primarily to the left hippocampus of anesthetized 5XFAD mice, for an hour a day, for three days for younger mice and for five days for older mice. On day three or five, respectively, we harvested their brains and performed histological analysis to assess Aβ burden, microglial activation and their co-localization with Aβ, as well as the burden of eNOS within neuronal nuclei (here called intra-neuronal eNOS) and outside of neurons. Results: Relative to untreated mice, the treated younger mice had more activated microglia co-localized with Aβ and reduced Aβ burden for large plaques, as well as no change in each measure of eNOS. In contrast, the treated older AD mice had no change in activated microglia co-localized with Aβ, and no change in Aβ burden. However, relative to untreated older AD mice, FUS decreased total and extra-neuronal eNOS and increased intra-neuronal eNOS. Conclusions: The ability of our FUS protocol to reduce Aβ burden and alter the eNOS distribution depends critically upon the age of the AD mice (more Aβ plaques for a comparable number of microglia for older mice relative to younger mice) and duration of the treatment. The observed decrease in extra-neuronal eNOS distribution in older AD mice caused by FUS raises the concern that our protocol may increase ischemia, while the increase in intra-neuronal eNOS may counteract that effect via protection of synaptic function. These findings also identify two candidate therapeutic windows for our FUS treatment protocol, each requiring more research before translation to humans. One window is early intervention to maximize Aβ plaque removal via activation of microglia. The second is later intervention to protect synaptic function if it is possible to mitigate the potential ischemic risk caused by the differential effects of FUS on eNOS. Full article

Crossing the blood–brain barrier (BBB) remains a central obstacle in central nervous system (CNS) therapeutics. Hirudin, a 65-amino acid, disulfide-stabilized, direct thrombin inhibitor with a long history in Traditional Chinese Medicine, has shown compelling efficacy in thrombotic disorders and mounting neuroprotective activity in preclinical stroke models, with supportive clinical signals. Although few studies have directly quantified its BBB permeability, available evidence indicates low but measurable brain exposure under pathological conditions, likely via paracellular leakage rather than receptor-mediated transport. To extend its therapeutic reach in cerebrovascular diseases and mitigate bleeding risk, researchers have engineered hirudin using nanocarrier encapsulation, hydrogel-based delivery systems, prodrug strategies, and other methods to enhance targeting, prolong half-life, and localize activation. These approaches also enable synergistic combinations with established CNS drugs and may facilitate delivery of co-therapeutics to the brain. This review synthesizes current evidence for hirudin in stroke, neurodegeneration, psychiatric disorders, and brain tumors; evaluates its context-dependent BBB access; and outlines a translational agenda centered on quantitative brain pharmacokinetics, pathology-guided targeting, stimulus-responsive formulations, controlled clinical evaluation, and rigorous management of bleeding risk and chemistry, manufacturing, and controls (CMC) readiness. Full article

Obesity is an escalating global health challenge, driven by adipose tissue dysfunction characterized by adipocyte hypertrophy, chronic low-grade inflammation and impaired insulin signaling, which together promote insulin resistance, dyslipidemia, hepatic steatosis and cardiovascular disease. Chlorogenic acid (CGA), a dietary phenolic phytochemical abundant in coffee, tea, fruits and vegetables, has attracted considerable interest as a modulator of adipocyte biology and metabolism. This review summarizes in vitro and in vivo evidence of the effects of CGA on adipogenesis, lipid metabolism, thermogenesis, inflammation and glucose homeostasis. In vitro studies employing murine and human adipocyte and progenitor cell models demonstrate that CGA attenuates adipocyte differentiation and lipid accumulation via downregulation of adipogenic transcription factors (PPARγ, C/EBPα) and lipogenic enzymes (FASN, ACC, SREBP 1c), alongside activation of AMPK, Shp2–Erk1/2 and Wnt–β catenin signaling. Several reports further show that CGA promotes browning of white adipocytes and enhances thermogenic and mitochondrial gene expression. Complementary in vivo studies in diet-induced obesity and diabetes models reveal that CGA reduces body weight gain, adiposity, adipocyte size and hepatic steatosis, improves lipid profiles, glucose tolerance and insulin sensitivity, and exerts anti-inflammatory and antioxidant effects in metabolic tissues. Collectively, current preclinical evidence supports CGA as a multifaceted modulator of adipose tissue function and whole-body metabolic homeostasis; however, rigorously designed, long-term clinical trials are required to establish its efficacy and safety in humans. Full article