Search Results (23,740)

Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to target cancer cells, offers promising solutions. Gamma delta (γδ) T cells are noteworthy due to their potent ability to kill various cancer cells without needing conventional antigen presentation. Recent studies have focused on the role of γδ T cells in α-galactosylceramide (α-GalCer)-mediated immunity, opening new possibilities for cancer immunotherapy. We engineered humanized T cell receptor (HuTCR)-T1 γδ mice by replacing mouse sequences with human counterparts. This study investigates the cytotoxic activity of humanized γδ T cells against several human cancer cell lines (A431, HT-29, K562, and Daudi) in vitro, aiming to elucidate mechanisms underlying their anticancer efficacy. Human cancer cells were co-cultured with humanized γδ T cells, with and without α-GalCer, for 24 h. The humanized γδ T cells showed enhanced cytotoxicity across all tested cancer cell lines compared to wild-type γδ T cells. Additionally, γδ T cells from HuTCR-T1 mice exhibited higher levels of anticancer cytokines (IFN-γ, TNF-α, and IL-17) and Granzyme B, indicating their potential as potent mediators of anticancer immune responses. Blocking γδ T cells’ cytotoxicity confirmed their γδ-mediated function. These findings represent a significant step in preclinical development of γδ T cell-based cancer immunotherapies, providing insights into their mechanisms of action, optimization of therapeutic strategies, and identification of predictive biomarkers for clinical application. Full article

The search for the biomarkers of Alzheimer’s disease (AD) may prove essential in the diagnosis and prognosis of the pathology, and the differential expression of key proteins may assist in identifying new therapeutic targets. In this proof-of-concept (POC) study, a new approach of data mining and matching combined with the biochemical analysis of proteins was applied to AD investigation. Three influential online open databases (UniProt, AlzGene, and Allen Human Brain Atlas) were explored to identify the genes and encoded proteins involved in AD linked to mitochondrial and iron dysmetabolism. The databases were searched using specific keywords to collect information about protein composition, and function, and meta-analysis data about their correlation with AD. The extracted datasets were matched to yield a list of relevant proteins in AD. The biochemical analysis of their amino acid content suggested a defective synthesis of these proteins in poorly oxygenated brain tissue, supporting their relevance in AD progression. The result of our POC study revealed several potential new markers of AD that deserve further molecular and clinical investigation. This novel database search approach can be a valuable strategy for biomarker search that can be exploited in many diseases. Full article

Cardiovascular disease (CVD) is the leading cause of death worldwide, with pathophysiological mechanisms often involving platelet activation and chronic inflammation. While antiplatelet agents targeting adenosine diphosphate (ADP)-mediated pathways are well established in CVD management, less is known about drug interactions with the platelet-activating factor (PAF) pathway, a key mediator of inflammation. This study aimed to evaluate the effects of several commonly used cardiovascular and anti-inflammatory drug classes—including clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin II receptor blockers (ARBs), β-blockers, and analgesics—on platelet function via both the ADP and PAF pathways. Using human platelet-rich plasma (hPRP) from healthy donors, we assessed platelet aggregation in response to these two agonists in the absence and presence of graded concentrations of each of these drugs or of their usually prescribed combinations. The study identified differential drug effects on platelet aggregation, with some agents showing pathway-specific activity. Clopidogrel and NSAIDs demonstrated expected antiplatelet effects, while some (not all) antihypertensives exhibited additional anti-inflammatory potential. These findings highlight the relevance of evaluating pharmacological activity beyond traditional targets, particularly in relation to PAF-mediated inflammation and thrombosis. This dual-pathway analysis may contribute to a broader understanding of drug mechanisms and inform the development of more comprehensive therapeutic strategies for the prevention and treatment of cardiovascular, hypertension, and inflammation-driven diseases. Full article

Background/Objectives: Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal genetic disease caused by a silent mutation in the LMNA gene, leading to the production of progerin, a defective prelamin A variant. Progerin accumulation disrupts nuclear integrity, alters chromatin organization, and drives systemic cellular dysfunction. While autophagy and inflammation are key dysregulated pathways in HGPS, the role of microRNAs (miRNAs) in these processes remains poorly understood. Methods: We performed an extensive literature review to identify miRNAs involved in autophagy and inflammation. Through stem-loop RT-qPCR in aging HGPS and control fibroblast strains, we identified significant miRNAs and focused on the most prominent one, miR-181a-5p, for in-depth analysis. We validated our in vitro findings with miRNA expression studies in skin biopsies from an HGPS mouse model and conducted functional assays in human fibroblasts, including immunofluorescence staining, β-Galactosidase assay, qPCR, and Western blot analysis. Transfection studies were performed using an miR-181a-5p mimic and its inhibitor. Results: We identified miR-181a-5p as a critical regulator of premature senescence in HGPS. miR-181a-5p was significantly upregulated in HGPS fibroblasts and an HGPS mouse model, correlating with Sirtuin 1 (SIRT1) suppression and induction of senescence. Additionally, we demonstrated that TGFβ1 induced miR-181a-5p expression, linking inflammation to miRNA-mediated senescence. Inhibiting miR-181a-5p restored SIRT1 levels, increased proliferation, and alleviated senescence in HGPS fibroblasts, supporting its functional relevance in disease progression. Conclusions: These findings highlight the important role of miR-181a-5p in premature aging and suggest its potential as a therapeutic target for modulating senescence in progeroid syndromes. Full article

Reactive molecules, including oxygen and nitrogen species, serve dual roles in human physiology. While they function as essential signaling molecules under normal physiological conditions, they contribute to cellular dysfunction and damage when produced in excess by normal metabolism or in response to stressors. Oxidative/nitrosative stress is a pathological state, resulting from the overproduction of reactive species exceeding the antioxidant capacity of the body, which is implicated in several chronic human diseases. Antioxidant therapies aimed at restoring redox balance and preventing oxidative/nitrosative stress have demonstrated efficacy in preclinical models. However, their clinical applications have met with inconsistent success owing to efficacy, safety, and bioavailability concerns. This summative review analyzes the role of reactive species in human pathophysiology, the mechanisms of action of antioxidant protection, and the challenges that hinder their translation into effective clinical therapies in order to evaluate potential emerging strategies such as targeted delivery systems, precision medicine, and synergistic therapeutic approaches, among others, to overcome current limitations. By integrating recent advances, this review highlights the value of targeting reactive species in the prevention and management of chronic diseases. Full article

Using the fly eye as a model system, we previously demonstrated that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration. Building upon this finding, we investigated whether the protective role of mask is conserved in mammals. To this end, we generated a transgenic mouse line carrying Cre-inducible ANKHD1, the human homolog of mask. Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we found that expressing ANKHD1 driven by CamK2a-Cre reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, ANKHD1 expression was associated with a trend toward reduced gliosis and preservation of the presynaptic marker Synaptophysin, suggesting a protective role of ANKHD1 against TauP301S-linked neuropathology. At 9 months of age, novel object recognition (NOR) testing revealed cognitive impairment in female, but not male, PS19 mice. Notably, co-expression of ANKHD1 restored cognitive performance in the affected female mice. Together, this study highlights the novel effect of ANKHD1 in counteracting the adverse effects induced by the mutant human Tau protein. This finding underscores ANKHD1’s potential as a unique therapeutic target for tauopathies. Full article

Rickettsia, Anaplasma, and Ehrlichia species are emerging tick-borne pathogens that cause zoonotic diseases, including rickettsiosis, anaplasmosis, and ehrlichiosis in both human and animal populations. This study aimed to investigate the prevalence of these pathogens in cattle-associated ticks from Ganzhou City, Jiangxi Province, China. Through molecular characterization using multilocus sequence analysis (16S rRNA, gltA, groEL, and ompA genes), we analyzed 392 Rhipicephalus microplus ticks collected from March to September in 2022. The PCR results showed that eight Rickettsiales bacteria were detected, including two species of Rickettsia (51/392, 13.0%), four species of Anaplasma (52/392, 13.3%), and two species of Ehrlichia (70/392, 17.9%). Notably, the circulation of multiple pathogen species within R. microplus populations demonstrates significant microbial diversity in this region. Further consideration and investigation should be given to the possible occurrence of rickettsiosis, ehrlichiosis, and anaplasmosis in humans and domestic animals. Our study provides critical baseline data for developing targeted surveillance strategies and informing public health interventions against tick-borne diseases in southeastern China. Full article

Staphylococcus aureus is a Gram-positive bacterium that causes significant human morbidity and mortality. The capacity of S. aureus to cause disease is primarily attributed to an array of virulence factors produced by this pathogen that collectively overcome immune defenses and promote survival in a variety of host tissues. These include an arsenal of different cytotoxins that compromise plasma membrane integrity, with the specificity of each dependent upon the host organism and cell type. S. aureus encounters a variety of peripheral blood cell types during infection that play important roles in maintaining homeostasis and defending against microbial invasion, namely erythrocytes, thrombocytes, and leukocytes. S. aureus targets each of these cell types with specific cytotoxins to successfully establish disease. This review summarizes our current understanding of the susceptibility of different human peripheral blood cell types to each of these cytotoxins. Full article

Background/Objective: Pharmacological interventions often exert systemic effects beyond their primary targets, underscoring the need for a comprehensive evaluation of their metabolic impact. Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that alleviates pain, fever, and inflammation by inhibiting cyclooxygenase-2 (COX-2), thereby reducing prostaglandin synthesis. While its pharmacological effects are well known, the broader metabolic impact and potential mechanisms underlying improved clinical outcomes remain underexplored. Untargeted metabolomics, which profiles the metabolome without prior selection, is an emerging tool in clinical pharmacology for elucidating drug-induced metabolic changes. In this study, untargeted metabolomics was applied to investigate metabolic changes following a single oral dose of etodolac in healthy male volunteers. By analyzing serial blood samples over time, we identified endogenous metabolites whose concentrations were positively or inversely associated with the drug’s plasma levels. This approach provides a window into both therapeutic pathways and potential off-target effects, offering a promising strategy for early-stage drug evaluation and multi-target discovery using minimal human exposure. Methods: Thirty healthy participants received a 400 mg dose of Etodolac. Plasma samples were collected at five time points: pre-dose, before Cmax, at Cmax, after Cmax, and 36 h post-dose (n = 150). Samples underwent LC/MS-based untargeted metabolomics profiling and pharmacokinetic analysis. A total of 997 metabolites were significantly dysregulated between the pre-dose and Cmax time points, with 875 upregulated and 122 downregulated. Among these, 80 human endogenous metabolites were identified as being influenced by Etodolac. Results: A total of 17 metabolites exhibited time-dependent changes closely aligned with Etodolac’s pharmacokinetic profile, while 27 displayed inverse trends. Conclusions: Etodolac influences various metabolic pathways, including arachidonic acid metabolism, sphingolipid metabolism, and the biosynthesis of unsaturated fatty acids. These selective metabolic alterations complement its COX-2 inhibition and may contribute to its anti-inflammatory effects. This study provides new insights into Etodolac’s metabolic impact under healthy conditions and may inform future therapeutic strategies targeting inflammation. Full article

Human colorectal cancer (CRC) encompasses tumors affecting a segment of the large intestine (colon) and rectum. It is the third most commonly diagnosed malignancy and the second leading cause of cancer deaths worldwide. It is a multifactorial disease, whose carcinogenesis process involves genetic and epigenetic alterations in oncogenes and tumor suppressor genes, including genes related to DNA repair. The pathogenic mechanisms are described based on the pathways of chromosomal instability, microsatellite instability, and CpG island methylator phenotype. When detected early, CRC is potentially curable, and its treatment is based on the pathological characteristics of the tumor and factors related to the patient, as well as on drug efficacy and toxicity studies. Therefore, the aim of this study was to review the pathogenesis and molecular subtypes of CRC and to describe the main targets of disease-directed therapy used in patients refractory to current treatments. Full article

This study evaluated the effectiveness of eDNA metabarcoding in assessing fish communities in two urban lakes (First Lake and Second Lake) in Zagreb, Croatia, following IAS removal. Water samples were collected in April and June 2024 and analyzed using MiFish primers targeting the 12S rRNA gene. The results indicated that the cleanup efforts were largely successful, as several IAS previously recorded in these lakes were not detected (Ameiurus melas, Lepomis gibbosus, and Hypophthalmichthys spp.). However, some others persisted in low relative abundances, such as grass carp (Ctenopharyngodon idella), topmouth gudgeon (Pseudorasbora parva), and prussian/crucian carp (Carassius sp.). Species composition differed between lakes, with common carp (Cyprinus carpio) dominating Maksimir First Lake, while chub (Squalius cephalus) was prevalent in Maksimir Second Lake. Unexpected eDNA signals from salmonid and exotic species suggest potential input from upstream sources, human activity, or the nearby Zoo Garden. These findings underscore the utility of eDNA metabarcoding in biodiversity monitoring and highlight the need for continuous surveillance and adaptive management strategies to ensure long-term IAS control. Full article

Schizophrenia (SZ) is a complex neuropsychiatric disorder characterized by heterogeneous symptoms, relatively poor clinical outcome, and widespread disruptions in neural connectivity and oscillatory dynamics. This article attempts to review current evidence linking genomic and proteomic alterations with aberrant neural oscillations observed in SZ, including aberrations in all oscillatory frequency bands obtained via human EEG. The numerous genes discussed are mainly involved in modulating synaptic transmission, synaptic function, interneuron excitability, and excitation/inhibition balance, thereby influencing the generation and synchronization of neural oscillations at specific frequency bands (e.g., gamma frequency band) critical for different cognitive, emotional, and perceptual processes in humans. The review highlights how polygenic influences and gene–circuit interactions underlie the neural oscillatory and connectivity abnormalities central to SZ pathophysiology, providing a framework for future research on common genetic-neural function interactions and on potential therapeutic interventions targeting local and global network-level neural dysfunction in SZ patients. As will be discussed, many of these genes affecting neural oscillations in SZ also affect other neurological disorders, ranging from autism to epilepsy. In time, it is hoped that future research will show why the same genetic anomaly leads to one illness in one person and to another illness in a different person. Full article

The eye, a complex organ essential for visual perception, is composed of diverse cell populations with specialized functions; however, the complex interplay between these cellular components and their underlying molecular mechanisms remains largely elusive. Traditional biotechnologies, such as bulk RNA sequencing and in vitro models, are limited in capturing cellular heterogeneity or accurately mimicking the complexity of human ophthalmic diseases. The advent of single-cell RNA sequencing (scRNA-seq) has revolutionized ocular research by enabling high-resolution analysis at the single-cell level, uncovering cellular heterogeneity, and identifying disease-specific gene profiles. In this review, we provide a review of scRNA-seq application advancement in ocular physiology and pathology, highlighting its role in elucidating the molecular mechanisms of various ocular diseases, including myopia, ocular surface and corneal diseases, glaucoma, uveitis, retinal diseases, and ocular tumors. By providing novel insights into cellular diversity, gene expression dynamics, and cell–cell interactions, scRNA-seq has facilitated the identification of novel biomarkers and therapeutic targets, and the further integration of scRNA-seq with other omics technologies holds promise for deepening our understanding of ocular health and diseases. Full article

This research presents the development of a novel object detection algorithm designed to identify humans in natural outdoor environments using minimal computational resources. The proposed system, SARGAS, combines a custom convolutional neural network (CNN) classifier with MOG2 background subtraction and partial affine transformations for camera stabilization. A secondary CNN refines detections and reduces false positives. Unlike conventional supervised models, SARGAS is trained in a partially unsupervised manner, learning to recognize feature patterns without requiring labeled data. The algorithm achieved a recall of 93%, demonstrating strong detection capability even under challenging conditions. However, the overall accuracy reached 65%, due to a higher rate of false positives—an expected trade-off when maximizing recall. This bias is intentional, as missing a human target in search and rescue applications carries a higher cost than producing additional false detections. While supervised models, such as YOLOv5, perform well on data resembling their training sets, they exhibit significant performance degradation on previously unseen footage. In contrast, SARGAS generalizes more effectively, making it a promising candidate for real-world deployment in environments where labeled training data is limited or unavailable. The results establish a solid foundation for further improvements and suggest that unsupervised CNN-based approaches hold strong potential in object detection tasks. Full article

Bladder cancer pathogenesis is closely linked to epigenetic alterations, particularly DNA methylation and demethylation processes. Environmental carcinogens and persistent inflammatory stimuli—such as recurrent urinary tract infections—can induce aberrant DNA methylation, altering gene expression profiles and contributing to malignant transformation. This review synthesizes current evidence on the role of DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and the hypermethylation of key tumour suppressor genes, including A2BP1, NPTX2, SOX11, PENK, NKX6-2, DBC1, MYO3A, and CA10, in bladder cancer. It also evaluates the therapeutic application of DNA-demethylating agents such as 5-azacytidine and highlights the impact of chronic inflammation on epigenetic regulation. Promoter hypermethylation of tumour suppressor genes leads to transcriptional silencing and unchecked cell proliferation. Urine-based DNA methylation assays provide a sensitive and specific method for non-invasive early detection, with single-target approaches offering high diagnostic precision. Animal models are increasingly employed to validate these findings, allowing the study of methylation dynamics and gene–environment interactions in vivo. DNA methylation represents a key epigenetic mechanism in bladder cancer, with significant diagnostic, prognostic, and therapeutic implications. Integration of human and experimental data supports the use of methylation-based biomarkers for early detection and targeted treatment, paving the way for personalized approaches in bladder cancer management. Full article