Search Results (13,695)

Background/Objectives: Zoonotic tuberculosis (TB) remains a persistent public health challenge worldwide. It is particularly common in settings with close human–livestock–environment interactions. In Tanzania, progress toward TB control is increasingly threatened by multidrug-resistant tuberculosis (MDR-TB), yet genomic data from regions characterized by pastoralist and mining activities remain scarce. This study employed whole-genome sequencing (WGS) to characterize M. tuberculosis complex (MTBC) strains circulating among human and cattle populations in the Manyara region of northern Tanzania, with a focus on resistance-associated mutations and phylogenetic relationships. Methods: This cross-sectional study was conducted between September 2024 and February 2025. A total of 178 presumptive human TB cases provided sputum samples. From cattle, 161 samples were collected (110 milk samples and 51 lymph node aspirates), with each animal contributing only one type of sample. Specimen were analyzed using GeneXpert MTB/RIF, Lowenstein–Jensen culture, and WGS. Phylogenetic reconstruction was performed using SNP-based methods and IQ-TREE2 version 2.2.0. Results: Among human participants, 14 (7.8%) sputum samples were GeneXpert positive and were confirmed as members of MTBC by LJ culture. In cattle, one (0.62%) lymph node aspirate was positive for MTBC. Significant predictors of MTBC positivity included previous TB history, weight loss, and occupation involving mining and cattle keeping. WGS of five human isolates identified Lineages 1, 3, and 4. One isolate (Sample 98) harbored mutations associated with XDR-TB. Conclusions: WGS revealed M. tuberculosis Lineages 1, 3 and 4 circulating in the Manyara region, with diverse genetic mutations conferring with resistance to first- and second-line anti-TB drugs. These findings highlight the importance of integrated genomic surveillance to monitor drug resistance patterns in Tanzania and similar settings across human and animal populations. Full article

Background: The emergence of antifungal resistance and the limited number of clinically available antifungal drug classes necessitate the development of new agents with improved efficacy and safety. We investigated how linker architecture influences the antifungal activity and lead properties of hybrid triazole-thiazolidine derivatives. Methods: A focused library of triazole-thiazolidine hybrids incorporating alkylamine, amide, cyclic amine, 2-hydroxypropyl, and thiazepane linkers was synthesized and characterized. Antifungal activity was evaluated against reference strains and clinical isolates of Candida spp., Aspergillus fumigatus, dermatophytes, and Cryptococcus neoformans. Structure–activity relationships were analyzed by molecular docking. Selected compounds were further assessed by SCRAPPY profiling, fluorescence microscopy, mammalian-cell cytotoxicity assays, acute oral toxicity studies, and evaluation of microsomal stability and interactions with human CYP450 isoforms. Results: Linker architecture strongly influenced antifungal potency. Amide- and cyclic amine-containing hybrids were generally the most active, whereas simple alkylamide derivatives showed narrower activity profiles. Compound 28 emerged as the most promising lead, exhibiting sub-microgram MIC values against several Candida isolates, particularly C. parapsilosis, and retaining measurable activity against an azole-resistant C. albicans strain. Docking generated putative CYP51-binding models, while SCRAPPY profiling and fluorescence microscopy revealed an azole-like cellular response consistent with perturbation of sterol-associated homeostasis. Compound 28 was tolerated at 300 mg/kg in an acute oral study but showed concentration- and time-dependent cytotoxicity and rapid CYP3A4-mediated microsomal metabolism. Conclusions: Systematic variation of linker architecture identified compound 28 as a promising exploratory antifungal lead. Further optimization should focus on improving metabolic stability and cytotoxicity, together with direct target validation, pharmacokinetic characterization, and in vivo efficacy studies. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, highlighting the need for safe and effective therapeutic strategies targeting multiple oncogenic pathways. Cinnamon (Cinnamomum spp.) contains several bioactive phytochemicals with reported antioxidant and anticancer properties; however, their potential interactions with key cancer-associated signaling proteins have not been comprehensively investigated. In this study, an integrated computational and preliminary experimental approach was employed to evaluate four major cinnamon phytochemicals, namely e-cinnamaldehyde, eugenol, p-cymene, and cinnamic acid. Consensus molecular docking was performed using AutoDock Vina (v1.2.7), Smina (v2020.12.10), and GNINA (v1.3.3) against phosphoinositide 3-kinase (PI3K), nuclear factor kappa B (NF-κB), and mammalian target of rapamycin (mTOR). Docking analyses were complemented by protein-ligand interaction profiling, pharmacokinetic and toxicity prediction (ADMET), and a 100 ns molecular dynamics simulation with MM/GBSA binding free-energy analysis of the selected mTOR-p-cymene complex. In addition, the antioxidant activity and cytotoxic effects of a crude methanolic cinnamon bark extract were evaluated using in vitro antioxidant assays and MTT assays against HCT-116 and HT-29 colorectal cancer cell lines. Consensus docking predicted that all four phytochemicals were capable of interacting with the selected protein targets, although the predicted binding profiles varied among the compounds. Eugenol showed comparatively more favorable predicted interactions with PI3K, p-cymene produced the lowest predicted docking score for NF-κB, and cinnamic acid displayed a comparatively consistent predicted multitarget binding profile across PI3K, NF-κB, and mTOR. ADMET analysis suggested that all compounds satisfied major drug-likeness criteria and exhibited predicted oral bioavailability, although potential cytochrome P450 interactions and hepatotoxicity were predicted for some compounds. Molecular dynamics simulation indicated that the selected mTOR-p-cymene complex maintained a stable binding pose throughout the simulation, while MM/GBSA analysis yielded a modest binding free-energy estimate (ΔG_bind = −4.70 ± 8.20 kcal/mol), which should be interpreted cautiously because of the observed energetic variability. The crude methanolic cinnamon bark extract exhibited antioxidant activity and reduced the viability of HCT-116 and HT-29 colorectal cancer cells in a concentration-dependent manner. Collectively, these findings provide computational predictions of potential interactions between selected cinnamon-derived phytochemicals and cancer-associated signaling proteins and are consistent with the preliminary observation that the crude cinnamon extract exhibits antioxidant activity and cytotoxic effects in colorectal cancer cell lines. However, the computational analyses do not establish direct inhibition of the PI3K/NF-κB/mTOR signaling pathway, and the biological assays were performed using a crude extract rather than isolated phytochemicals. Therefore, further studies using purified compounds, biochemical target validation, pathway-specific cellular analyses, and in vivo models are required to determine whether the predicted protein-ligand interactions contribute to the observed biological activity. Full article

Background: Phosphatidylinositol 3-kinase (PI3K) is a promising anticancer drug target, and selective PI3Kα inhibition may provide both efficacy and an improved safety profile. This study aimed to design new potentially selective PI3Kα inhibitors using computer-aided drug design (CADD). Methods: Benzoxazepine and thiazole derivatives were investigated using molecular dynamics, ensemble docking, and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) analyses. Scaffold hopping, substituent replacement, structure-based virtual screening, and density functional theory (DFT) calculations were then applied to guide the design and characterization of new derivatives. Results: The study identified new chemotypes capable of interacting with PI3Kα Val851 (αVal851) in the hinge region, including chromeno[3,4-d]imidazole, 2H-benzo[b]oxazine, and quinoline derivatives. Additional substructures directed toward hydrophobic region II and the αGln859 interaction environment supported predicted selectivity over PI3Kβ, PI3Kγ, and PI3Kδ. Conclusions: The results establish a comprehensive CADD framework for the rational design of selective PI3Kα inhibitors and provide new compounds with improved predicted selectivity profiles for further development. Full article

Background: Autophagy is a process that diversely impacts the stages of both tumor initiation and progression. Elucidating the molecular mechanisms underlying autophagy and its role in tumorigenesis is a key component of anticancer strategies in both prostate cancer and other malignancies. Because advanced prostate cancer frequently exploits enhanced autophagy as a defense mechanism against therapy-induced stress (e.g., from abiraterone), the pharmacological modulation of miRNA levels presents a tremendous opportunity to block the tumor’s escape route and overcome drug resistance. Methods: A comprehensive literature review was conducted to evaluate the molecular pathways determining cancer cell survival and death. The analysis focused on the dual nature of autophagy (functioning as a ‘double-edged sword’) within the tumor microenvironment, microRNA (miRNA) regulatory networks, and the efficacy of synergistic therapeutic strategies in overcoming treatment resistance. Results: The primary focus of this paper is the dual and complex role of autophagy, which serves, on the one hand, as a cellular protective shield against metabolic stress—thereby facilitating metastasis—and, on the other hand, as a potential pathway leading to autophagic cell death. The progression of this crucial process is regulated by intricate interactions (crosstalk) with apoptotic pathways, mediated by Bcl-2 family proteins, key kinases (such as mTOR, JNK, and DAPK), and transcription factors, such as p53. Furthermore, the autophagic machinery is precisely regulated by specific miRNA molecules (e.g., miR-21, miR-141, and miR-375). These not only act as crucial intracellular modulators of autophagy but also serve as promising circulating biomarkers, enabling the monitoring of this process’s activity throughout disease progression. Conclusions: Autophagy, and in particular its modulation via miRNA signaling networks, represents a major and highly promising translational target. By directly impairing this autophagic survival mechanism, ‘double-hit’ combination therapies—integrating autophagy inhibitors (such as hydroxychloroquine or VPS34 inhibitors) with standard antiandrogen or cytotoxic agents—demonstrate promising preclinical potential in overcoming treatment resistance and favorably modulating the immune microenvironment in advanced prostate cancer. Full article

Elite athletes experience diverse biological, psychological, and social challenges during injury rehabilitation, yet few qualitative studies have explored these experiences and their interactions from a biopsychosocial perspective. This exploratory qualitative study investigated the biopsychosocial experiences of elite athletes during injury rehabilitation and the interactions among these experiences through semi-structured interviews with five participants, using inductive content analysis. Athletes reported biological experiences including musculoskeletal symptoms, limitations in daily activities, adverse drug reactions, psychosomatic symptoms, and physical development; psychological experiences including negative emotions (anger, anxiety, and depression) and positive experiences (restoration and psychological resilience); and social experiences including informational, instrumental, and emotional support, as well as negative social influences such as blame and pressure to return to play. Participants perceived that these biological, psychological, and social experiences were closely interconnected throughout rehabilitation. Biological experiences, such as pain and physical impairment, were perceived to contribute to negative emotions, including anxiety, whereas negative emotions were associated with stress-related psychosomatic symptoms, such as gastrointestinal symptoms and headaches. Emotional support was associated with positive emotional experiences, whereas negative social influences, including blame and pressure to return to play, were associated with negative emotional responses. These findings contribute to an understanding of the multidimensional experiences of injured elite athletes and may inform development of integrated rehabilitation approaches that address biological, psychological, and social aspects of recovery. Full article

Background/Objectives: Brain pericytes are contractile mural cells of the neurovascular unit whose responses to endothelin-1 (ET-1) are mediated primarily by endothelin type A (ETA) receptors. ET-1/ETA signaling has been implicated in pathological pericyte contraction in neurovascular disorders such as Alzheimer’s disease and in cerebrovascular dysfunction after subarachnoid hemorrhage, motivating pharmacological evaluation of selective ETA receptor antagonists at the pericyte level. Clazosentan is a selective ETA receptor antagonist used clinically for cerebral vasospasm; however, its pharmacodynamic effects on brain pericytes remain insufficiently characterized. Methods: Pericyte impedance-based contractile and recovery responses to ET-1 were evaluated by xCELLigence real-time cell index analysis. Pericyte viability, morphology, and ETA protein abundance were examined using Cell Counting Kit-8 assay, immunocytochemistry, and Western blotting. As a secondary barrier-related assessment, transendothelial electrical resistance (TEER) was measured in primary rat brain endothelial cell-based in vitro blood–brain barrier models. Results: ET-1 induced impedance-based contractile responses with a concentration-related trend, followed by recovery responses, and increased ETA protein abundance in a time- and concentration-related manner; clazosentan significantly attenuated ET-1-induced ETA upregulation. Repeated ET-1 exposure was associated with an enhanced subsequent ET-1-induced impedance-based contractile response and a more sustained response, suggesting contractile sensitization; both effects were significantly attenuated by clazosentan. Clazosentan did not overtly disrupt TEER-assessed barrier properties. Conclusions: These findings suggest that ET-1/ETA signaling may shift brain pericytes toward a sensitized contractile response state and that selective ETA blockade by clazosentan attenuates this process without overtly disrupting TEER-assessed barrier properties under the present in vitro conditions. These observations support further pharmacological characterization of clazosentan as a modulator of pericyte ET-1 responses. Full article

Drug resistance arising during cancer development and progression remains a major challenge in the treatment of epidermal growth factor receptor (EGFR)-driven tumors, particularly those harboring the clinically relevant T790M/L858R double mutation. In this study, we developed an integrated computational workflow combining explainable machine learning, virtual screening, molecular dynamics simulations, and binding free-energy calculations to identify novel inhibitors of this drug-resistant EGFR variant. An XGBoost regression model was trained using scaffold-aware cross-validation, Bayesian hyperparameter optimization, and sequential feature selection, resulting in a compact model based on 16 molecular descriptors. The model demonstrated robust predictive performance on external validation data, while SHAP analysis identified descriptors related to the local electronic environment, fragment distribution, and molecular topology as the primary contributors to activity prediction. The optimized model was subsequently applied to screen compounds from the Enamine REAL database. Top-ranked candidates were evaluated using explicit-solvent molecular dynamics simulations and MM/GBSA binding free-energy calculations. Several compounds formed stable protein–ligand complexes and maintained key interactions with residues known to be important for EGFR inhibition, including Lys745, Met790, and Leu718. These results demonstrate that the proposed workflow can efficiently prioritize computational candidates of drug-resistant EGFR mutants and may support the development of new therapeutic strategies for overcoming resistance in EGFR-driven cancers. Full article

Background/Objectives: The concomitant use of conventional medicines with foods, food supplements, and herbal products has increased, raising concerns about interactions. Despite this, healthcare professionals’ knowledge and clinical practices in this domain remain incompletely characterised. This study aimed to assess knowledge, attitudes, and clinical practices regarding food–drug, herb–drug, and supplement–drug interactions among healthcare professionals (HPs) in Portugal. Methods: A cross-sectional pilot study was conducted among 311 HPs using an online questionnaire; participants were recruited through convenience and snowball sampling. The instrument evaluated perceptions, practices, and knowledge (22 items; score 0–22). Descriptive statistics and non-parametric tests were used for group comparisons. Results: Most participants (90.6%) recognised the clinical relevance of herb–drug interactions; however, only 57.6% reported routinely asking patients about food supplements or herbal product use, and 46.0% about teas or infusions. The median knowledge score was 9.00 (interquartile range 9.00), with a mean of 9.34 ± 5.91. Significant differences were observed between professions (p < 0.001): pharmacists achieved the highest scores and nurses the lowest. In exploratory analyses, academic training and continuing education were associated with higher knowledge, whereas professional experience was not. Conclusions: Among the professionals studied, a discrepancy exists between perceived clinical relevance and actual practice, with important gaps in technical knowledge. Within the limits of this sample, the findings point to a need for improved education and structured clinical approaches to enhance patient safety when medicines and natural products are used concomitantly. Full article

Defined natural products are often framed as intrinsically safer multi-target alternatives to selective drugs, but this assumption is not pharmacologically justified. This critical review evaluates product-specific adjunctive evidence in respiratory allergy, inflammatory bowel disease, type 2 diabetes, depression, and insomnia. MEDLINE/PubMed records published from 2020 to 23 June 2026 were prioritized, while earlier pivotal randomized trials and quantitative safety studies were retained. Evidence was gated by product identity, human exposure, exposure-compatible target engagement, incremental efficacy, and safety boundaries. Nigella sativa oil improved Asthma Control Test scores by 1.5 points over placebo after 4 weeks, although the clinical importance is uncertain and FEV1 was not significantly improved. Curcumin plus mesalamine induced remission in mild-to-moderate ulcerative colitis (53.8% versus 0%), whereas indigo naturalis produced strong response rates but is constrained by pulmonary arterial hypertension. Berberine improves glycemic surrogates but lacks cardiovascular or renal outcome evidence and shows commercial potency variability. Saffron has a short-term antidepressant signal, while St John’s wort combines extract-dependent efficacy with CYP3A4/P-glycoprotein induction. Overall, selected defined natural products may merit narrow adjunctive roles, but undefined mixtures should not be treated as mechanistically established interventions without batch-level characterization, human pharmacokinetics, objective endpoints, and prospective interaction surveillance. Full article

Obesity is an increasingly important and modifiable driver of chronic kidney disease (CKD), with effects that extend well beyond its associations with type 2 diabetes, hypertension, and dyslipidemia. To synthesize the evidence that excess adiposity is a causal and modifiable determinant of kidney disease, and to examine how specific adipose depots injure the glomerulus and the tubulointerstitium, and then map these mechanisms onto established and emerging therapies. Throughout, obesity-related kidney disease (ORKD) denotes the full spectrum of diposity-driven renal injury, whereas obesity-related glomerulopathy (ORG) is reserved for the biopsy-defined glomerular lesion. Central, visceral, perirenal and renal-sinus adiposity act first through structural and haemodynamic mechanisms, promoting glomerular hyperfiltration, mechanical renal compression and activation of the adipose-derived renin–angiotensin–aldosterone system (RAAS). In parallel, these depots drive cellular and metabolic injury through lipotoxicity, adipokine imbalance, sterile inflammation, oxidative stress, gut dysbiosis, mitochondrial dysfunction, epigenetic remodelling and cellular senescence. Ectopic lipid accumulation within the renal parenchyma—fatty kidney—offers a unifying description of these changes and is most marked in type 2 diabetes mellitus. These interacting processes converge on podocyte stress, tubular metabolic failure, endothelial dysfunction and interstitial fibrosis, producing a phenotypic continuum that ranges from early albuminuria to obesity-related glomerulopathy and progressive CKD. Within the RAAS limb we highlight two comparatively underappreciated, adiposity-linked routes to injury: adipocyte-derived leptin directly upregulates adrenal aldosterone synthase (CYP11B2), and mast-cell chymase generates angiotensin II independently of angiotensin-converting enzyme, together reinforcing aldosterone- and angiotensin II–mediated damage that conventional RAAS blockade only partially interrupts. We further consider the counter-regulatory ghrelin–leptin axis, in which the suppression of ghrelin that accompanies obesity may withdraw an antioxidant, anti-inflammatory and podocyte-protective signal precisely as leptin-driven glomerular injury intensifies, positioning ghrelin as a plausible modulator and candidate biomarker of obesity-related kidney injury. We also examine how obesity complicates renal risk assessment, drug dosing, dialysis delivery and transplant access. Emerging, mechanism-matched therapies—SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, structured lifestyle intervention, metabolic-bariatric surgery and, most recently, aldosterone synthase inhibitors that suppress the chymase- and leptin-driven aldosterone escaping receptor blockade—now enable a precision cardiovascular-kidney-metabolic framework that aligns adipose-depot biology, biomarkers, histology and treatment response to guide mechanism-based care in ORKD. Full article

Bruton tyrosine kinase inhibitors have transformed the management of chronic lymphocytic leukemia and other B-cell malignancies, but their clinical use is increasingly influenced by cardiovascular safety. In contemporary practice, patients receiving these therapies are typically older and characterized by a high burden of comorbidities, including cardiovascular disease, metabolic disorders, and renal impairment. In this setting, cardiovascular complications should not be interpreted as isolated adverse events, but rather as clinical expressions of underlying patient vulnerability and frailty. Atrial fibrillation and arterial hypertension represent the most frequent complications, while heart failure, ventricular arrhythmias, and bleeding, although less common, may carry significant prognostic implications. Importantly, these events often arise from the interaction between drug exposure and pre-existing comorbidities, and may lead to treatment interruption, dose reduction, or discontinuation, ultimately compromising the long-term benefit of otherwise highly effective therapies. This review provides a comprehensive overview of the clinical burden, mechanisms, and management of cardiovascular complications associated with these agents, and proposes a practical, patient-centered framework to guide clinical decision-making. A structured approach based on risk assessment, early detection, and proactive management is essential to prevent complications, optimize treatment continuity, and preserve the long-term benefit of therapy in a complex and vulnerable population. Full article

Neuroprotection in childhood developmental and epileptic encephalopathies may require approaches, distinct from adult brain injury models of neuroprotection, with a primary focus on preservation of synaptic density rather than prevention of cellular necrosis. There is growing evidence to indicate early-life seizures activate complement cascade proteins C1q and C3. Subsequently, localized microglia may excessively phagocytose structurally intact synaptic neurons disrupting normal brain maturation. This review incorporates kinetic models of neuro-immune interactions based on human histopathology from epileptogenic tissues and quantitative neuro-immune biomarkers to provide suggestions that complement-mediated synaptic pruning may contribute to structural network disruption and cognitive decline in pediatric epilepsy. While standard anti-seizure medications effectively stabilize electrical activity, they do not mitigate underlying neuro-inflammatory responses. Consequently, targeted pharmacological inhibition of the complement microglia axis may provide a potential disease modifying strategy to protect developing neural circuits. The translational feasibility of using targeted complement inhibitors should be evaluated addressing critical challenges such as central nervous system drug delivery across the blood–brain barrier, immunosuppression management and the application of non-invasive biomarkers to define the precise therapeutic window for intervention. Full article

Hydrophobins are small, cysteine-rich amphipathic proteins predominantly produced by filamentous fungi, known for their ability to self-assemble at hydrophobic–hydrophilic interfaces. These proteins are essential for fungal development, surface interactions, pathogenicity, and environmental adaptation, and they have attracted growing interest for biotechnological applications. In this work, we provide a narrative review of fungal hydrophobins, based on a systematic literature search and manual curation of eligible studies integrated with protein database records from Ascomycota and Basidiomycota. Information was compiled from peer-reviewed publications selected according to predefined eligibility criteria and complemented with UniProt records, covering taxonomic distribution, functional and biophysical properties, and physiological and pathogenic roles. Significant diversity in molecular features and physicochemical profiles was observed, indicating functional specialization across different ecological niches and lifestyles. Additionally, the compiled data highlight various biotechnological applications, such as surface modification, enzyme immobilization, drug delivery systems, biomaterial development, and environmentally sustainable technologies. By consolidating molecular, functional, and applied information across a wide range of fungal species, this review provides a comprehensive reference framework for hydrophobin research and biotechnological innovation. Full article

Background/Objectives: Antimicrobial resistance among ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens has become a major global health threat, significantly reducing the effectiveness of conventional antibiotics. Plant-derived compounds have emerged as promising antibiotic adjuvants capable of restoring antibiotic activity through multiple resistance-modulating mechanisms. This review aims to critically evaluate the current evidence regarding phytochemicals that enhance antibiotic efficacy against drug-resistant ESKAPE pathogens. Methods: Relevant studies investigating plant-derived compounds with antibiotic adjuvant activity against ESKAPE pathogens were identified and critically analyzed. Particular attention was given to mechanisms of action, synergistic interactions with conventional antibiotics, structure–activity relationships, and translational evidence from in vivo studies. Results: Numerous phytochemicals have demonstrated the ability to potentiate antibiotic activity through efflux pump inhibition, biofilm disruption, membrane permeabilization, and quorum sensing interference. For instance, the flavonoid quercetin inhibits the NorA efflux pump in Staphylococcus aureus, restoring ciprofloxacin susceptibility, while the sulfur-containing compound ajoene from garlic disrupts quorum sensing in Pseudomonas aeruginosa, sensitizing biofilms to tobramycin. Although several compounds exhibit promising synergistic effects in vitro, significant barriers remain regarding bioavailability, standardization, pharmacokinetics, and clinical translation. Conclusions: Plant-derived antibiotic adjuvants represent a promising strategy to combat multidrug-resistant ESKAPE pathogens. However, greater emphasis on translational research, standardized methodologies, and clinically relevant experimental models is required to facilitate their development toward therapeutic applications. Full article