Search Results (432)

Paediatric Focal Segmental Glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome and progressive kidney failure in children. Early subclassification into primary, secondary, genetic, or undetermined forms is crucial for guiding appropriate management. Primary FSGS typically necessitates immunosuppressive therapy, whereas secondary FSGS benefits from supportive measures and treatment of the underlying cause. Emerging treatments—including SGLT2 inhibitors, endothelin receptor antagonists, and APOL1-targeted agents—show promise in reducing proteinuria and preserving kidney function. Insights into podocyte biology, including TRPC channel dysregulation and fibrotic signalling pathways, are opening new therapeutic avenues. As research continues to evolve, the future of paediatric FSGS management lies in individualised, pathophysiology-driven therapies that may significantly improve clinical outcomes. Full article

Background/Objectives: Infections after stroke are a serious medical problem and have a significant impact on the outcome of stroke, but data regarding the Asian population are limited. This study aims to determine the bacterial and fungal profile of pathogenic organisms of infections after acute ischemic stroke (AIS). Methods: This is a retrospective study using the medical records of patients at least 18 years old who were hospitalized with AIS in a tertiary stroke hospital from 1 January 2018 to 31 December 2022. Demographic, patient-related, and other examination data were extracted from hospital medical records. Infections after AIS were defined as any infection that developed during the acute phase of ischemic stroke and was confirmed by microbiologic culture as the gold standard. Factors associated with infection were analyzed using multiple logistic regression. Results: Among 599 AIS patients with infection who underwent microbiologic culture, the prevalence of infection with an isolated pathogen was 21.4%, and most organisms were from sputum. Positive microbiologic culture revealed that bacteria such as K. pneumoniae, E. coli, A. baumannii, and S. aureus were the most common causes of infection, while fungi were rare. During the COVID-19 period, bacteria developed resistance to antimicrobials, including β-lactamase antibiotics for Gram-negative bacteria and methicillin for Gram-positive bacteria. Care in the intensive ward, including the stroke unit, reduced the risk of a positive microbiological culture in the COVID-19 and non-COVID-19 period. Urinary catheters promoted infections in the non-COVID-19 period, whereas steroids, total parenteral nutrition, and tracheostomy were negatively associated with infections after AIS in the COVID-19 period. Conclusions: The prevalence and factors associated with infection after stroke changed during the COVID-19 period. The risk of infection after stroke requires preventive measures such as early dysphagia screening. Full article

Background: Small airway dysfunction (SAD) plays a critical role in the management of severe asthma, particularly in patients at risk of requiring biological therapies (BTs). Short-term studies have shown that switching to single-inhaler triple therapy (SITT) with extrafine beclomethasone–formoterol–glycopyrronium improves outcomes and helps achieve quiet asthma, a state marked by symptom control, no exacerbations or oral steroids, reduced inflammation, and better small airway function. This study investigated whether, over one year, patients could maintain this state as Steady Quiet Asthma (SQA) and whether baseline measures could predict this sustained response. Methods: Twenty-six patients with severe asthma and SAD were transitioned from open triple-inhaler therapy to a closed, single-inhaler triple therapy containing extrafine beclomethasone–formoterol–glycopyrronium. Assessments at baseline (T0) and at one-year follow-up (T12) included clinical evaluations, spirometry, and impulse oscillometry, with a focus on Fres as a predictor for the need for BT. When prescribed, biologic therapies included mepolizumab, benralizumab, and dupilumab. Results: Of the 26 patients, 9 (34.6%) achieved SQA and did not require biologic therapy at the one-year follow-up, while 17 patients (65.4%) initiated biologic treatment. At T0, patients who required biologics had significantly higher median Fres (21 (19.47; 24.58) vs. 17.61 (15.82; 20.63); p = 0.049) compared to those who remained biologic-free. They also exhibited higher residual volume to total lung capacity ratio (%RV/TLC) values and lower forced expiratory volume in one second/forced vital capacity ratios (FEV₁/FVC). At T12, patients spared from BT showed significant reductions in Fres (p = 0.014) and improvements in small airway function (difference in airway resistance between 5 Hz and 20 Hz (R5–20), forced expiratory flow between 25% and 75% of FVC (%FEF25–75), and better asthma control (ACT). In contrast, patients on BT demonstrated less favorable changes in these parameters. Conclusions: Baseline Fres, FEV1/FVC ratio, and %FEV25–75 are valuable predictors of achieving Steady Quiet Asthma (SQA) and sparing biologic therapy. These findings support the use of SITT in severe asthma and highlight the importance of early functional assessments to guide personalized management. Full article

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

Glioblastoma (GBM) is a highly aggressive and heterogeneous brain tumor. Glioma stem-like cells (GSCs) play a central role in tumor progression, therapeutic resistance, and recurrence. Although immune cells are known to shape the GBM microenvironment, the impact of antigen-presenting-cell (APC) signature genes on tumor-intrinsic phenotypes remains underexplored. We analyzed both bulk- and single-cell RNA sequencing datasets of GBM to investigate the association between APC gene expression and tumor-cell states, including stemness and metabolic reprogramming. Signature scores were computed using curated gene sets related to APC activity, KEGG metabolic pathways, and cancer hallmark pathways. Protein–protein interaction (PPI) networks were constructed to examine the links between immune regulators and metabolic programs. The high expression of APC-related genes, such as HLA-DRA, CD74, CD80, CD86, and CIITA, was associated with lower stemness signatures and enhanced inflammatory signaling. These APC-high states (mean difference = –0.43, adjusted p < 0.001) also showed a shift in metabolic activity, with decreased oxidative phosphorylation and increased lipid and steroid metabolism. This pattern suggests coordinated changes in immune activity and metabolic status. Furthermore, TNF-α and other inflammatory markers were more highly expressed in the less stem-like tumor cells, indicating a possible role of inflammation in promoting differentiation. Our findings revealed that elevated APC gene signatures are associated with more differentiated and metabolically specialized GBM cell states. These transcriptional features may also reflect greater immunogenicity and inflammation sensitivity. The APC metabolic signature may serve as a useful biomarker to identify GBM subpopulations with reduced stemness and increased immune engagement, offering potential therapeutic implications. Full article

Salmonella colonization in the gastrointestinal tract of turkeys presents a risk to the safety of products derived from them. Lactobacillus-based probiotics and a plant-derived compound, trans-cinnamaldehyde, have previously been found to be effective in reducing multidrug-resistant Salmonella enterica subsp. enterica serovar Heidelberg (S. Heidelberg) in turkey poults. However, the effect of the challenge and the application of the treatments on the cecal metabolome has yet to be elucidated. Thus, the objective of the present study was to characterize alterations in the metabolic profiles of cecal contents collected from poults following S. Heidelberg challenge and treatment with Lactobacillus salivarius UMNPBX2 and L. ingluviei UMNPBX19 (LB), trans-cinnamaldehyde (TC), or a combination of both (CO) using untargeted gas chromatography–mass spectrometry (GC-MS). Poults in the challenged control (PC) group had the most distinct and convergent metabolome profiles, with the most pronounced disparity observed compared to the unchallenged control (NC), indicating the effect of the S. Heidelberg challenge. Perturbations in metabolites in the primary bile acid biosynthesis, pentose and glucuronate interconversions, and steroid biosynthesis were the most prominent. The greater abundance of metabolites, such as primary bile acids and sugars, in the PC group may be associated with S. Heidelberg colonization or potential shifts in microbiota. The treatments yielded varying effects on the metabolome profiles, with the TC and CO groups exhibiting the closest similarity, although TC was more similar to NC. The findings revealed alterations to ceca-associated metabolites, which are likely a response to the S. Heidelberg challenge and the application of the TC and LB treatments. Additional studies are needed to validate the possible causal relationship between the observed shifts. Gaining insight into the alterations to the metabolic microenvironment in the avian cecum will help elucidate the mechanisms by which they facilitate Salmonella persistence. Understanding these relationships can aid in designing more effective pre-harvest Salmonella control strategies and enhancing the efficacy of interventions within the flock. Full article

Background/Objectives: This study aimed to assess the frequency, risk factors, and clinical implications of cytomegalovirus (CMV) colitis in patients undergoing colectomy due to refractory ulcerative colitis (UC). Methods: A retrospective analysis was conducted on patients with drug-resistant UC who underwent colectomy at a tertiary referral center between 2009 and 2017. Histological inflammatory activity in surgical specimens was assessed using the Simplified Geboes Score. The presence and density of CMV expression were estimated immunohistochemically. Preoperative clinical, biochemical, and endoscopic data, as well as the short- and long-term postoperative disease courses, were evaluated in relation to the presence of CMV colitis at the time of surgery. Results: CMV colitis was identified in 14% (7/49) of patients. The CMV-positive group exhibited significantly shorter disease durations and higher C-reactive protein concentrations at the time of surgery. This subgroup also demonstrated consistently numerically higher steroid use, both in terms of the usage frequency and cumulative treatment duration. Patients with concomitant CMV colitis had lower likelihoods of stoma closure and restoration of gastrointestinal continuity in the long-term. Conclusions: Concomitant CMV colitis is not uncommon in patients with treatment-refractory UC. Testing for CMV should be considered, particularly in individuals with a short-term, dynamic, and aggressive disease course unresponsive to standard therapy, especially steroids. Full article

Plant-growth-promoting fungi (PGPF) play a central role in promoting sustainable agriculture by improving plant growth and resilience. The aim of this literature review is to survey the impacts of Trichoderma spp. and Penicillium spp. on various agricultural and horticultural plants. The information provided in this manuscript was obtained from randomized control experiments, review articles, and analytical studies and observations gathered from numerous literature sources such as Scopus, Google Scholar, PubMed, and Science Direct. The keywords used were the common and Latin names of various agricultural and horticultural species, fungal endophytes, plant-growth-promoting fungi, Trichoderma, Penicillium, microbial biostimulants, and biotic and abiotic stresses. Endophytic fungi refer to fungi that live in plant tissues throughout part of or the entire life cycle by starting a mutually beneficial symbiotic relationship with its host without any negative effects. They are also capable of producing compounds and a variety of bioactive components such as terpenoids, steroids, flavonoids, alkaloids, and phenolic components. Penicillium is extensively known for its production of secondary metabolites, its impact as a bioinoculant to help with crop productivity, and its effectiveness in sustainable crop production. The plant-growth-promotion effects of Trichoderma spp. are related to better absorption of mineral nutrients, enhanced morphological growth, better reproductive potential and yield, and better induction of disease resistance. Both Penicillium spp. and Trichoderma spp. are effective, affordable, safe, and eco-friendly biocontrol agents for various plant species, and they can be considered economically important microorganisms for both agricultural and horticultural sciences. The present review article aims to present the most up-to-date results and findings regarding the practical applications of two important types of PGPF, namely Penicillium spp., and Trichoderma spp., in agricultural and horticultural species, considering the mechanisms of actions of these species of fungi. Full article

Persister cells are a subset of bacterial cells that exhibit transient antibiotic tolerance without genetic resistance, contributing to the persistence of chronic infections. This study investigates the ability of diosgenin, a naturally occurring steroidal saponin, to inhibit persister cell formation in Staphylococcus aureus through metabolic suppression and membrane modulation. Diosgenin treatments at 80 µM and 160 µM significantly reduced persister cell survival under oxacillin, ciprofloxacin, and gentamicin stress, with reductions ranging from 82% to 94% after 3 h diosgenin pre-exposure. Gene expression analysis revealed that diosgenin downregulated relP and relQ, key genes involved in (p)ppGpp synthesis, by up to 60%, accompanied by 36–38% decreases in intracellular ATP levels. Diosgenin did not significantly alter membrane permeability or membrane potential but reduced membrane fluidity by 35% and 41% at 80 µM and 160 µM, respectively. Taken together, our findings suggest that diosgenin exerts a dual-action regulatory effect on persister cell formation by disrupting metabolic pathways essential for dormancy and altering membrane dynamics, potentially affecting membrane-associated signaling. This study provides a framework for the further exploration of diosgenin as a potential anti-persister agent with particular promise for use in combination with conventional antibiotics to enhance therapeutic efficacy against chronic bacterial infections. Full article

Thyroid eye disease (TED) is a complex autoimmune disorder characterized by orbital inflammation and tissue remodeling. Teprotumumab, a fully human monoclonal antibody targeting insulin-like growth factor-1 receptor (IGF-1R), represents a significant breakthrough in TED treatment. This review comprehensively analyzes the therapeutic role of teprotumumab in TED management. Mechanistically, teprotumumab inhibits the IGF-1R/TSHR signaling complex, thereby reducing orbital fibroblast differentiation and inflammatory responses. Phase II and III clinical trials have demonstrated its remarkable efficacy in reducing proptosis and improving clinical activity scores, with the benefits extending to both active and chronic TED cases. Real-world studies have validated these findings further and expanded its potential applications to various clinical scenarios, including dysthyroid optic neuropathy and steroid-resistant cases. However, several challenges remain. These include treatment-related adverse effects such as hyperglycemia and hearing impairment, with emerging evidence suggesting ethnic variations in susceptibility. The high cost of treatment poses significant accessibility barriers, while limited long-term follow-up data and potential disease recurrence necessitate further investigation. This review synthesizes the current evidence to inform clinical decision-making and highlights areas requiring additional research to optimize teprotumumab’s therapeutic application in TED management. Full article

Sitosterol (Sito) is a phytosterol with bioactive properties, including reducing atherosclerosis risk and anti-inflammatory and antitumoral effects. However, it can be oxidized by reactive oxygen species such as ozone (O₃), producing oxyphytosterols with harmful effects such as cytotoxicity, oxidative stress, and proatherogenicity. Ozone, a strong oxidant and common pollutant, can alter plant steroid compounds, raising concerns about dietary oxyphytosterol intake. Studies identify β-Secosterol (βSec) as the primary ozone-derived oxyphytosterol from Sito, exhibiting cytotoxic effects on HepG2 human liver tumor cells. This study investigated βSec’s biological effects on two rat liver cell lines: BRL-3A (immortalized) and HTC (tumoral), examining cell death, cell cycle progression, morphology, and cytoskeleton organization. While Sito influenced cell metabolic activity without affecting cell survival or morphology, βSec demonstrated significant cytotoxicity in both cell lines. It induced G0/G1 cell cycle arrest and disrupted cytoskeleton organization, with different implications: BRL-3A cells showed persistent cytoskeletal changes potentially linked to tumor induction, while HTC cells displayed chemoresistance, restoring cytoskeletal integrity and enhancing metastatic potential. These findings reveal βSec’s complex, context-dependent effects, suggesting it may promote tumor-like behavior in non-tumoral cells and resistance mechanisms in cancer cells, contributing to understanding oxyphytosterols’ implications for physiological and pathological conditions. Full article

Background and Clinical Significance: Non-small-cell lung cancer (NSCLC) with EGFR mutations, particularly de novo compound mutations such as exon 19 deletions (Ex19del) with T790M substitutions, present a significant clinical challenge due to resistance to many treatments. While treating these patients, the administration of osimertinib, a third-generation EGFR inhibitor, after immunotherapy can lead to unique immune-related adverse events (irAEs), such as pneumonitis and, rarely, hepatitis. Case Presentation: A 36-year-old Filipino woman presented with metastatic NSCLC harboring de novo Ex19del and T790M mutations. Despite initial therapy with carboplatin and paclitaxel, followed by chemoimmunotherapy, the patient’s disease progressed. She subsequently developed severe hepatitis from osimertinib after her prior immunotherapy with pembrolizumab. After the hepatitis resolved with high-dose steroids, osimertinib was switched to afatinib, but her disease rapidly progressed with new metastases. A second attempt at osimertinib rechallenge, with concomitant prednisone, resulted in substantial disease control, including improved leptomeningeal disease (LMD) and no recurrence of hepatitis. Conclusions: This case underscores the feasibility of rechallenging with osimertinib in patients who experience adverse events such as hepatotoxicity, provided that appropriate management strategies, such as steroid therapy, are employed. The successful rechallenge in this case highlights the potential of osimertinib as a viable option in advanced EGFR-mutant NSCLC, even after prior treatment-related complications. Full article

Skeletal muscle, traditionally recognized for its motor function, has emerged as a key endocrine organ involved in metabolic regulation and interorgan communication. This narrative review addresses the dual role of muscle as a target tissue for classical hormones—such as growth hormone (GH), insulin-like growth factor type 1 (IGF-1), thyroid hormones, and sex steroids—and as a source of myokines, bioactive peptides released in response to muscle contraction that exert autocrine, paracrine, and endocrine effects. Several relevant myokines are discussed, such as irisin and Metrnl-like myokines (Metrnl), which mediate exercise-associated metabolic benefits, including improved insulin sensitivity, induction of thermogenesis in adipose tissue, and immunometabolic modulations. It also examines how muscle endocrine dysfunction, caused by chronic inflammation, hormone resistance, or sedentary lifestyle, contributes to the development and progression of metabolic diseases such as obesity, type 2 diabetes, and sarcopenia, highlighting the importance of muscle mass in the prognosis of these pathologies. Finally, the therapeutic potential of interventions aimed at preserving or enhancing muscle function—through physical exercise, hormone therapy and anabolic agents—is highlighted, together with the growing research on myokines as biomarkers and pharmacological targets. This review expands the understanding of muscle in endocrinology, proposing an integrative approach that recognizes its central role in metabolic health and its potential to innovate the clinical management of endocrine–metabolic diseases. Full article

Emerging evidence highlights the profound and lasting impact of severe illnesses such as COVID-19, particularly among individuals with underlying comorbidities. Patients with pre-existing conditions like diabetes mellitus (DM) are disproportionately affected, facing heightened risks of both disease exacerbation and the onset of new complications. Notably, the convergence of advanced age and DM has been consistently associated with poor COVID-19 outcomes. However, the long-term metabolic consequences of SARS-CoV-2 infection, especially its role in disrupting glucose homeostasis and potentially triggering or worsening DM, remain incompletely understood. This review synthesizes current clinical and experimental findings to clarify the bidirectional relationship between COVID-19 and diabetes. We critically examine literature reporting deterioration of glycemic control, onset of hyperglycemia in previously non-diabetic individuals, and worsening of metabolic parameters in diabetic patients after infection. Furthermore, we explore proposed mechanistic pathways, including pancreatic β-cell dysfunction, systemic inflammation, and immune-mediated damage, that may underpin the development or progression of DM in the post-COVID setting. Collectively, this work underscores the urgent need for continued research and clinical vigilance in managing metabolic health in COVID-19 survivors. Full article