Search Results (43,306)

Cardiac inflammation and hypertrophy develop as a pathologic response to an array of insults, such as myocardial infarctions, chronic systemic hypertension, and valvular defects. Due to the high prevalence of such conditions, there is an increasing need to prevent and halt cardiac hypertrophy. Because cardiac damage and subsequent remodeling can lead to arrhythmias, heart failure, and even sudden cardiac death, inhibition of cardiac hypertrophy is key to reducing cardiovascular-related mortality. The immune system is the driving force behind inflammatory reactions. All three pathways of complement system activation—classical, lectin, and alternative—are implicated in developing cardiac damage, inflammation, and hypertrophy due to infectious and non-infectious causes, autoimmune diseases, genetic polymorphisms, and forms of complement dysregulation. Of interest in this review is the role of the complement system, a collection of soluble and membrane-bound proteins that mediate inflammatory processes through interactions with signaling molecules and immune cells. This review comprehensively discusses the roles of these complement pathways in contagious, chronic inflammatory, genetic, and metabolic diseases. An overview of the completed and terminated clinical trials aimed at preventing cardiovascular mortality by targeting various aspects of the complement system and inflammatory reaction is included. Most current treatments for cardiac inflammation and remodeling primarily target the renin–angiotensin–aldosterone system (RAAS), which prevents further remodeling by reducing myocardial workload. However, moving forward, there may be a place for emerging anti-complement therapeutics, which impair the inflammatory response that generates hypertrophy itself. Full article

Background: Cardiovascular disease (CVD) is the leading global cause of death and is shaped by interacting biological, environmental, lifestyle, and social factors. Traditional models often treat risk factors in isolation and may miss dependencies among exposures and biomarkers. Objective: To map interdependencies among environmental, social, behavioral, and biological predictors of CVD risk using Bayesian network models. Methods: A cross-sectional analysis was conducted using NHANES 2017–2018 data. After complete-case procedures, the analytic sample included 601 adults and 22 variables: outcomes (systolic/diastolic blood pressure, total/LDL/HDL cholesterol, triglycerides) and predictors (BMI, C-reactive protein (CRP), allostatic load, Dietary Inflammatory Index, income, education, age, gender, race, smoking, alcohol, and serum lead, cadmium, mercury, and PFOA). Spearman’s correlations summarized pairwise associations. Bayesian networks were learned with two approaches: Grow–Shrink (constraint-based) and Hill-Climbing (score-based, Bayesian Gaussian equivalent score). Network size metrics included number of nodes, directed edges, average neighborhood size, and Markov blanket size. Results: Correlation screening reproduced expected patterns, including very high systolic–diastolic concordance (p ≈ 1.00), strong LDL–total cholesterol correlation (p = 0.90), inverse HDL–triglycerides association, and positive BMI–CRP association. The final Hill-Climbing network contained 22 nodes and 44 directed edges, with an average neighborhood size of ~4 and an average Markov blanket size of ~6.1, indicating multiple indirect dependencies. Across both learning algorithms, BMI, CRP, and allostatic load emerged as central nodes. Environmental toxicants (lead, cadmium, mercury, PFOS, PFOA) showed connections to sociodemographic variables (income, education, race) and to inflammatory and lipid markers, suggesting patterned exposure linked to socioeconomic position. Diet and stress measures were positioned upstream of blood pressure and triglycerides in the score-based model, consistent with stress-inflammation–metabolic pathways. Agreement across algorithms on key hubs (BMI, CRP, allostatic load) supported network robustness for central structures. Conclusions: Bayesian network modeling identified interconnected pathways linking obesity, systemic inflammation, chronic stress, and environmental toxicant burden with cardiovascular risk indicators. Findings are consistent with the view that biological dysregulation is linked with CVD and environmental or social stresses. Full article

Hypertension affects over 1.39 billion people globally, causing 9.4 million deaths annually. This paper examines the intricate relationship between the immune system and hypertension, highlighting the contributions of both innate and adaptive immune responses. The innate response, involving natural killer (NK) cells, macrophages, toll-like receptors (TLRs), and dendritic cells, contributes to organ damage and inflammatory responses, exacerbating hypertension. Adaptive immunity, particularly T cells, further exacerbates vascular and renal dysfunction through the release of cytokines such as IFN-γ, IL-17A, and TNF-α, ultimately leading to multisystem damage. Therapeutic strategies targeting these immune responses are being explored, including immunosuppressants such as mycophenolate mofetil (MMF) and methotrexate (MTX), as well as monoclonal antibodies against IL-1β and TNF-α. While these strategies show promise, further research is needed to evaluate their efficacy and safety. Furthermore, this paper highlights the potential benefits of immunological approaches in managing the root causes of hypertension, offering an alternative to conventional therapies focused on the renin–angiotensin–aldosterone system. In conclusion, this work highlights the immune mechanisms in the hypertension pathogenesis, identifying them as potential therapeutic targets for enhanced management and improved patient outcomes. Full article

Pine wilt disease, transmitted primarily by Monochamus alternatus (Hope, 1842) adults, causes severe ecological and economic losses globally. Conventional chemical controls face challenges of resistance and non-target toxicity. This study identified Beauveria bassiana (Bals.-Criv.) Vuill. strain B4 as a high-virulence biocontrol agent against adult M. alternatus. Laboratory bioassays compared four strains (B1–B4), with B4 exhibiting rapid lethality (LT₅₀ = 6.61 days at 1 × 10⁸ spores/mL) and low median lethal concentration (LC₅₀ = 9.63 × 10⁵ spores/mL). Critically, B4 infection induced significant behavioral suppression, including reduced appetite and mobility prior to death. In forest trials, pheromone-enhanced nonwoven fabric bags impregnated with B4 spores reduced trap catches by 66.4% within one month, with effects persisting for over a year without reapplication. The slow-release carrier system enabled continuous spore dissemination and sustained population suppression. These results demonstrate that B4’s dual action—rapid lethality and behavioral disruption—provides an effective, eco-friendly strategy for sustainable pine wilt disease management. Full article

Nocardiosis is an infection caused by Gram-positive, saprophytic bacteria most often affecting immunocompromised hosts. The lungs, central nervous system, and skin are the sites most typically involved, although any organ may be affected. Skeletal involvement, particularly osteomyelitis, remains uncommon. This study is a review of all published cases of Nocardia osteomyelitis in humans, emphasizing epidemiology, microbiology, clinical features, management, and patient outcomes. A narrative review was performed using data from the PubMed/MedLine and Scopus databases. Fifty studies describing 55 patients were included. The median age was 54 years, and 65.5% were male. The main risk factors were immunosuppression (21.8%) and trauma (18.2%). The vertebrae constituted the most commonly affected site (25.5%), followed by the lower limb bones (20%); 23.6% had multifocal disease. Nocardia asteroides accounted for the majority of cases (34.8%). Trimethoprim-sulfamethoxazole was the most frequently administered agent (81.5%), followed by cephalosporins (29.6%) and carbapenems (27.8%). Overall mortality was 9.3%, with 5.6% of reported deaths directly attributed to the infection. Although uncommon, osteomyelitis due to Nocardia spp. should be considered when Gram-positive, filamentous microorganisms are detected in bone specimens, particularly in immunocompromised or post-trauma patients, as early suspicion and targeted therapy may improve survival. Full article

Type 2 diabetes is a major global health burden, causing approximately 2 million deaths annually. Recent studies have revealed a strong positive correlation between elevated triglyceride levels and plasma glucose, as well as increased prevalence, incidence, and mortality of type 2 diabetes, suggesting a potential causal link. This review explores the metabolic interconversion between triglycerides and glucose, emphasizing how excess carbohydrate intake leads to ectopic triglyceride accumulation, which in turn enhances hepatic gluconeogenesis. It highlights key signaling pathways through which ectopic triglyceride deposition drives insulin resistance, hyperinsulinemia, β-cell dysfunction and apoptosis, and increased glucose production—central mechanisms in diabetes pathogenesis. Evidence from clinical interventions, such as the reversal of type 2 diabetes through bariatric surgery and dietary energy restriction, supports the hypothesis that ectopic triglyceride accumulation is a driving factor. Furthermore, this review explains why omega-3 fatty acids and niacin, in contrast to fibrates, do not protect against type 2 diabetes, despite lowering triglycerides. Overall, this review emphasizes the contribution of ectopic triglyceride accumulation—driven by obesity, hypertriglyceridemia, excessive consumption of carbohydrates and fats, and physical inactivity—to the onset and progression of type 2 diabetes, offering valuable insights into potential therapeutic strategies. Full article

We investigate the quantum dynamics of entanglement and fidelity in the hyperfine structure of hydrogen atoms under dephasing noise, modeled via the Lindblad master equation. The effective Hamiltonian captures the spin–spin interaction between the electron and proton, with dephasing incorporated through local Lindblad operators. Analytical solutions for the time-dependent density matrix are derived for various initial states, including separable, partially entangled, and maximally entangled configurations. Entanglement is quantified using the concurrence, while fidelity measures the similarity between the evolving state and the initial state. Numerical results demonstrate that entanglement exhibits oscillatory decay modulated by the dephasing rate, with anti-parallel spin states displaying greater robustness compared to parallel configurations, often leading to entanglement sudden death. Fidelity dynamics reveal similar damped oscillations, underscoring the interplay between coherent hyperfine evolution and environmental dephasing. These insights elucidate strategies for preserving quantum correlations in atomic systems, with implications for quantum information processing and metrology. Full article

Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, has emerged as a promising therapeutic target in breast cancer, particularly in aggressive subtypes such as triple-negative breast cancer (TNBC). This systematic review explores the molecular mechanisms underlying ferroptosis sensitivity and resistance, focusing on the interplay between iron metabolism, antioxidant defenses, and tumor microenvironmental factors. Literature retrieved from PubMed and Scopus up to May was analyzed in accordance with PRISMA guidelines, including mechanistic studies, preclinical experiments, and ongoing clinical trials. Findings reveal that breast cancer cells evade ferroptosis through enhanced glutathione synthesis, upregulation of GPX4 and system Xc- and adaptive metabolic reprogramming; yet these same mechanisms create exploitable vulnerabilities, including dependence on cystine, polyunsaturated lipids, and dysregulated iron handling. Therapeutic strategies that target key ferroptosis regulators, such as GPX4, ACSL4, and SLC7A11, or that harness agents like statins, sulfasalazine, and nanoparticle-based iron complexes demonstrate strong potential to overcome chemoresistance and selectively eliminate therapy-resistant cancer cell populations. Taken together, the evidence highlights ferroptosis as a critical Achilles’ heel of breast cancer biology and supports further clinical translation of ferroptosis-inducing therapies to improve outcomes in otherwise refractory breast cancer subtypes. Full article

Background: Critically ill patients in the intensive care unit (ICU) are characterized by complex comorbidities and a high risk of short-term mortality. Traditional severity scoring systems rely on physiological and laboratory variables but lack direct integration of electrocardiogram (ECG) data. This study aimed to construct an interpretable machine learning (ML) model combining ECG-derived and clinical variables to predict 28-day mortality in ICU patients. Methods: A retrospective cohort analysis was performed with data from the MIMIC-IV v2.2 database. The primary outcome was 28-day mortality. An ECG-based risk score was generated from the first ECG after ICU admission using a deep residual convolutional neural network. Feature selection was guided by XGBoost importance ranking, SHapley Additive exPlanations, and clinical relevance. A three-variable model comprising ECG score, APS-III score, and age (termed the E3A score) was developed and evaluated across four ML algorithms. We evaluated model performance by calculating the AUC of ROC curves, examining calibration, and applying decision curve analysis. Results: A total of 18,256 ICU patients were included, with 2412 deaths within 28 days. The ECG score was significantly higher in non-survivors than in survivors (median [IQR]: 24.4 [15.6–33.4] vs. 13.5 [7.2–22.1], p < 0.001). Logistic regression demonstrated the best discrimination for the E3A score, achieving an AUC of 0.806 (95% CI: 0.784–0.826) for the test set and 0.804 (95% CI: 0.772–0.835) for the validation set. Conclusions: Integrating ECG-derived features with clinical variables improves prognostic accuracy for 28-day mortality prediction in ICU patients, supporting early risk stratification in critical care. Full article

Severe acute respiratory syndrome (SARS), caused by the COVID-19 virus, continues to pose a significant public health challenge in Brazil, particularly in 2024, with high mortality rates among vulnerable groups. This study aimed to describe the sociodemographic, clinical and vaccination profiles of SARS cases due to COVID-19 in Brazil in 2024, as well as analysing factors associated with clinical outcomes such as death, admission to the intensive care unit (ICU) and the need for ventilatory support. A total of 30,529 reported cases were analysed. On average, the interval between the last vaccine dose and symptom onset was 30.31 months (SD = 6.77), while the interval between symptom onset and clinical outcome was 13.26 days (SD = 16.55), revealing significant variability. The results showed higher mortality rates among men (23.7%) than women (19.1%) (p < 0.0001). Mortality increased progressively with age, reaching 24.4% in individuals aged 60 years or older, whereas rates were below 2% in children under 10 years of age. The highest proportions of deaths were observed regionally in the Northeast (26.8%) and North (22.6%), in contrast to the Midwest (17.7%) (p < 0.0001). Men were also more likely to require ICU admission (38.1% vs. 33.6%) and ventilation (62.9% vs. 60.5%). A time interval of over 24 months since the last vaccine dose was associated with higher mortality (21.9% vs. 20.6%; p = 0.0005). These results highlight the importance of ongoing surveillance and updating the vaccination schedule, particularly for more vulnerable populations. Full article

Selenoprotein thioredoxin reductase 1 (TXNRD1) is frequently upregulated in various cancer cells to sustain cellular redox homeostasis, and its inhibition has emerged as a promising anti-cancer strategy. In this study, we identified PK11007, a thiol-modifying compound previously characterized as a p53 reactivator, as a potent inhibitor of TXNRD1. PK11007 irreversibly inhibited recombinant TXNRD1 in a time- and dose-dependent manner. Using differential scanning fluorimetry (DSF) and LC–MS/MS analysis, we confirmed that PK11007 covalently modifies the C-terminal redox motif (Cys⁴⁹⁷-Sec⁴⁹⁸) of TXNRD1. In non-small cell lung cancer (NSCLC) H1299 cells, PK11007-induced TXNRD1 inhibition disrupted cellular redox balance, leading to impaired autophagy flux and cell death. Similar autophagy suppression was observed in TXNRD1-knockdown cells, as well as pharmacological inhibition of TXNRD1 by Auranofin (AF) and TXNRD1 inhibitor 1 (TRi-1). Taken together, these findings highlight that oxidative stress contributes to the cytotoxic effects of PK11007 and uncover autophagy disorder as a downstream consequence of TXNRD1 inhibition. Full article

Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with dysfunction, with or without a structural substrate. They are frequently genetically determined. The dysfunction may be mechanical, both of the systole and diastole, or electrical, including arrhythmias or conduction disorders. Originally, only dilated, hypertrophic, restrictive–obliterative and arrhythmogenic dysfunctions were considered cardiomyopathies. Nowadays, since dysfunction can also be electric, disorders affected by electrical dysfunction without a structural substrate can be regarded as cardiomyopathies as well. This is the case of channellopathies and ryanodine receptors. This paper is a review of the history of cardiomyopathies, including the issues of their classification and nomination, genetic background and gene therapy. Full article

Immunotherapy and RAF-targeted therapy have become standard treatments for melanoma, significantly improving outcomes compared to earlier therapies. When resistance to initial treatment develops, the older chemotherapy drug Dacarbazine is used. However, resistance to both therapies has emerged, promoting ongoing research to further enhance survival rates. Among various theories, autophagy is believed to play a critical role in acquired drug resistance, as increased autophagy has been observed in resistance to multiple anticancer agents. In this study, Dabrafenib was administered to melanoma cells with an RAF mutation, while Dacarbazine was given to cells with an Raf wild type. Both cell lines showed increased autophagy and FAO following treatment with the anticancer drugs. When FAO was blocked during drug treatment, melanoma cells became more susceptible to cell death. In xenograft models, B16F10 melanoma (Raf wild type) demonstrated regrowth due to acquired resistance after two weeks of Dacarbazine treatment. Conversely, a combination of Dacarbazine and the FAO inhibitors KN510 and KN713 (a combination of KN510 and KN713:KN510713) caused near-complete remission without regrowth. A375 melanoma (BRAF^V600E) developed resistance after four weeks of Dabrafenib treatment, yet the combination of Dabrafenib and KN510713 resulted in near-complete remission with no signs of regrowth. Based on these findings, combining FAO inhibitors with first-line therapies may be a promising approach for managing melanoma, regardless of RAF mutation status. Full article

Background/Objectives: Oxidative stress is the major cause of retinal pigment epithelial cell death. We used oxidative stress-injured retinal pigment epithelial cells to investigate the protective effects of curcumin, a strong antioxidant, on the Nod-like receptor protein 3 (NLRP3) inflammasome pathway. Methods: To evaluate the effect of curcumin, cell viability was measured with cell counting kit-8 and lactate dehydrogenase assays. Hydrogen peroxide (H₂O₂)-injured ARPE-19 cells were treated with different curcumin concentrations. We performed a wound healing assay and dichlorodihydrofluorescein diacetate staining. Western blotting and immunofluorescence staining were performed to evaluate the changes in inflammasome levels in the ARPE-19 cells. Result: H₂O₂ (300 μM) reduced the viability of ARPE-19 cells. However, treatment with 7.5 μM curcumin enhanced ARPE-19 cell viability and reduced cell toxicity. Curcumin also reduced reactive oxygen species (ROS) levels in the H₂O₂-induced damaged ARPE-19 cells and attenuated the H₂O₂-dependent levels of the NLRP3 inflammasome and its related signaling proteins. Conclusions: Curcumin demonstrated protective effects against oxidative stress in retinal pigment epithelial cells by attenuating the activation of the NLRP3 inflammasome pathway. These findings suggest the therapeutic potential of curcumin as an anti-inflammatory and antioxidant agent for macular degeneration. Full article

Background: Acute lung injury (ALI) is a life-threatening respiratory condition and one of the leading causes of mortality worldwide, accounting for approximately 20% of global annual deaths. Despite its high prevalence and severity, effective therapeutic options remain limited. Eupatorium lindleyanum DC., a traditional medicinal herb, has demonstrated therapeutic potential against pulmonary diseases, particularly ALI, in both clinical and experimental settings. However, the protective effects and underlying mechanisms of its characteristic sesquiterpene lactone components against ALI remain unclear. Objective: This study aimed to evaluate the protective effects of sesquiterpene lactones from Eupatorium lindleyanum DC. (SLEL) against lipopolysaccharide (LPS)-induced ALI both in vivo and in vitro. Furthermore, it sought to elucidate the underlying mechanisms by integrating network pharmacology, multi-omics approaches (transcriptomics, metabolomics, and 16S rRNA sequencing), and various molecular biology techniques. Results: SLEL significantly attenuated inflammatory injury in alveolar epithelial cells and alleviated pulmonary edema, hemorrhage, and inflammatory infiltration in rats, accompanied by reduced TNF-α, IL-6, and IL-1β levels and improved lung injury indices. Mechanistically, SLEL exerted dual suppression of the PI3K-Akt and MAPK-NF-κB pathways. Network pharmacology, molecular docking, and UPLC-MS analyses identified Eupalinolide A and Eupalinolide K as potential bioactive constituents, which were further validated to inhibit phosphorylation of key signaling proteins, thereby partially accounting for SLEL’s pharmacological effects. Multi-omics integration further revealed that SLEL restored bile acid metabolism, reshaped gut microbial diversity, and reconstructed the microbiota–metabolite–inflammatory cytokine network, thereby maintaining gut–lung axis homeostasis and enhancing anti-inflammatory effects. Conclusions: SLEL alleviates ALI through multi-component synergistic actions that suppress pro-inflammatory signaling and modulate the gut–lung axis. These findings highlight the potential of SLEL as a promising therapeutic candidate for the treatment of ALI. Full article