Search Results (872)

Acetaminophen (APAP) overdose is a major cause of acute liver failure and can be fatal, often without early symptoms. Protein deficiency, arising from illness or inadequate diet, impairs growth, immunity, and tissue repair. Both conditions can harm the kidneys, yet the impact of energy imbalance on renal physiology remains unclear. In this study, APAP toxicity and a low-protein diet induced behavioral suppression and tissue damage, as evidenced by reduced whole-body, liver, and kidney weights in rats. In kidney mitochondria of rats exposed to only toxic APAP doses, ATP levels declined sharply while ADP and AMP increased. AMP deaminase and ATPases’ activities rose about twofold and 1.5-fold, respectively, whereas cytosolic 5′-nucleotidase activity fell nearly threefold, suggesting compensatory responses to disrupted energy balance. The strongest reductions in ATP and the greatest increases in AMP and ATPase activity occurred in APAP-intoxicated rats fed a low-protein diet. This combination also intensified lipid peroxidation and oxidative protein damage, evidenced by elevated TBARS, reduced protein SH-groups, and increased protein carbonyls. Overall, APAP intoxication with protein deficiency disrupts renal energy metabolism, leading to mitochondrial dysfunction and structural kidney injury. Nutritional status therefore critically influences drug-induced nephrotoxicity, and antioxidant strategies may help prevent damage under metabolic stress. Full article

During the COVID-19 pandemic, the prevalence of death in men was higher than in women. Using transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2), we demonstrated that SARS-CoV-2 infects Leydig cells and uses its steroidogenic machinery for replication. This study investigates the impact of SARS-CoV-2 in the seminiferous epithelium of K18-hACE2 mice, focusing on the immune response, junctional proteins, and spermatogenesis. The seminiferous tubules (STs) and epithelial (EA) areas were measured. The number of SCs, spermatocytes, and damaged ST was quantified. Ultrastructural analysis was performed under transmission electron microscopy. Angiotensin II levels and immunolocalization of hACE2, spike, and nucleocapsid were evaluated. TUNEL and immunoreactions for Ki-67, TNF-α, INF-γ, iNOS, NF-κB, and Conexin-43 were performed and correlated with Jam-α, Stat1, Stat3, and iNOS expressions. hACE2, spike, and nucleocapsid immunolabeling were detected in the epithelium along with high angiotensin II levels in the infected mice. The infection caused a significant reduction in ST, EA, spermatocytes, SCs, Ki-67+ cells, Cx43 immunoexpression, and Jam-a expression. In the epithelium, TNF-α, IFN-γ, iNOS, and nuclear NF-κB immunolabeling increased along with Stat1 upregulation. These findings, combined with the increased epithelial hACE2 and high angiotensin II levels, confirm epithelial responsiveness to the infection and explain the spermatogenic failure and impaired junctional proteins. The presence of viral particles, increased TNF-α immunolabeling, and apoptotic features in Sertoli cells suggests that these sustentacular cells are targets for viral infection in the epithelium, and, due to their extensive projections and ability to phagocytize dying infected germ cells, they may disseminate the viruses throughout the epithelium. Full article

Background/Objectives: Metabolic syndrome (MetS) conditions lead to structural and functional alterations in cardiomyocytes, microvasculature, and extracellular matrix (ECM), leading to myocardial fibrosis and impaired diastolic function. Cardiac lymphatic vessels (LVs) are increasingly recognized as key regulators of myocardial homeostasis, yet their response to MetS remains poorly understood. Therefore, we aimed to investigate transcriptional changes in cardiac lymphatic endothelial cells (LECs) in db/db mice, a well-established model of MetS. Methods: Using flow cytometry-sorted LECs and RT-PCR, we analyzed mRNA expression of genes involved in lymphangiogenesis, metabolism, mechanotransduction, immune cell trafficking, and ECM interactions. Results: Our findings show the transcriptional plasticity of cardiac LECs in response to MetS. Conclusions: Although our study is limited by the lack of protein-level validation and functional assays, our approach provides a broader interpretative framework and identifies potential directions for future research, including functional studies and pathway-specific investigations of the identified genes to assess their impact on lymphatic flow and cardiac function. Understanding LEC responses to metabolic stress may uncover novel therapeutic targets for heart failure associated with MetS. Full article

Sarcoidosis is an immune-mediated granulomatous disease whose etiology has remained unresolved despite more than a century of investigation. Accumulating microbiological and immunopathological evidence now implicates Cutibacterium acnes—a ubiquitous indigenous commensal—as the most consistent antigenic trigger. Its frequent detection within sarcoid granulomas by quantitative PCR, in situ hybridization, and species-specific immunohistochemistry suggests latent intracellular persistence and the potential for endogenous reactivation. To explain how a noncontagious commensal can drive granulomatous inflammation, this review proposes the concept of Endogenous Hypersensitivity Infection (EHI). EHI describes a host-centered process in which reactivation of latent intracellular microbes leads to the breakdown of immune tolerance and provokes Th1-dominant hypersensitivity responses in genetically and immunologically susceptible individuals. This framework bridges the traditional divide between infection and autoimmunity, reframing sarcoidosis as a disorder of disrupted host–commensal homeostasis rather than a classical infectious or autoimmune disease. By integrating microbiological, immunological, and pathological evidence, this review synthesizes the mechanistic basis of EHI and outlines how tolerance failure to C. acnes can account for the paradoxical clinical behavior of sarcoidosis. The EHI paradigm further provides a unifying conceptual lens through which related chronic inflammatory disorders—including Crohn’s disease, chronic rhinosinusitis, and atopic dermatitis—may be reinterpreted. Full article

Cardiac fibrosis is a major component of heart failure (HF) and develops when reparative wound healing becomes chronic, leading to excessive extracellular matrix accumulation. Cardiac fibroblasts (CFs), the main regulators of matrix remodeling, are heterogeneous in developmental origins, regional localizations, and activation states. This diversity determines whether tissue repair resolves normally or progresses into maladaptive scarring that disrupts myocardial structure and function after injuries. Recent single-cell and spatial transcriptomic studies show that CFs exist in distinct yet interrelated molecular states in murine models and human cardiac tissue with specialized roles in matrix production, angiogenesis, immune signaling, and mechanical sensing. These insights redefine cardiac fibrosis as a dynamic and context-dependent process rather than a uniform cellular response. Although CFs are promising targets for preventing HF progression and enhancing cardiac remodeling, translation into effective therapies remains limited by the unclear heterogeneity of pathological fibroblasts, the lack of distinctive CF markers, and the broad activity of fibrogenic signaling pathways. In this review, we discuss the dynamics of CF activations during the development and progression of HF and assess the underlying pathways and mechanisms contributing to cardiac dysfunction. Additionally, we highlight the potential of targeting CFs for developing therapeutic strategies. These include nonspecific suppression of fibroblast activity and targeted modulation of the signaling pathways and cell populations that sustain chronic remodeling. Furthermore, we assess regenerative approaches that can reprogram fibroblasts or modulate their paracrine functions to restore functional myocardium. Integrating antifibrotic and regenerative strategies with advances in precision drug discovery and gene delivery offers a path toward reversing established fibrosis and achieving recovery in HF. Full article

Background: Diabetes mellitus (DM) is a condition that may increase the severity of acute pancreatitis (AP) through chronic inflammation and disturbances in immune responses. However, the independent effect of DM on clinical outcomes in AP has not yet been fully elucidated. Methods: In this retrospective cohort study, 492 patients diagnosed with acute pancreatitis at the Gastroenterology Clinic of Ankara Bilkent City Hospital between January 2022 and March 2025 were included. Patients were divided into two groups based on the presence of diabetes, and outcomes were compared using statistical methods. Results: Of the total 492 patients (mean age 58.6 ± 17.2 years; 50.2% female) included, 98 (19.9%) had DM. Moderate-to-severe AP occurred in 67.3% of diabetic versus 37.8% of non-diabetic patients (p < 0.0001), and severe disease developed more frequently in the diabetic group (6.1% vs. 1.0%, p = 0.0057). Systemic complications were significantly more common in patients with diabetes (45.9% vs. 26.9%, p = 0.0004). Hospital mortality was higher among patients with diabetes (9.2% vs. 4.6%, p = 0.0344), and Kaplan–Meier analysis demonstrated numerically lower overall survival in patients with diabetes (log-rank p = 0.095), with early divergence in survival curves. Cox proportional hazards analysis confirmed diabetes as an independent predictor of in-hospital mortality (adjusted HR 2.64, 95% CI 1.17–5.97; p = 0.019). After adjustment for confounders, diabetes remained independently associated with the development of moderate/severe pancreatitis (adjusted OR 2.00, 95% CI 1.24–3.22; p = 0.004). Diabetes also independently predicted in-hospital mortality (adjusted OR 3.36, 95% CI 1.35–8.34; p = 0.009), along with APACHE II score. ROC analysis demonstrated that adding diabetes mellitus to the APACHE II score significantly improved mortality prediction compared with APACHE II alone (AUC 0.785 vs. 0.724). The retrospective and single-center design of this study may limit its generalizability and create potential selection bias. There were insufficient data on the type of diabetes, its duration, and glycemic control (e.g., HbA1c), and therefore, we could not assess these factors, all of which may influence risk estimates. Although the survival curves showed early divergence, the borderline log-rank significance (p = 0.095) highlights the limited statistical power to detect long-term survival differences in this cohort. Conclusions: DM is associated with substantially increased severity and in-hospital mortality in AP, primarily through an elevated risk of systemic organ failure. Incorporation of diabetes status into early severity stratification may improve prognostic accuracy and guide closer monitoring and timely interventions in this high-risk population. Full article

Oral squamous cell carcinoma (OSCC) remains a highly prevalent and aggressive malignancy with limited improvements in survival rates. One of the major obstacles to successful treatment is the development of chemoresistance, which contributes to recurrence, metastasis, and treatment failure. This narrative review aims to integrate current evidence on the molecular and cellular mechanisms that drive chemoresistance in OSCC and to delineate how these processes converge under therapeutic pressure. A structured search was performed to identify relevant studies addressing chemoresistance in OSCC, focusing on preclinical and translational evidence. Multiple interconnected mechanisms have been implicated in driving resistance in OSCC, including epigenetic alterations, deregulated signaling pathways, cancer stem cell plasticity, epithelial–mesenchymal transition (EMT), interactions with the tumor microenvironment (TME), drug efflux mediated by ATP-binding cassette (ABC) transporters, and enhanced DNA damage response. In combination, these mechanisms support tumor persistence and limit effective antitumor immunity. Emerging strategies such as epigenetic modulators, signaling pathway inhibitors, immunomodulation, and nanomedicine-based delivery systems have shown promising results in preclinical models. By highlighting convergent resistance networks, this integrative perspective supports the rational design of combination therapies and biomarker-guided strategies aimed at overcoming chemoresistance in OSCC. Full article

Patients with inflammatory bowel disease (IBD) frequently fail to achieve protective immunity after hepatitis B vaccination, even with intensified vaccination schedules. In this observational real-world study, 18 patients with IBD who were seronegative for hepatitis B virus (HBV) received three standard doses of the Engerix-B^® vaccine (at 0, 1, and 6 months). After immunisation, patients were classified into responders and non-responders according to their serological response. Blood samples were collected before the first dose and after completion of the vaccination schedule. Responders activated pathways that supported durable protection, including conventional dendritic cells type 1 mobilisation, expansion of IgG plasmablasts, and preservation of B- and T-cell memory. In contrast, non-responders displayed a more inflammatory innate profile, characterised by enrichment of CCR2⁺ monocytes. They also showed higher baseline Treg frequencies, which may suppress effective effector responses, together with impaired natural killer (NK) activation and progressive loss of memory potential. This study shows that hepatitis B vaccine failure in inflammatory bowel disease reflects a convergence of excessive immune regulation, inflammatory activation, and loss of memory potential, underscoring that no single pathway can explain the impaired response. Full article

Although there have been advancements in stroke treatment (reperfusion) therapy, and it has been shown that many individuals continue to suffer from partial recoveries and continuing decline in their neurological status as a result of suffering a stroke, a primary barrier to providing precise care to patients with stroke continues to be the inability to capture changes in molecular and cellular programs over time and in biological compartments. This review synthesizes evidence that represents the entire continuum of ischemia, beginning with acute metabolic failure and excitotoxicity, and ending with immune response in the nervous system, reprogramming of glial cells, remodeling of vessels, and plasticity at the level of networks, and organizes this evidence in a temporal framework that includes three biological compartments:central nervous system tissue, cerebrospinal fluid, and peripheral blood. Additionally, this review discusses new technologies which enable researchers to discover biomarkers at an extremely high resolution, including single-cell and spatial multi-omics, profiling of extracellular vesicles, proteoform-resolved proteomics, and glymphatic imaging, as well as new computational methods and machine-learning algorithms to integrate data from multiple modalities and predict trajectories of disease progression. The final section of this review will provide an overview of translationally relevant and ethically relevant issues regarding the deployment of predictive biomarkers, such as privacy, access, equity, and fairness, and emphasize the importance of global coordination of research efforts in order to ensure the clinical applicability and global equity of biomarker-based diagnostics and treatments. Full article

Hepatocellular carcinoma (HCC) ranks among the top causes of cancer-related mortality worldwide, and its complex tumor microenvironment (TME) contributes to poor responses to immunotherapy. Although PD-1/PD-L1 blockade has emerged as an effective treatment strategy, therapeutic resistance frequently limits its clinical benefit. Here, we uncover a distinct macrophage population associated with anti-PD-1 resistance in HCC. Single-cell transcriptomic profiling reveals an NFKBIZ⁺ M0 macrophage subset predominantly present in non-responders. Notably, these macrophages exhibit a hypoxia-induced phenotype characterized by the secretion of VEGFA and HBEGF, which cooperatively enhance tumor angiogenesis, alongside an elevated expression of the inflammatory chemokines CXCL2, CXCL3, and CXCL8 that consolidate an immunosuppressive, pro-tumorigenic microenvironment. Transcriptional regulatory network analysis further identified FOSB–VEGFA and FOS–HBEGF axes as key drivers of this pathogenic macrophage phenotype. Our findings define a distinct NFKBIZ⁺ macrophage population that mechanistically links hypoxia, angiogenesis, and immune evasion to PD-1 blockade resistance. This work provides new insights into the cellular and molecular basis of immunotherapy failure in HCC and highlights potential targets for overcoming treatment resistance. Full article

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways. Full article

The global incidence of multidrug-resistant (MDR) ESKAPE pathogens—comprising Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—has surged alarmingly in recent years, posing a significant challenge to healthcare systems worldwide. These organisms are notorious for their capacity to evade the effects of multiple classes of antibiotics, leading to treatment failures, increased morbidity and mortality, and escalating healthcare costs, all of which have placed unprecedented strain on existing infection control measures. This review encapsulates the progress in target-driven vaccine research, including the genomic discovery of highly conserved surface antigens, iron acquisition systems, biofilm- and quorum-sensing-related proteins, and computationally predicted epitopes, which are considered the most attractive targets for broad-spectrum vaccination. Novel vaccine platforms, such as outer membrane vesicles (OMVs), mRNA technologies, and multi-epitope constructs, will rapidly drive the translation of these targets into next-generation vaccine formulations. Nevertheless, challenges such as antigenic variation and immune evasion, as well as the need for a robust mucosal and cross-protective immune response, persist. The sustainability in interdisciplinary investigations are required, along with adjunctive measures and investment in the development of advanced discovery and delivery systems, to achieve the ultimate goal of successful vaccines against MDR ESKAPE infections and to mitigate the worldwide burden of antimicrobial resistance. Full article

Background: Heart failure (HF) remains a major global health challenge, with orthotopic heart transplantation (OHT) serving as the gold-standard therapy for end-stage disease. Chronic immunosuppression required to prevent graft rejection increases the risk of infections and malignancies. The COVID-19 pandemic underscored the particular vulnerability of transplant recipients to severe SARS-CoV-2 infection. Specific immunosuppressive agents used in OHT patients may differentially affect SARS-CoV-2 infection. In particular, mTOR inhibitors may modulate viral replication and immune responses, potentially influencing disease severity. Objectives: This study evaluated the impact of immunosuppressive regimens—particularly mTOR inhibitors—on COVID-19 outcomes in heart transplant recipients, comparing mTOR-based therapy (with or without calcineurin inhibitors, CNIs) to non-mTOR-based regimens. Methods: This single-center retrospective observational study included 556 orthotopic heart transplant recipients (76.3% male; median age, 58 years) followed from March 2020 to March 2024. To compare patients receiving mTOR inhibitors with similar non-mTOR recipients, 3:1 propensity score matching was performed based on age, sex, and body mass index. Among the study population, 88 patients (15.8%) received mTOR inhibitors (everolimus or sirolimus), of whom 66 were concomitantly treated with calcineurin inhibitors and 22 without. Data were obtained from the National Health Fund database and clinical follow-ups. Results: Overall mortality was 13.5%, and COVID-19-related mortality 3.2%. COVID-19 incidence was 33% in the mTOR group versus 36.7% in the non-mTOR group (p = 0.52). Hospitalization rates were 3.4% and 6.4% (p = 0.29), respectively. All-cause mortality was higher among mTOR users (21.6% vs. 11.7%, p = 0.02), especially in the mTOR+CNI subgroup. Notably, no COVID-19-related deaths occurred in the mTOR CNI-free group. Conclusions: mTOR-based immunosuppression was non-inferior to standard therapy for COVID-19 outcomes. The absence of COVID-19-related deaths in patients on mTOR CNI-free regimens suggests potential protective effects that merit further investigation. Full article

Background/Objectives: We conducted an untargeted metabolomic study in serum, urine, and fecal water in colorectal cancer (CRC) patients compared to healthy controls. The aim was to define the interactions between metabolites and microbiota. Methods: Effluents were collected before colonoscopy. Metabolites were analyzed using LC-HRMS. Bioinformatics analyses included Limma test, along with spectral house and public databases for annotations. Whole-genome shotgun sequencing was performed on fecal samples. Species–metabolite interactions were calculated using Spearman correlation. Interleukins and inflammatory proteins were measured. Results: Fifty-three patients (11 stage I, 10 stage II, 10 stage III, and 22 stage IV) and twenty controls were included. Derivatives of deoxycholic acid, cholic acid, and fatty acids were lower in serum, while urinary bile acids were higher in stage IV CRC patients (versus controls). Metabolites related to tryptophan and glutamate were found significantly altered in stage IV: upregulation of kynurenine and downregulation of indole pathways. This was linked to increased inflammatory protein and microbial metabolites and to the imbalance between virulent pro-inflammatory bacteria (Escherichia and Desulfovibrio) and symbiotic (Ruminococcus and Bifidobacterium) bacteria. Conclusions: E. coli-related tryptophan catabolism shift is shown through stage IV CRC as compared to controls. As a consequence, tryptophan/kynurenine metabolite may become a promising marker for detecting the failure to immune response during therapy. Full article

Background: Immunocompromised patients, particularly those with humoral immune deficiencies or receiving B-cell-targeted therapies, are at increased risk of persistent SARS-CoV-2 infection, a condition often underrecognized and lacking standardized treatment. Methods: We present a case series of patients with persistent SARS-CoV-2 infection and underlying humoral immunodeficiency, treated at the General University Hospital “Attikon” from February 2023 to September 2024. Persistent infection was defined by prolonged symptoms, compatible imaging findings, and RT-PCR positivity beyond 21 days. All patients received combination antiviral therapy with remdesivir and nirmatrelvir/ritonavir, and intravenous immunoglobulin (IVIG), using a structured diagnostic and therapeutic algorithm. Results: Eleven patients (55% male), median age 56 [IQR 50–66] years, were included. Seven (64%) had hematologic malignancy, 10 (91%) received anti-CD20 therapy, and 6 (55%) had both. Median symptom duration before diagnosis was 63 [58–135] days. Ten (91%) experienced recurrent symptoms; one (9%) had progressive symptoms with severe respiratory failure requiring high-flow nasal cannula. Persistent infection was confirmed via bronchoscopy with bronchoalveolar lavage in 6 patients (55%). Prior to diagnosis, 5 patients (45%) required one hospitalization, 1 (9%) was hospitalized twice, and 2 (18%) had more than two hospitalizations. Following combination therapy, 10 (91%) achieved complete response at 180-day follow-up. Conclusions: The proposed diagnostic and therapeutic algorithm combining remdesivir, nirmatrelvir/ritonavir, and IVIG enhanced diagnostic value and therapeutic outcomes in this high-risk population. Full article