Search Results (1,045)

People with cystic fibrosis may experience polypharmacy, which can increase the risk of drug induced complications such as adverse events and drug–drug interactions. This study aimed to examine the prevalence of adverse events and to identify potential drug–drug interactions associated with elexacaftor/tezacaftor/ivacaftor (ETI). Three databases, the Australian Therapeutic Goods Administration Database of Adverse Event Notification (TGA DAEN), the Canada Vigilance Adverse Reaction Online Database (CVAROD), and the USA Food and Drug Administration Adverse Event Reporting System (FAERS) Database were searched for spontaneous ETI adverse events between 2019 and 2024. Descriptive analysis of the data was undertaken. The FAERS database was analysed to identify adverse events of interest such as anxiety and depression and concomitant drugs prescribed with ETI. A total of 10,628 ETI associated adverse events were identified in all system organ classes. The incidence of psychiatric adverse events ranged from 7 to 15% across the three databases. Potential drug–drug interactions with CYP 3A4/5 strong inhibitors and strong inducers were identified from the FAERS database and azole antifungals were implicated in several ETI dose modifications. The prevalence and types of ETI adverse events were varied and use of concomitant drugs with potential drug interactions was significant, requiring more research to manage them. Full article

Introduction: Cystic fibrosis (CF) is a genetic condition affecting several organs and systems, including the pancreas, colon, respiratory system, and reproductive system. The detection of a growing number of CFTR variants and genotypes has contributed to an increase in the CF population which, in turn, has had an impact on the overall statistics regarding the prognosis and outcome of the condition. Given the increase in life expectancy, it is critical to better predict outcomes and prognosticate in CF. Thus, each person’s choice to aggressively treat specific disease components can be more appropriate and tailored, further increasing survival. The objective of our narrative review is to summarize the most recent information concerning the value and significance of clinical parameters in predicting outcomes, such as gender, diabetes, liver and pancreatic status, lung function, radiography, bacteriology, and blood and sputum biomarkers of inflammation and disease, and how variations in these parameters affect prognosis from the prenatal stage to maturity. Materials and methods: A methodological search of the available data was performed with regard to prognostic factors in the evolution of CF in children and young adults. We evaluated articles from the PubMed academic search engine using the following search terms: prognostic factors AND children AND cystic fibrosis OR mucoviscidosis. Results: We found that it is crucial to customize CF patients’ care based on their unique clinical and biological parameters, genetics, and related comorbidities. Conclusions: The predictive significance of more dynamic clinical condition markers provides more realistic future objectives to center treatment and targets for each patient. Over the past ten years, improvements in care, diagnostics, and treatment have impacted the prognosis for CF. Although genotyping offers a way to categorize CF to direct research and treatment, it is crucial to understand that a variety of other factors, such as epigenetics, genetic modifiers, environmental factors, and socioeconomic status, can affect CF outcomes. The long-term management of this complicated multisystem condition has been made easier for patients, their families, and physicians by earlier and more accurate identification techniques, evidence-based research, and centralized expert multidisciplinary care. Full article

Background: Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Full article

Background: Chronic Kidney Disease (CKD) is a major global health issue, with diabetes being its primary cause and cardiovascular disease contributing significantly to patient mortality. Recently, two classes of medications—sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)—have shown promise in protecting both kidney and heart health beyond their effects on blood sugar control. Methods: We conducted a narrative review summarizing the findings of different clinical trials and mechanistic studies evaluating the effect of SGLT2i and GLP-1 RAs on kidney function, cardiovascular outcomes, and overall disease progression in patients with CKD and DKD. Results: SGLT2i significantly mitigate kidney injury by restoring tubuloglomerular feedback, reducing intraglomerular hypertension, and attenuating inflammation, fibrosis, and oxidative stress. GLP-1 RAs complement these effects by enhancing endothelial function, promoting weight and blood pressure control, and exerting direct anti-inflammatory and anti-fibrotic actions on renal tissues. Landmark trials—CREDENCE, DAPA-CKD, and EMPA-KIDNEY—demonstrate that SGLT2i reduce the risk of kidney failure and renal or cardiovascular death by 25–40% in both diabetic and non-diabetic CKD populations. Likewise, trials such as LEADER, SUSTAIN, and AWARD-7 confirm that GLP-1 RAs slow renal function decline and improve cardiovascular outcomes. Early evidence suggests that using both drugs together may offer even greater benefits through multiple mechanisms. Conclusions: SGLT2i and GLP-1 RAs have redefined the therapeutic landscape of CKD by offering organ-protective benefits that extend beyond glycemic control. Whether used individually or in combination, these agents represent a paradigm shift toward integrated cardiorenal-metabolic care. A deeper understanding of their mechanisms and clinical utility in both diabetic and non-diabetic populations can inform evidence-based strategies to slow disease progression, reduce cardiovascular risk, and improve long-term patient outcomes in CKD. Full article

Euphorbia hirta L. is traditionally used to treat tumors and has demonstrated anticancer effects. This study evaluated the phytochemical composition, toxicity, and antitumor activity of saline extract (SE) from E. hirta leaves in mice. Phytochemical analysis included thin layer chromatography, high-performance liquid chromatography, and quantification of phenols, flavonoids, and proteins. Acute toxicity (2000 mg/kg) assessed mortality, hematological, biochemical, histological parameters, water/feed intake, and body weight. Genotoxicity was evaluated via comet and micronucleus assays. Antitumor activity was tested in vitro and in vivo on sarcoma 180. SE contained 107.3 mg GAE/g phenolics and 22.9 mg QE/g flavonoids; the presence of gallic and ellagic acids was detected. Protein concentration was 12.16 mg/mL with lectin activity present. No mortality, organ damage, or genotoxic effects occurred in toxicity tests. SE demonstrated in vitro cytotoxicity against sarcoma cells (IC₅₀: 10 µg/mL). In vivo, SE (50–200 mg/kg) reduced tumor weight by 70.2–72.3%. SE modulated IL-2, IL-4, IL-6, IL-17, IFN-γ, and TNF-α in tumor environment. Tumors showed inflammatory infiltrate, necrosis, and fibrosis after treatment. These findings position the extract as a promising candidate for further development as a safe, plant-based antitumor agent. Full article

Background and Objectives: Coronavirus Disease 2019 (COVID-19) may cause extensive multi-organ pathology, particularly in the lungs, heart, kidneys, and liver. While hypercoagulability—often signaled by elevated D-dimer—has been thoroughly investigated, the concurrent pathological findings across organs and their interrelation with distinct D-dimer levels remain incompletely characterized. This study aimed to evaluate the pathological changes observed in autopsied or deceased COVID-19 patients, focusing on the prevalence of organ-specific lesions, and to perform subgroup analyses based on three D-dimer categories. Methods: We conducted a retrospective review of 69 COVID-19 patients from a Romanian-language dataset, translating all clinical and pathological descriptions into English. Pathological findings (pulmonary microthrombi, bronchopneumonia, myocardial fibrosis, hepatic steatosis, and renal tubular necrosis) were cataloged. Patients were grouped into three categories by admission D-dimer: <500 ng/mL, 500–2000 ng/mL, and ≥2000 ng/mL. Laboratory parameters (C-reactive protein, fibrinogen, and erythrocyte sedimentation rate) and clinical outcomes (intensive care unit [ICU] admission, mechanical ventilation, and mortality) were also recorded. Intergroup comparisons were performed with chi-square tests for categorical data and one-way ANOVA or the Kruskal–Wallis test for continuous data. Results: Marked organ pathology was significantly more frequent in the highest D-dimer group (≥2000 ng/mL). Pulmonary microthrombi and bronchopneumonia increased stepwise across ascending D-dimer strata (p < 0.05). Myocardial and renal lesions similarly showed higher prevalence in patients with elevated D-dimer. Correlation analysis revealed that severe lung and heart pathologies were strongly associated with high inflammatory markers and a greater risk of ICU admission and mortality. Conclusions: Our findings underscore that COVID-19-related organ damage is magnified in patients with significantly elevated D-dimer. By integrating pathology reports with clinical and laboratory data, we highlight the prognostic role of hypercoagulability and systemic inflammation in the pathogenesis of multi-organ complications. Stratifying patients by D-dimer may inform more tailored management strategies, particularly in those at highest risk of severe pathology and adverse clinical outcomes. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF. Full article

Fibrotic disorders pose a significant global health burden due to limited treatment options, creating an urgent need for novel therapeutic strategies. Amphiregulin (AREG), a low-affinity ligand for the epidermal growth factor receptor (EGFR), has emerged as a key mediator of fibrogenesis through dual signaling pathways. Unlike high-affinity EGFR ligands, AREG induces sustained signaling that activates downstream effectors and promotes the integrin-mediated activation of transforming growth factor (TGF)-β. This enables both canonical and non-canonical EGFR signaling pathways that contribute to fibrosis. Elevated AREG expression correlates with disease severity across multiple organs, including the lungs, kidneys, liver, and heart. The therapeutic targeting of AREG has shown promising antifibrotic and anticancer effects, suggesting a dual-benefit strategy. The increasing recognition of the shared mechanisms between fibrosis and cancer further supports the development of unified treatment approaches. The inhibition of AREG has been shown to sensitize fibrotic tumor microenvironments to chemotherapy, enhancing combination therapy efficacy. Targeted therapies, such as Self-Assembled-Micelle inhibitory RNA (SAMiRNA)-AREG, have demonstrated enhanced specificity and favorable safety profiles in preclinical studies and early clinical trials. Personalized treatment based on AREG expression may improve clinical outcomes, establishing AREG as a promising precision medicine target for both fibrotic and malignant diseases. This review aims to provide a comprehensive understanding of AREG biology and evaluate its therapeutic potential in fibrosis and cancer. Full article

Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets. Full article

Objective: This study aimed to investigate the cardioprotective effects of bosentan, an endothelin receptor antagonist, in a rat model of lung ischemia–reperfusion (I/R) injury, with a focus on myocardial tissue involvement. Methods: Twenty-four male Wistar rats were randomly assigned to four groups: sham, bosentan, I/R, and I/R + bosentan. Lung I/R injury was induced by hilar clamping for 45 min, followed by 60 min of reperfusion. Bosentan (30 mg/kg) was administered intraperitoneally 30 min prior to the procedure. Myocardial tissue was evaluated histopathologically for structural disorganization, inflammation, fibrosis, and edema. TGF-β1 protein levels in myocardial tissue were compared across the groups using β-actin as the loading control. ELISA was used to quantify ET-1, NF-κB, and p53 levels, while spectrophotometric analysis was employed to assess MDA levels and the activities of SOD and CAT enzymes in heart tissue. Results: The I/R group exhibited significant myocardial disorganization, inflammation, and interstitial edema compared to the sham and bosentan groups. Bosentan treatment markedly ameliorated these histopathological alterations. Additionally, the I/R group showed elevated levels of ET-1, NF-κB, p53, and MDA, along with reduced SOD and CAT activities; these changes were significantly attenuated by bosentan administration. Bosentan treatment significantly reduced myocardial ET-1 levels (from 136.88 ± 5.02 to 120.18 ± 2.67 nmol/g, p = 0.003), NF-κB levels (from 0.87 ± 0.04 to 0.51 ± 0.03 ng/mg, p = 0.002), and TGF-β1 expression (from 1.72 ± 0.10 to 0.91 ± 0.08 relative units, p = 0.001). Moreover, bosentan increased antioxidant enzyme activities, elevating SOD levels from 21.45 ± 1.23 to 32.67 ± 1.45 U/mg protein (p = 0.001) and CAT levels from 15.22 ± 0.98 to 25.36 ± 1.12 U/mg protein (p = 0.002). Conclusions: Bosentan exerts cardioprotective effects in rats subjected to lung I/R injury by reducing myocardial damage, inflammation, and oxidative stress. These findings suggest that bosentan may serve as a potential therapeutic agent for preventing remote organ injury associated with pulmonary I/R. Full article

Background/Objective: Pulmonary fungal infections are a significant diagnostic challenge, primarily affecting immunocompromised individuals, such as those with HIV, cancer, or organ transplants, and they often lead to substantial morbidity and mortality if untreated. These infections trigger acute inflammatory and immune responses, which may progress to chronic inflammation. This process involves myofibroblast recruitment, the deposition of extracellular matrix, and vascular remodeling, ultimately contributing to pulmonary hypertension. Despite its clinical relevance, pulmonary hypertension secondary to fungal infections remains under-recognized in practice and poorly studied in research. Results/Conclusion: This narrative mini-review explores three key mechanisms underlying vascular remodeling in this context: (1) endothelial injury caused by fungal emboli or autoimmune reactions, (2) direct vascular remodeling during chronic infection driven by inflammation and fibrosis, and (3) distant vascular remodeling post-infection, as seen in granulomatous diseases like paracoccidioidomycosis. Further research and clinical screening for pulmonary hypertension in fungal infections are crucial to improving patient outcomes. Full article

The treatment of type 1 diabetes through pancreatic islet transplantation faces significant limitations, including donor organ shortages and poor islet survival due to post-transplantation loss of extracellular matrix support and inadequate vascularization. Developing biocompatible scaffolds that mimic the native islet microenvironment could substantially improve transplantation outcomes. This study aimed to create and evaluate decellularized (DCL) matrices from porcine organs as potential platforms for islet transplantation. Porcine lung and pancreatic tissues were decellularized using four different protocols combining detergents (Triton X-100, SDS and SDC) with optimized incubation times. The resulting matrices were characterized through DNA quantification and histological staining (H&E and Van Gieson). Islet viability was assessed in vitro using Live/Dead staining after 3 and 7 days of culture on the matrices. In vivo biocompatibility was evaluated by implanting matrices into rat omentum or peritoneum, with histological analysis at 1-, 4-, and 8 weeks post-transplantation. Protocols 3 (for lung tissue) and 4 (for pancreas tissue) demonstrated optimal decellularization efficiency with residual DNA levels below 8%, while preserving the collagen and elastin networks. In vitro, islets cultured on decellularized lung matrix had maintained 95% viability by day 7, significantly higher than the controls (60%) and pancreatic matrix (83%). The omentum showed superior performance as an implantation site, exhibiting minimal inflammation and fibrosis compared to the peritoneum sites throughout the 8-week study period. These findings establish DCL as a promising scaffold for islet transplantation due to its superior preservation of ECM components and excellent support of islet viability. This work provides a significant step toward developing effective tissue-engineered therapies for diabetes treatment. Full article

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder primarily affecting adults. The disease in pediatric age is unusual and preferentially affects adolescents. In contrast to adults, who commonly exhibit the involvement of multiple organs simultaneously or sequentially over time, young patients tend to present with a localized disease, typically affecting the orbits. Proptosis, ptosis, diplopia, and restricted eye movement may be observed in these patients. Symptoms are proteiform, and the disease is chronic and indolent with a relapsing–remitting course. Diagnostic criteria have been developed for adults, which may not fully capture the pediatric disease phenotype. If untreated or poorly managed, IgG4-RD can lead to progressive fibrosis and scarring of affected organs, potentially causing irreversible damage. We conducted a narrative review using the IMRAD approach, presenting a nonsystematic analysis of the literature on pediatric IgG4-RD. Original papers, case reports/series, and relevant reviews in English were selected from PubMed, EMBASE, and Web of Science up to January 2024. Keywords included “IgG4-Related Disease” and “pediatric” and, additionally, we presented two original pediatric cases. Our purpose is to offer an overview of IgG4-RD manifestations, and challenges in diagnosing and managing this rare condition in children. Full article

Hepato-renal crosstalk is a complex biological communication between liver and kidneys mediated by various factors, including cellular, endocrine, and paracrine molecules. This interaction highlights the functional consequences that damage in one organ can have on the other. In particular, the liver and kidney play a pivotal role in maintaining body homeostasis, as they are both involved in the excretion of toxic bioproducts and drugs. The overlap of liver and kidney disease has both therapeutic and prognostic implications. Therefore, a better understanding of the mechanisms involved in the pathogenesis of this bidirectional crosstalk is essential for improving the management of these clinical conditions and patient outcomes. Specifically, a multidisciplinary approach involving hepatologists and nephrologists is crucial to reduce the long-term burden of these clinical settings. This review focuses on the hepato-renal crosstalk in the context of liver and kidney disease, with particular attention to acute kidney injury associated with liver injury, hepatorenal syndrome and, chronic kidney disease in the context of liver fibrosis. Full article

Dilated cardiomyopathy affects greater than 1 in 2500 patients worldwide, including those with the neuromuscular disorder Duchenne muscular dystrophy (DMD). While inflammation within skeletal muscle is strongly associated with DMD pathology, the key biomarkers for inflammation and possible targets for therapy within cardiac tissue in DMD-associated dilated cardiomyopathy remain to be identified. One such potential target is the myocardial ghrelin-growth hormone secretagogue receptor (GHSR) system, which is associated with cardiomyocyte survival and inhibition of inflammation. We sought to determine alterations in myocardial GHSR together with markers of cardiac inflammation using mdx:utrn^−/− mice as a model for DMD-associated dilated cardiomyopathy. With traditional histopathology, we determined that the pathology of DMD in mdx:utrn^−/− mice was characterized by disruption of myofiber organization, lymphocytic infiltration, and extensive cardiomyocyte vacuolization and necrosis surrounding areas of fibrosis in the left ventricular wall and apex. Using a fluorescent ghrelin analog, Cy5-ghrelin (1–19), to visualize GHSR with fluorescence confocal microscopy, we demonstrate that GHSR is elevated in mdx/utrn^−/− myocardial tissues and correlates strongly with both F4-80 (activated macrophages) and IL-6 (pro-inflammatory cytokine), and negatively with cardiac function. We also show that GHSR can be visualized in pro-inflammatory macrophages, suggesting a direct role for GHSR in the inflammatory progression of DMD. Full article