Search Results (2,718)

Mitochondrial integrity is indispensable for pulmonary cellular homeostasis, with its dysfunction increasingly being implicated as a central mechanism in the etiology of respiratory disorders. We present a comprehensive overview of the integral role played by mitochondrial dynamics, such as fusion, fission, mitophagy, intracellular trafficking, and biogenesis, in maintaining pulmonary homeostasis. This study further explores how perturbations in these processes contribute to the pathogenesis of diverse lung disorders, including chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and drug-induced lung disease. It further explores how perturbations in these processes contribute to the pathogenesis of diverse lung disorders—for example, chronic obstructive pulmonary disease (COPD; responsible for roughly 55% of chronic respiratory disease cases), bronchopulmonary dysplasia (BPD; affecting up to 45% of infants born before 29 weeks of gestation), pulmonary arterial hypertension (PAH; a rare condition causing about 22,000 deaths worldwide in 2021), idiopathic pulmonary fibrosis (IPF; 0.33–4.51 cases per 10,000 persons), and drug-induced lung disease. Evidence demonstrates that mitochondria-triggered apoptosis, metabolic shifts, and subsequent inflammatory signaling act together to drive airway tissue remodeling and fibrotic progression across these lung diseases. Furthermore, this review evaluates the therapeutic potential of mitochondrial-targeted drugs, such as MitoQ and SS31, and metformin, which have shown promise in basic and preclinical studies. Preclinical and early clinical evaluations include an ongoing trial of the mitochondrial-targeted antioxidant MitoQ (NCT02966665, phase 1) in COPD, a 4-month open-label DCA study in PAH patients, and studies determining the preclinical efficacy of SS-31 and metformin in IPF models. Ultimately, integrating mitochondrial biomarkers into clinical practice holds the potential not only to facilitate early disease detection but also to enable the development of precision therapies, thereby offering renewed hope for patients afflicted with chronic lung diseases. Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously referred to as Non-Alcoholic Fatty Liver Disease (NAFLD), is a prevalent chronic liver condition strongly linked to Type 2 Diabetes Mellitus (T2DM) and obesity. Globally, MASLD is the most common cause of chronic liver disease. The bidirectional relationship between MASLD and T2DM underscores the pivotal role of insulin resistance in disease progression, which contributes to hepatic steatosis, oxidative stress, and inflammation, forming a vicious cycle. MASLD is also associated with heightened risks of cardiovascular and chronic kidney diseases, necessitating comprehensive treatment approaches. While lifestyle interventions and weight loss remain the cornerstone of management, their sustainability is challenging. This review highlights the evolving pharmacological landscape targeting MASLD and its advanced form, Metabolic Dysfunction-Associated Steatohepatitis (MASH). Currently, Resmetirom is the only FDA-approved drug for MASH. Current and investigational therapies, including insulin-sensitizing agents like peroxisome proliferator-activated receptor (PPAR) agonists, glucose-lowering drugs such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), drugs that target intermediary metabolism such as Vitamin E, de novo lipogenesis inhibitors, and emerging agents targeting the gut-liver axis and oxidative stress, are explored. These therapies demonstrate promising effects on hepatic steatosis, inflammation, and fibrosis, providing new avenues to address the multifaceted pathophysiology of MASLD. Full article

Radiation-induced cardiac toxicity is a recognized complication in patients undergoing thoracic radiotherapy. A crucial manifestation of this toxicity is the damage caused to coronary arteries, which can result in accelerated atherosclerosis that may remain undetected for many years. As cancer survival rates continue to improve, the incidence of radiation-induced coronary artery disease (RICAD) is increasing, making it one of the leading causes of morbidity and mortality among patients treated with radiotherapy for mediastinal cancers. The pathophysiology of RICAD involves a complex interplay of cellular mechanisms, including endothelial dysfunction, inflammation, and fibrosis. These processes are related to several molecular insults such as DNA damage, telomere erosion, and mitochondrial dysfunction. However, to fully understand the initiation and progression of the disease, further research is critical to uncover additional contributing factors. Different strategies for preventing cardiovascular complications in cancer patients are gaining significant attention. Recent advancements in radiotherapy, particularly the new FLASH radiotherapy technique, show promise in reducing the incidence of these complications. This review focuses on the effects of radiotherapy on coronary artery disease, exploring the underlying cellular and molecular mechanisms, as well as potential strategies to prevent RICAD. Full article

Background/Objectives: Insulin resistance is a key factor in the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD), but accurately measuring it in patients with type 2 diabetes (T2D) remains challenging. This study examines the relationship between a recently proposed insulin resistance index and the presence of liver steatosis and fibrosis in individuals with T2D. Methods: This cross-sectional study utilized data from the 2017–2020 National Health and Nutrition Examination Survey. Patients with T2D who did not have chronic viral hepatitis or significant alcohol intake were included. The insulin sensitivity (IS) index was calculated using a formula incorporating body mass index, urine albumin-to-creatinine ratio, triglycerides, and gamma-glutamyl transferase. Liver stiffness and steatosis were assessed through transient elastography. MASLD was defined as a controlled attenuation parameter (CAP) of ≥274 decibels/meter (dB/m), while significant liver fibrosis was defined as a liver stiffness measurement (LSM) of ≥8 kPa. Multivariable logistic regression models, adjusted for potential confounders, were used to evaluate the association between IS and these liver outcomes. Results: A total of 1084 patients with T2D were analyzed. The prevalence of MASLD and significant liver fibrosis was 74.1% (95% CI 68.7–78.9) and 25.4% (95% CI 21.2–30.2), respectively. After adjusting for age, sex, waist circumference, and race/ethnicity, lower IS scores (indicating higher insulin resistance) were independently associated with increased odds of both MASLD (quartile 1 vs. quartile 4: OR 2.66, 95% CI 1.23–5.71) and significant liver fibrosis (quartile 1 vs. quartile 4: OR 3.30, 95% CI 1.45–7.51). These findings remained consistent across subgroups stratified by age, sex, and obesity status. Conclusions: This novel IS model, derived from commonly available clinical and biochemical markers, is independently associated with liver steatosis and fibrosis. Its application may help identify patients with more advanced MASLD, facilitating early intervention and risk stratification. Full article

This case report details the successful rehabilitation of a 31-year-old male Asian elephant (Elephas maximus) presenting with an abnormal left forelimb gait following chronic traumatic injury. The elephant exhibited a distinctive circumduction gait with a semicircular arc movement, characterized by limited flexion at the elbow and carpus, along with compensatory proximal shrugging during the swing phase. Diagnostic evaluations revealed joint space narrowing and ligament fibrosis, while biomechanical gait analysis using inertial measurement units highlighted significant asymmetries between affected and unaffected limbs. An interprofessional team developed a comprehensive rehabilitation protocol that integrated peripheral magnetic stimulation, task-specific therapeutic walking with adjustable obstacles, and progressive strengthening exercises. At the eight-week follow-up, improvements were observed in cross-correlation coefficients of limb movement and imaging assessments, indicating enhanced symmetry and structural improvements with reduced fibrosis. However, persistent discrepancies in elbow functions suggest that further targeted rehabilitation may be warranted. This report underscores the potential of a coordinated interprofessional approach to restore functional gait patterns in elephants and offers valuable insights for future rehabilitative strategies in managing complex musculoskeletal injuries in large mammals. Full article

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally, driven by chronic liver disease and a complex tumor microenvironment (TME). Recent advances in spatial omics, single-cell analyses, and AI-driven digital pathology have shed light on the intricate heterogeneity of HCC, highlighting key roles for immune suppression, angiogenesis, and fibrosis in tumor progression. This review synthesizes current epidemiological trends, noting a shift from viral hepatitis to metabolic syndrome as a primary etiology in Western populations, and elucidates how TME components—such as tumor-associated macrophages, cancer-associated fibroblasts, vascular endothelial cells, and immunosuppressive cytokines—contribute to resistance against conventional therapies. We detail the evolution of immunotherapeutic strategies from monotherapy to combination regimens, including dual immune checkpoint blockade and the integration of antiangiogenic agents. Emerging circulating and tissue-based biomarkers offer promise for enhanced patient stratification and real-time monitoring of treatment responses. Collectively, these innovations herald a paradigm shift toward TME-directed precision oncology in HCC, emphasizing the need for multi-targeted approaches to synergistically modulate interacting cellular constituents and ultimately improve clinical outcomes. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with limited therapeutic options. This review focuses on the role of retinoids, particularly all-trans retinoic acid (atRA), and hypoxia in the pathogenesis of IPF. Despite an established understanding of genetic and environmental factors in IPF, the interplay between retinoid signaling and the response to hypoxia remains poorly explored due to its complexity. Preclinical evidence suggests that atRA could help reduce pulmonary fibrosis by modulating TGF-β signaling pathways and epithelial-to-mesenchymal transition (EMT). Additionally, we mention other diseases where a relationship between hypoxia and retinoids has been observed. We review how hypoxia, a key factor in the progression of IPF, may influence the efficacy of retinoid therapy. Combination strategies are explored to overcome hypoxia-induced treatment resistance. Finally, we address the complex role of retinoids in lung regeneration, balancing their potential benefits against the risk of exacerbating fibrotic processes. This review suggests that retinoids have potential as a treatment or adjuvant for IPF and highlights the need for further research to elucidate the precise mechanisms of retinoid action in IPF, particularly in hypoxia. Full article

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH), characterized by liver inflammation, fibrosis, and fat accumulation, can develop into cirrhosis and liver cancer. Despite its increasing prevalence worldwide, there are few established therapies for advanced MASH. We previously demonstrated that stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM) exerted therapeutic effects in a MASH mouse model. The gut–liver axis is thought to be associated with liver disease progression, and soluble Siglec-9 (sSiglec-9), an immunoinhibitory receptor, is a key protein in SHED-CM that induces anti-inflammatory macrophages and has intestinal epithelial protective effects. Therefore, we evaluated sSiglec-9’s role in intestinal barrier protection in MASH mice. Methods: We evaluated sSiglec-9 effects on intestinal barrier function using in vitro Caco-2 cell monolayers injured by TNF-α and IFN-γ. For the MASH mouse model, male C57BL/6J mice were given a Western diet and high-sugar solution orally; to induce liver injury, CCl4 was intraperitoneally administered for 12 weeks. Mice were treated weekly with 10 ng/g sSiglec-9 or vehicle. Intestinal permeability was assessed by blood 4 kDa FITC-dextran concentration, and intestinal transcriptomes and liver histology were analyzed. Results: sSiglec-9 decreased intestinal permeability and liver inflammation in MASH mice. sSiglec-9 and SHED-CM reduced 4 kDa FITC-dextran permeability in injured Caco-2 cells, and sSiglec-9 significantly reduced intestinal permeability and modulated expression of 34 intestinal genes. The NAFLD Activity Score indicated significantly reduced inflammation following sSiglec-9 treatment. Conclusions: sSiglec-9 may protect intestinal barrier function by mitigating mucosal inflammation. sSiglec-9 treatment may represent a novel therapeutic approach for MASH via gut–liver axis modulation. Full article

Background/Objectives: Filamentous fungi, in particular the species Aspergillus, Scedosporium, and Exophiala, frequently colonize the lungs of cystic fibrosis (CF) patients. Chronic colonization is linked to hypersensitivity reactions and persistent infections leading to a significant long-term decline in lung function. Azole antifungal therapy such as voriconazole (VRC) slows disease progression, particularly in patients with advanced CF; however, excessive mucus production in CF lungs poses a diffusional barrier to effective treatment. Methods: Here, biodegradable nanohydrogels (NHGs) recently developed as nanocarriers were evaluated for formulating VRC as a platform for treating fungal infections in CF lungs. The NHGs entrapped up to about 30 μg/mg of VRC, and physicochemical properties were investigated via dynamic laser light scattering and nanoparticle tracking analysis. Diameters were 100–400 nm, and excellent colloidal stability was demonstrated in interstitial fluids, indicating potential for pulmonary delivery. Nano-formulations exhibited high in vitro cytocompatibility in A549 and HEK293T cells and were tested for the release of VRC under two different sink conditions. Results: Notably, the antifungal activity of VRC-loaded nanohydrogels was up to eight-fold greater than an aqueous suspension drug against different fungal species isolated from CF sputum, regardless of the presence of a CF artificial mucus layer. Conclusions: These findings support the development of potent VRC nano-formulations for treating fungal disorders in CF lungs. Full article

Galectin-1 (Gal-1), a β-galactoside-binding lectin, plays a complex role in cardiovascular diseases (CVDs), exerting both protective and pathological effects depending on the context. This review synthesizes findings from the past decade to explore Gal-1’s involvement in key aspects of CVD pathogenesis, including vascular homeostasis, inflammation regulation, atherosclerosis progression, myocardial remodeling, and heart failure. While Gal-1 supports endothelial integrity and immune modulation, its dysregulation contributes to disease progression through pro-inflammatory signaling, fibrosis, and adverse cardiac remodeling. Emerging evidence suggests that Gal-1 holds potential as both a biomarker for risk assessment and a therapeutic target. However, critical knowledge gaps remain, particularly regarding its context-dependent effects, the limited scope of clinical trials, and unresolved mechanistic insights. Addressing these challenges will be essential to fully harness Gal-1’s therapeutic potential in cardiovascular medicine, guiding future research efforts toward precision interventions and clinical applications. Full article

Background: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are chronic conditions often accompanied by a prothrombotic state. Antifibrotic therapies, including nintedanib and pirfenidone, have demonstrated efficacy in slowing disease progression. Despite the known interactions between coagulation pathways and fibrotic processes, there is a lack of data in the literature on the safety of the concomitant use of anticoagulants and antifibrotics. Objectives: This study aimed to evaluate the safety and clinical impact of combining antifibrotics and anticoagulants in patients with IPF or PPF. A single-center, retrospective study was conducted on 137 patients diagnosed with IPF or PPF, 25 of whom were on concurrent anticoagulant therapy (AC+). Baseline demographics, pulmonary function tests (PFTs), bleeding risk scores (HAS-BLED, RIETE), and clinical outcomes were analyzed over a 12-month follow-up period. Methods: Statistical analyses included t-tests, χ² tests, Kaplan–Meier survival analysis, and multivariate logistic regression. Results: Two clinically relevant bleeding events were observed, with one in the AC+ group. No major bleeding episodes occurred in either group. Baseline forced vital capacity (FVC) was lower in the AC+ group (73.4 ± 16.9% vs. 83.0 ± 21.9%; p = 0.04), but no significant differences were observed in FVC, forced expiratory volume (FEV1), or diffusing capacity for carbon monoxide (DLCO) at 6 and 12 months. Survival rates and radiological progression were comparable between groups. Multivariate analysis revealed that DLCO was an independent predictor of mortality (HR 0.84; p = 0.005), while anticoagulant use was not. Conclusions: The concomitant use of antifibrotics and anticoagulants appears safe, with no significant increase in bleeding risk or adverse effects on disease progression. Future prospective studies are required to confirm these findings and explore the long-term impact of this therapeutic combination. Full article

Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD⁺), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca²⁺ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD⁺ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD⁺-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD⁺ content, and supplementation with NAD⁺ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD⁺ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD⁺ in mitochondrial homeostasis and for the development of targeted therapies for heart failure. Full article

Introduction: Idiopathic pulmonaryy fibrosis (IPF) is a progressive interstitial lung disease with a poor prognosis. While comorbidities like pulmonary hypertension and lung cancer have been studied extensively, less attention has been paid to the implications of malnutrition and sarcopenia in patients with IPF. This study aimed to assess the prevalence of malnutrition, sarcopenia, and the combined malnutrition-sarcopenia syndrome in patients with IPF using the latest diagnostic criteria from the Global Leadership Initiative on Malnutrition (GLIM) and the European Working Group on Sarcopenia in Older People 2 (EWGSOP2). Methods: A prospective, observational, multicenter study was conducted, focusing on patients with idiopathic pulmonary fibrosis (IPF). All participants provided informed consent, and the study followed ethical guidelines. Malnutrition was diagnosed based on the GLIM criteria, requiring one phenotypic and one etiological criterion, with muscle mass assessed via bioelectrical impedance analysis (BIA). Sarcopenia was screened following the EWGSOP2 recommendations. The statistical analysis was performed using JAMOVI version 2.3.22, with significance set at p < 0.05. Results: The findings revealed that 77.65% of the participants were malnourished, and 20% had sarcopenia. The malnourished patients had significantly lower body weight, height, and muscle mass compared to the non-malnourished patients. Furthermore, the patients with malnutrition exhibited poorer health-related quality of life scores. This study also identified the malnutrition-sarcopenia syndrome in 8.23% of the participants. Conclusions: Malnutrition, based on the GLIM criteria was identified in three out of four patients with IPF, while sarcopenia according to the EWGSOP2 was present in one out of five. This study underscores the necessity for routine screening for malnutrition and sarcopenia in patients with IPF. Full article

Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia–reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial–ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions—ranging from Drp1 inhibition to mitochondrial transplantation—hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies. Full article

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by chronic epithelial injury and excessive deposition of extracellular matrix (ECM) driven by dysregulated repair. Increasing evidence has shown that epithelial cell dysfunction plays a key role in PF, involving epithelial–mesenchymal transition (EMT), chronic oxidative stress, disruption of epithelial–immune interactions, and promoting pathological remodeling. Single-cell analyses have identified functionally distinct subpopulations of type 2 alveolar (AT2) cells with pro-fibrotic potential. Epithelial cells exhibit metabolic and epigenetic alterations during PF, which provide new approaches for therapeutic targets. This review summarizes the molecular mechanisms driving epithelial dysfunction in fibrosis progression, with a focus on key regulatory pathways, including transforming growth factor-beta (TGF-β), Wnt, and Notch signaling pathways, as well as miRNA-mediated networks. We also explored emerging epithelial-targeted therapies, ranging from FDA-approved agents (pirfenidone, nintedanib) to experimental inhibitors targeting Galectin-3 and Wnt/β-catenin, providing insights into precision anti-fibrosis strategies for clinical translation. Full article