Search Results (431)

Chemotherapy remains a cornerstone in the treatment of esophageal cancer (EC), yet chemoresistance remains a critical challenge, leading to poor outcomes and limited therapeutic success. Mitochondrial DNA (mtDNA) has emerged as a pivotal player in mediating these responses, influencing cellular metabolism, oxidative stress regulation, and apoptotic pathways. This review provides a comprehensive overview of the mechanisms by which mtDNA alterations, including mutations and copy number variations, drive chemoresistance in EC. Specific focus is given to the role of mtDNA in metabolic reprogramming, including its contribution to the Warburg effect and lipid metabolism, as well as its impact on epithelial–mesenchymal transition (EMT) and mitochondrial bioenergetics. Recent advances in targeting mitochondrial pathways through novel therapeutic agents, such as metformin and mitoquinone, and innovative approaches like CRISPR/Cas9 gene editing, are also discussed. These interventions highlight the potential for overcoming chemoresistance and improving patient outcomes. By integrating mitochondrial diagnostics with personalized treatment strategies, we propose a roadmap for future research that bridges basic mitochondrial biology with translational applications in oncology. The insights offered in this review emphasize the critical need for continued exploration of mtDNA-targeted therapies to address the unmet needs in EC management and other diseases associated with mitochondria. Full article

Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes. Full article

Colorectal cancer (CRC) remains a predominant cause of global cancer-related mortality, highlighting the pressing demand for innovative therapeutic strategies. Natural polysaccharides have emerged as promising candidates in cancer research due to their multifaceted anticancer mechanisms and tumor-suppressive potential across diverse malignancies. In this study, we enzymatically extracted a polysaccharide, named ERPP, from Ruditapes philippinarum and comprehensively evaluated its anti-colorectal cancer activity. We conducted in vitro assays, including CCK-8 proliferation, clonogenic survival, scratch wound healing, and Annexin V-FITC/PI apoptosis staining, and the results demonstrated that ERPP significantly inhibited HT-29 cell proliferation, suppressed colony formation, impaired migratory capacity, and induced apoptosis. JC-1 fluorescence assays provided further evidence of mitochondrial membrane potential (MMP) depolarization, as manifested by a substantial reduction in the red/green fluorescence ratio (from 10.87 to 0.35). These antitumor effects were further validated in vivo using a zebrafish HT-29 xenograft model. Furthermore, ERPP treatment significantly attenuated tumor angiogenesis and downregulated the expression of the vascular endothelial growth factor A (Vegfaa) gene in the zebrafish xenograft model. Mechanistic investigations revealed that ERPP primarily activated the mitochondrial apoptosis pathway. RT-qPCR analysis showed an upregulation of the pro-apoptotic gene Bax and a downregulation of the anti-apoptotic gene Bcl-2, leading to cytochrome c (CYCS) release and caspase-3 (CASP-3) activation. Additionally, ERPP exhibited potent antioxidant capacity, achieving an 80.2% hydroxyl radical scavenging rate at 4 mg/mL. ERPP also decreased reactive oxygen species (ROS) levels within the tumor cells, thereby augmenting anticancer efficacy through its antioxidant activity. Collectively, these findings provide mechanistic insights into the properties of ERPP, underscoring its potential as a functional food component or adjuvant therapy for colorectal cancer management. Full article

Hodgkin lymphoma (HL) is a common neoplasm in adolescents and young adults, primarily treated with doxorubicin (DOX) and bleomycin (BLM), which may cause severe adverse effects. The cure rate decreases to 75% in advanced-stage disease, highlighting the need for improved treatment strategies. Pentoxifylline (PTX), an NF-κB pathway inhibitor, enhances chemotherapy-induced apoptosis in cancer cells, making it a promising candidate for HL therapy. This study assessed the effects of PTX, DOX, and BLM on apoptosis, proliferation, and senescence in Hs-445 HL cells. Cell viability and clonogenicity were measured by spectrophotometry and spectrofluorimetry, while apoptosis, caspase activity, cell cycle, mitochondrial membrane potential (ΔΨm), proliferation, and senescence were analyzed via flow cytometry. Gene expression was assessed by qPCR. PTX significantly induced apoptosis, especially when combined with BLM or BLM+DOX (triple therapy), and modulated gene expression by upregulating proapoptotic and downregulating antiapoptotic markers. PTX increased caspase-3, -8, and -9 activity and disrupted the ΔΨm, particularly with BLM or triple therapy. Furthermore, PTX abolished DOX-induced G2 cell cycle arrest, reduced proliferation, and clonogenicity, and reversed DOX- and BLM-induced senescence. In conclusion, PTX induces apoptosis in HL cells, enhances DOX and BLM cytotoxicity synergistically, and reverses senescence, suggesting its potential as an adjunct therapy for HL. Full article

Alzheimer’s disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and tau protein neurofibrils. The current treatment strategies for AD are mainly symptomatic, highlighting the urgent need for the development of new, more effective therapies for the disease. The purpose of this paper is to provide a comprehensive and scientific review of the latest research regarding novel therapeutic options in the treatment of AD. In recent years, research has focused on more advanced and diversified strategies, including immunotherapy, gene therapy, tyrosine kinase inhibitors, therapies targeting mitochondrial function, and neurogenesis-related process modulation. One of the most promising treatment strategies for AD is immunotherapy. Intensive research is currently underway on both passive immunization, which involves the administration of monoclonal antibodies, and active immunization through vaccinations that stimulate the body to produce specific antibodies. Further research into novel therapeutic directions is essential, particularly concerning the role of the immune system in the pathogenesis of AD. Immunization appears to be a highly promising approach to developing effective methods for preventing AD or delaying the progression of this disease. Full article

Background: Methylene blue (MB), a versatile redox agent, is emerging as a promising therapeutic in diseases associated with mitochondrial dysfunction. Its ability to optimize the electron transport chain increases ATP synthesis (30–40%) and reduces oxidative stress, protecting cellular components such as mitochondrial DNA. The protective role of this compound has been described in several neurodegenerative disease such as Alzheimer’s and Parkinson’s diseases. However, its role in cardiovascular disease has been poorly explored. Methods: In this study, we explored the impact of MB on murine (HL1) and human (AC16) cardiomyocyte redox signaling and cellular survival using RT-Qpcr analysis and immunochemistry assays. Results: Our results revealed that MB increased functional mitochondria, reversed H₂O₂-induced oxidative damage, and modulated antioxidant gene expression. Furthermore, it regulated the microRNA16–UPR signaling axis, reducing CHOP expression and promoting cell survival. Conclusions: These findings underscore its potential in cardioprotective therapy; however, its putative use as a drug requires in vivo validation in preclinical animal models. Full article

Mitochondrial Membrane Protein-Associated Neurodegeneration is a rare monogenic form of neurodegeneration characterized by iron accumulation in the brain. It is due to variants in the orphan gene C19orf12. Since its definition in 2011, many scientific groups have investigated the clinical features and molecular underpinnings of the disorder. In this review, we summarize the main points of progress in this field, trying to highlight the issues that need further attention and efforts to speed up the diagnostic path, improve the existing treatment options, and define targeted therapies. Full article

Skeletal muscle atrophy is a debilitating condition characterized by the loss of muscle mass and function. It is commonly associated with aging, chronic diseases, disuse, and prolonged glucocorticoid therapy. Oxidative stress and catabolic signaling pathways play significant roles in the progression of muscle degradation. Despite its clinical relevance, few effective therapeutic options are currently available. In this study, we investigated the protective effects of an ethanolic extract of Glycine Semen Preparata (GSP), i.e., fermented black soybeans, using in vitro and in vivo models of dexamethasone (Dexa)-induced muscle atrophy. In C2C12 myoblasts and myotubes, GSP significantly attenuated both oxidative stress-induced and Dexa-induced damages by reducing reactive oxygen species levels and by suppressing the expression of the muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1. Moreover, GSP upregulated key genes involved in muscle regeneration (Myod1 and Myog) and mitochondrial biogenesis (PGC1α), indicating its dual role in muscle protection and regeneration. Oral administration of GSP to mice with Dexa-induced muscle atrophy resulted in improved muscle fiber integrity, increased proportion of large cross-sectional area fibers, and partial recovery of motor function. Isoflavone aglycones, such as daidzein and genistein, were identified as active compounds that contribute to the beneficial effects of GSP through antioxidant activity and gene promoter enhancement. Thus, GSP is a promising nutraceutical that prevents or mitigates muscle atrophy by targeting oxidative stress and promoting myogenesis and mitochondrial function. Further studies are warranted to standardize the bioactive components and explore their clinical applications. Full article

Background/Objectives: Cardiac aging involves the progressive structural and functional decline of the myocardium. Endurance training is a well-recognized non-pharmacological intervention that counteracts this decline, yet the molecular mechanisms driving exercise-induced cardiac rejuvenation remain inadequately elucidated. This study aimed to identify key effector genes and regulatory pathways by integrating human cardiac aging transcriptomic data with multi-omic exercise response datasets. Methods: A systems biology framework was developed to integrate age-downregulated genes (n = 243) from the GTEx human heart dataset and endurance-exercise-responsive genes (n = 634) from the MoTrPAC mouse dataset. Thirty-seven overlapping genes were identified and subjected to Enrichr for pathway enrichment, KEA3 for kinase analysis, and ChEA3 for transcription factor prediction. Candidate effector genes were ranked using ToppGene and ToppNet, with integrated prioritization via the FLAMES linear scoring algorithm. Results: Pathway enrichment revealed complementary patterns: aging-associated genes were enriched in mitochondrial dysfunction and sarcomere disassembly, while exercise-responsive genes were linked to protein synthesis and lipid metabolism. TTN, PDK family kinases, and EGFR emerged as major upstream regulators. NKX2-5, MYOG, and YBX3 were identified as shared transcription factors. SMPX ranked highest in integrated scoring, showing both functional relevance and network centrality, implying a pivotal role in mechano-metabolic coupling and cardiac stress adaptation. Conclusions: By integrating cardiac aging and exercise-responsive transcriptomes, 37 effector genes were identified as molecular bridges between aging decline and exercise-induced rejuvenation. Aging involved mitochondrial and sarcomeric deterioration, while exercise promoted metabolic and structural remodeling. SMPX ranked highest for its roles in mechano-metabolic coupling and redox balance, with X-inactivation escape suggesting sex-specific relevance. Other top genes (e.g., KLHL31, MYPN, RYR2) form a regulatory network supporting exercise-mediated cardiac protection, offering targets for future validation and therapy. Full article

Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions—including dietary modulation, cofactor replacement, and gene therapy—are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer. Full article

Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life. Full article

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. While timely reperfusion therapies such as percutaneous coronary intervention (PCI) and thrombolysis are essential for salvaging ischemic myocardium, they can paradoxically exacerbate tissue injury through a process known as myocardial infarction reperfusion injury (MIRI). MIRI can contribute to up to 50% of the final infarct size, significantly diminishing the benefits of revascularization and leading to worsened cardiac outcomes. The pathophysiology of MIRI involves complex, interrelated mechanisms including oxidative stress, calcium overload, mitochondrial dysfunction, inflammatory responses, apoptosis, and dysregulated autophagy. Post-reperfusion recovery is further complicated by structural and functional abnormalities such as microvascular obstruction, endothelial dysfunction, and myocardial stunning. Clinically, distinguishing reperfusion injury from ischemic damage is challenging and often requires the use of sensitive biomarkers, such as cardiac troponins, alongside advanced imaging modalities. Although a range of pharmacological (e.g., antioxidants, calcium channel blockers, mitochondrial stabilizers, anti-inflammatory agents) and non-pharmacological (e.g., hypothermia, gene therapy, stem cell-based therapies) interventions have shown promise in preclinical studies, their clinical translation remains limited. This is largely due to the multifactorial and dynamic nature of MIRI. In this context, network pharmacology offers a systems-level approach to understanding the complex biological interactions involved in MIRI, facilitating the identification of multi-target therapeutic strategies. Integrating network pharmacology with omics technologies and precision medicine holds potential for advancing cardioprotective therapies. This review provides a comprehensive analysis of the molecular mechanisms underlying MIRI, examines the current clinical challenges, and explores emerging therapeutic strategies. Emphasis is placed on bridging the translational gap through validated, multi-target approaches and large-scale, multicenter clinical trials. Ultimately, this work aims to support the development of innovative and effective interventions for improving outcomes in patients with myocardial infarction. Full article

Dry age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over 50, yet no approved therapies exist for early or intermediate stages of the disease. Oxidative stress is a central driver of retinal degeneration in AMD, and sodium iodate (NaIO₃)-induced injury serves as a well-characterized model of oxidative damage to the retinal pigment epithelium (RPE) and photoreceptors. BMI1, a poly-comb group protein involved in DNA repair, mitochondrial function, and cellular renewal, has emerged as a promising therapeutic target for retinal neuroprotection. We evaluated the efficacy of AAV-mediated BMI1 gene delivery in murine models using two administration routes: subretinal (SR) and suprachoroidal (SC). AAV5.BMI1 (1 × 10⁹ vg/eye) was delivered SR in Balb/c mice and evaluated at 4 and 15 weeks post-injection. AAV8.BMI1 (5 × 10⁹ or 1 × 10¹⁰ vg/eye) was administered SC in C57BL/6 mice and assessed at 4 weeks. Control groups received BSS or AAV8.stuffer. Following NaIO₃ exposure, retinal structure and function were analyzed by optical coherence tomography (OCT), electroretinography (ERG), histology, and molecular assays. SC delivery of AAV8.BMI1 achieved the highest levels of retinal BMI1 expression with no evidence of local or systemic toxicity. Treated eyes showed dose-dependent preservation of outer nuclear layer (ONL) thickness and significantly improved ERG responses indicating structural and functional protection. These findings support SC AAV.BMI1 gene therapy as a promising, minimally invasive, and translatable approach for early intervention in intermediate AMD. Full article

The central nervous system (CNS) is highly susceptible to damage due to its limited ability to regenerate. Injuries to the CNS, whether from trauma, ischemia, or neurodegenerative diseases, disrupt both cellular and vascular structures, leading to immediate (primary) and subsequent (secondary) damage. Primary damage involves the physical disruption of cells and blood vessels, weakening the blood–brain barrier (BBB) and triggering excitotoxicity and calcium overload. Secondary damage develops over hours to days and is marked by ionic imbalance, mitochondrial dysfunction, oxidative stress, and chronic inflammation, which further aggravates tissue damage. Inflammation plays a dual role: acute inflammation helps in repair, while chronic inflammation accelerates neurodegeneration. Microglia and astrocytes play key roles in this inflammatory response, with M1-like microglia promoting pro-inflammatory responses and M2-like microglia supporting anti-inflammatory and repair processes. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins such as Tau, amyloid-beta, TDP-43, and α-synuclein, which impair cellular function and lead to neuronal loss. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins and influenced by genetic risk factors (e.g., APOE4, TARDBP). Despite the CNS’s limited regenerative abilities, processes like synaptogenesis, neurogenesis, axonal regeneration, and remyelination offer potential for recovery. Therapeutic approaches aim to target inflammatory pathways, enhance repair mechanisms, and develop neuroprotective treatments to counter excitotoxicity, oxidative stress, and apoptosis. Advances in stem cell therapy, gene therapy, and personalized medicine hold promise for improving outcomes. Future research should focus on combining strategies, utilizing advanced technologies, and conducting translational studies to bridge the gap between preclinical research and clinical application. By better understanding and leveraging the complex processes of CNS injury and repair, researchers hope to develop effective therapies to restore function and enhance the quality of life for individuals with CNS disorders. Full article

Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H₂S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H₂S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants. Full article