Search Results (882)

Curcumin, a natural polyphenol derived from turmeric, functions as a potent exogenous antioxidant and exhibits a range of benefits in the prevention and management of metabolic diseases. Despite its extremely low systemic bioavailability, curcumin demonstrates significant bioactivity in vivo, a phenomenon likely attributable to its accumulation in the intestines and subsequent modulation of systemic oxidative stress and inflammation. This article systematically reviews the comprehensive regulatory effects of curcumin on systemic metabolic networks—including glucose metabolism, amino acid metabolism, lipid metabolism, and mitochondrial metabolism—and explores their molecular basis, particularly how curcumin facilitates systemic metabolic improvements by alleviating oxidative stress and interacting with inflammation. Preclinical studies indicate that curcumin accumulates in the intestines, where it remodels the microbiota through prebiotic effects, enhances barrier integrity, and reduces endotoxin influx—all of which are critical drivers of systemic oxidative stress and inflammation. Consequently, curcumin improves insulin resistance, hyperglycemia, and dyslipidemia across multiple organs (liver, muscle, adipose) by activating antioxidant defense systems (e.g., Nrf2), enhancing mitochondrial respiratory function (via PGC-1α/AMPK), and suppressing pro-inflammatory pathways (e.g., NF-κB). Clinical trials have corroborated these effects, demonstrating that curcumin supplementation significantly enhances glycemic control, lipid profiles, adipokine levels, and markers of oxidative stress and inflammation in patients with obesity, type 2 diabetes, and non-alcoholic fatty liver disease. Therefore, curcumin emerges as a promising multi-target therapeutic agent against metabolic diseases through its systemic antioxidant and anti-inflammatory networks. Future research should prioritize addressing its bioavailability limitations and validating its efficacy through large-scale trials to translate this natural antioxidant into a precision medicine strategy for metabolic disorders. Full article

Crucial regulators of gamete metabolism and signaling, mitochondria synchronize energy generation with redox equilibrium and developmental proficiency. Once thought of as hazardous byproducts, reactive oxygen species (ROS) are now understood to be vital signaling molecules that provide a “redox window of competence” that is required for oocyte maturation, sperm capacitation, and early embryo development. This review presents the idea of mitochondrial metabolic checkpoints, which are phases that govern gamete quality and fertilization potential by interacting with cellular signaling, redox balance, and mitochondrial activity. Recent research shows that oocytes may sustain a nearly ROS-free metabolic state by blocking specific respiratory-chain components, highlighting the importance of mitochondrial remodeling in gamete competence. Evidence from in vitro and in vivo studies shows that ROS act as dynamic gatekeepers at critical points in oogenesis, spermatogenesis, fertilization, and early embryogenesis. However, assisted reproductive technologies (ARTs) may inadvertently disrupt this redox–metabolic equilibrium. Potential translational benefits can be obtained via targeted techniques that optimize mitochondrial function, such as modifying oxygen tension, employing mitochondria-directed antioxidants like MitoQ and SS-31, and supplementing with nutraceuticals like melatonin, CoQ10, and resveratrol. Understanding ROS-mediated checkpoints forms the basis for developing biomarkers of gamete competence and precision therapies to improve ART outcomes. By highlighting mitochondria as both metabolic sensors and redox regulators, this review links fundamental mitochondrial biology to clinical reproductive medicine. Full article

Puerarin is a naturally occurring isoflavone with reported anticancer activity, yet its topical translation is constrained by limited stability and suboptimal dermal delivery. A Puerarin-loaded proniosomal gel was developed as a potential dermal delivery platform, and we performed an initial assessment of its antimelanoma activity and safety. The gel was produced by coacervation–phase separation using Span 60, Tween 80, phosphatidylcholine, and cholesterol. Physicochemical characterization included pH, entrapment efficiency, rheology, FTIR, DSC, and vesicle properties (DLS, PDI, ζ-potential). In silico geometry optimization and docking were carried out for melanoma-associated targets (MITF and DNMT3B). Biological effects were investigated in vitro on A375 melanoma cells using MTT, morphological analysis, and nuclear/mitochondrial staining, while irritation potential was evaluated in ovo by HET-CAM. The optimized formulation exhibited a skin-compatible pH and an entrapment efficiency of 62 ± 0.26%. DLS indicated a multimodal population, with a major number-weighted vesicle population in the 100–200 nm range, and a ζ-potential of −34.9 ± 0.14 mV. FTIR and DSC supported component incorporation without evidence of chemical incompatibility. The gel showed non-Newtonian, pseudoplastic, thixotropic flow, which is advantageous for topical use. Docking predicted meaningful affinities of Puerarin toward MITF and DNMT3B. The formulation reduced A375 viability in a dose-dependent manner (to 44.66% at 200 µg/mL) and, at higher concentrations, produced nuclear condensation and disruption of the mitochondrial network. HET-CAM classified the gel as non-irritant. The Puerarin-loaded proniosomal gel represents a promising topical platform with preliminary in vitro antimelanoma cytotoxic potential, warranting additional studies to validate skin delivery, efficacy, and safety. Full article

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

Down Syndrome Regression Disorder (DSRD) is a rare but severe neuropsychiatric condition characterized by abrupt loss of speech, autonomy, and cognitive abilities in individuals with Down syndrome, often associated with immune dysregulation and gut–brain axis dysfunction. We report the case of an 11-year-old girl with Down syndrome who developed developmental regression at age five, in temporal proximity to a family transition (the birth of a younger sibling), with loss of continence, language, and comprehension, alongside persistent behavioral agitation and gastrointestinal symptoms. Laboratory assessment revealed Giardia duodenalis infection, elevated fecal calprotectin and secretory IgA, and microbial imbalance with overgrowth of Streptococcus anginosus and S. sobrinus. The patient received a single oral dose of tinidazole (2 g), daily folinic acid (1 mg/kg), and a 90-day course of transcranial and abdominal photobiomodulation (PBM) (1064 nm, 10 min per site). Post-treatment, stool analysis showed normalized inflammation markers and restoration of beneficial bacterial genera (Bacteroides, Bifidobacterium, Lactobacillus) with absence of Enterococcus growth. Behaviorally, she exhibited marked recovery: CARS-2-QPC decreased from 106 to 91, ABC from 63 to 31, and ATEC from 62 to 57, alongside regained continence, speech, and fine-motor coordination. These outcomes suggest that abdominal and transcranial PBM, by modulating mitochondrial metabolism, mucosal immunity, and microbiota composition, may facilitate systemic and neurobehavioral recovery in DSRD. This translational case supports further investigation of PBM as a non-invasive, multimodal therapy for neuroimmune regression in genetic and developmental disorders including validation through future randomized controlled clinical trials. Full article

Osteogenesis imperfecta (OI) is a rare genetic disease caused by mutations in collagen type I, leading to defective protein folding and an impaired extracellular matrix structure and remodelling. Beyond skeletal fragility, these molecular defects trigger a network of intracellular stress responses with multiorgan implications: the accumulation of misfolded collagen can induce persistent endoplasmic reticulum stress, which can in turn compromise mitochondrial function and autophagy or lead to cell death activation, and it can even promote widespread redox imbalance and inflammation. The interplay between intracellular stress, widespread oxidative damage and inflammation not only underlies cellular dysfunction but also the multisystemic manifestations of osteogenesis imperfecta. Targeting these interconnected pathways may result in new insights for a better understanding of OI and possibly offer novel therapeutic strategies designed to restore proteostasis and improve cell homeostasis and overall patient outcomes, highlighting the need for an integrated understanding of the cellular and molecular mechanisms involved in the pathogenesis of this disease and their translation into patient-centred therapeutic interventions. Full article

Acute kidney injury (AKI) remains a major clinical challenge, with high morbidity and limited therapeutic options. In recent years, mitochondria have gained considerable attention as key regulators of the metabolic and immune responses during renal injury. Beyond their classical role in ATP production, mitochondria participate directly in inflammatory signaling, releasing mitochondrial DNA and other DAMPs that activate pathways such as TLR9, cGAS–STING, and the NLRP3 inflammasome. At the same time, immune cells recruited to the kidney undergo significant metabolic shifts that influence whether injury progresses or resolves. Increasing evidence also shows that immune-modulating therapies, including immune checkpoint inhibitors and innovative cell-based immunotherapies, can influence mitochondrial integrity, thereby altering renal susceptibility to injury. This review first summarizes the established knowledge on mitochondrial dysfunction in AKI, with emphasis on distinct mechanistic pathways activated by chemotherapy and immunotherapy. It then discusses emerging mitochondrial-targeted therapeutic strategies, logically integrating preclinical insights with data from ongoing and proposed clinical trials to present a coherent translational outlook. Full article

Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC—an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities. Full article

Background: Aging exerts a progressive and multifaceted impact on the microcirculatory system, undermining the structural and molecular integrity that sustains endothelial stability across both peripheral and cerebral vascular territories. A sustained shift toward oxidative imbalance, chronic low-grade inflammation, and progressive endothelial exhaustion converges to destabilize microvascular networks, linking peripheral artery disease (PAD) with heightened susceptibility to cerebral microvascular dysfunction and neurovascular decline. As redox homeostasis deteriorates, endothelial cells progressively lose barrier-selective properties, intercellular communication with pericytes weakens, and pro-thrombotic tendencies subtly emerge, creating a permissive environment for early neurovascular injury and impaired cerebrovascular resilience. Methods: This narrative review integrates mechanistic evidence derived from experimental, clinical, and translational studies examining the interplay between oxidative stress, inflammatory signaling cascades, endothelial senescence, and blood–brain barrier (BBB) disruption across peripheral and cerebral microvascular systems. A comparative framework was applied to PAD and cerebral microcirculatory pathology to identify convergent molecular drivers and systemic mechanisms underlying endothelial deterioration. Results: Accumulating evidence demonstrates that oxidative stress disrupts endothelial mitochondrial function, compromises tight junction architecture, and accelerates angiogenic failure. Concurrent inflammatory activation amplifies these alterations through cytokine-mediated endothelial activation, enhanced leukocyte adhesion, and promotion of a pro-thrombotic microenvironment. Progressive endothelial senescence consolidates these insults into a persistent state of microvascular dysfunction characterized by diminished nitric oxide bioavailability, capillary rarefaction, and compromised barrier integrity. Notably, these pathological features are shared between PAD and the aging cerebral circulation, reinforcing the concept of a unified systemic microvascular aging phenotype. Conclusions: Microvascular failure in the aging brain should be understood as an extension of systemic endothelial deterioration driven by oxidative stress, chronic inflammation, and senescence-associated vascular exhaustion. Recognizing the shared molecular architecture linking peripheral and cerebral microcirculatory dysfunction offers a strategic framework for developing targeted therapeutic interventions aimed at restoring endothelial resilience, stabilizing BBB integrity, and preserving neurovascular homeostasis in aging populations. Full article

Severe emotional stress constitutes a significant public-health concern associated with negative health outcomes. Although the clinical effects are well acknowledged, the specific biological mechanisms that translate emotional suffering into systemic disease remain incompletely understood. Psychological stress activates the sympathetic nervous system and hypothalamic–pituitary–adrenal axis, which directly target mitochondria and alter their bioenergetic and redox capacity. For this reason, this narrative review proposes that mitochondria serve as the primary subcellular link in the mind–body connection, as they play a pivotal role in converting neuroendocrine signals into cellular dysfunction. In particular, we focus on the concept of mitochondrial allostatic load (MALT), a framework explaining how the progressive decline in mitochondrial functions, from their initial adaptive roles in energy production, reactive oxygen species signaling, and calcium regulation, to being sources of inflammation and systemic damage, occurs when stress exceeds regulatory limits. We also, discuss how this transition turns mitochondria from adaptive responders into drivers of multi-organ disease. In subsequent sections, we examine diagnostic potentials related to MALT, including the use of biomarkers, such as growth differentiation factor 15, cell-free mitochondrial desoxyribonucleic acid, and functional respirometry. Furthermore, we evaluate mitochondria-targeted therapeutic strategies, encompassing pharmacological compounds, such as mitoquinone mesylate, Skulachev ions, and elamipretide, alongside lifestyle and psychological interventions. Here, we aim to translate MALT biology into clinical applications, positioning mitochondrial health as a target for preventing and treating stress-related disorders. We propose that MALT may serve as a quantifiable bridge between emotional stress and somatic disease, enabling future precision medicine strategies integrating mitochondrial care. Full article

Nitric oxide (NO), a fundamental gaseous signaling molecule, is indispensable for cardiovascular homeostasis. This review synthesizes the expansive field of NO biology within the unifying framework of Nitric Oxide Equilibrium (NOE), i.e., the critical balance between its synthesis, bioavailability, and degradation. In a physiological state, NOE maintains vascular health by regulating blood pressure, preventing thrombosis, suppressing inflammation, and optimizing both cardiac and mitochondrial function. Here, we analyze how NOE disruption, primarily through oxidative stress and enzymatic dysfunction, underlies the pathogenesis of major cardiovascular diseases, including atherosclerosis, heart failure, ischemia–reperfusion injury, and cerebrovascular diseases like stroke. A critical evaluation of therapeutic strategies designed to restore NOE is presented, encompassing classic NO donors and phosphodiesterase-5 inhibitors, alongside next-generation soluble guanylate cyclase modulators and precision nanomedicine approaches. By identifying key knowledge gaps and methodological hurdles, this review charts a course for future research focused on biomarker-guided interventions and personalized medicine. Ultimately, we frame the restoration of NOE as a paramount therapeutic goal, crucial to translating decades of molecular research into effective clinical practice. Full article

Forkhead box protein O1 (Foxo1) is an insulin-suppressed transcription factor that governs multiple biological processes, including cell proliferation, apoptosis, autophagy, mitochondrial function, and energy metabolism. Over the past 25 years, Foxo1 has evolved from a liner insulin effector to a pleiotropic integrator of systemic metabolic stress during obesity and aging. Foxo1 integrates hormonal signals with energy balance and plays a central role in glucose and lipid metabolism, organ homeostasis, and immune responses. Given its pleiotropic functions, therapeutic targeting of Foxo1 pathway will require a nuanced, context-specific approach. Here, we reviewed key advances in Foxo1 studies over the past 25 years, including multi-hormonal control of Foxo1 activity, Foxo1-mediated inter-organ crosstalk, immune modulation, and contributions to aging-associated pathologies. Understanding the regulation of Foxo1 and its pleiotropic function across multiple tissues will advance insight into the pathogenesis of metabolic diseases and promote the translation potential of Foxo1 signaling manipulation for the treatment of metabolic disorders, including insulin resistance and type 2 diabetes. Full article

Background/Objectives: Roux-en-Y gastric bypass (RYGB) improves obesity-related metabolic disorders, yet post-operative dietary composition critically shapes outcomes. This study explored how RYGB and high-fat diet (HFD) differentially regulate hepatic transcriptional programs. Methods: We performed RNA-seq on liver tissues from diet-induced obese C57BL/6 male mice 8 weeks post-RYGB or sham surgery, maintained on chow or HFD. Differentially expressed genes (DEGs) were identified using DESeq2. Gene sets were categorized as RYGB-induced (commonly regulated by surgery across diets), Reversal (RYGB-driven counter-regulation of obesity-induced changes), and HFD-induced (commonly regulated by diet). A subset of RYGB-specific HFD-induced genes was derived by excluding HFD-induced genes from the RYGB Chow vs. RYGB HFD contrast. Pathway enrichment was conducted using STRING. Results: RYGB induced 365 DEGs, including pathways related to extracellular remodeling and reduced mitochondrial/antioxidant activity. Among these, 119 Reversal genes countered obesity-associated transcriptional patterns and accounted for ~27% of the RYGB-induced enrichment results. HFD regulated 860 DEGs, highlighting stress responses and translational repression. Lastly, a set of 426 RYGB-specific HFD-induced genes revealed persistent hepatic inflammation, coagulation, and iron dysregulation under HFD despite surgery. Conclusions: RYGB induces robust hepatic transcriptomic changes that attenuate obesity-driven dysregulation, including a coordinated reprogramming of iron-handling pathways. However, high dietary fat partially overrides these benefits, promoting inflammatory, metabolic stress, and iron-related stress. Optimizing post-operative diets and carefully managing micronutrient intake, especially iron, may enhance RYGB’s metabolic efficacy and long-term liver health. Full article

Mitochondrial dysfunction and oxidative stress are crucial contributors to the pathogenesis of Alzheimer’s disease (AD) and dementia exhibiting cognitive decline at the early stage of neurodegeneration. Natural vitamin antioxidants (NVAs) and novel mitochondria-targeted antioxidants (MTAs) are proposed as potential therapeutics though conclusive evidence is lacking. Objectives were to examine in vivo evidence on NVAs and MTAs for preventing and/or treating cognitive decline leading to dementia, to identify the most promising antioxidants, and highlight translational gaps. Methods followed PRISMA-ScR guidelines. MEDLINE, EMBASE and Scopus were searched for English language in vivo experiments assessing NVAs or MTAs in AD and dementia. A total of 25 studies (13 NVAs; 12 MTAs) met inclusion criteria. NVAs (Vitamin A, B, C, E) demonstrated mixed efficacy in reducing oxidative stress and improving cognitive outcomes, with Vitamin E showing the most consistent neuroprotective effects. MTAs (MitoQ, MitoTEMPO, SS31, SkQ1) improved mitochondrial dynamics and cognitive performance and reduced dementia-related pathology. Both NVAs and MTAs improved biomarker profiles and cognitive outcomes in vivo animal models of AD and dementia, but MTAs showed more robust and consistent efficacy by directly targeting mitochondrial pathways. Given the favourable safety profiles of MTAs in other clinical conditions, early-phase human trials in dementia and AD are warranted to evaluate their long-term cognitive benefits. Full article

Bakuchiol (BAK), a natural meroterpenoid with antioxidant, anti-inflammatory and anticancer properties, has recently gained attention as a potential adjunct in breast cancer therapy. This review contextualizes breast cancer as a major global health challenge and highlights BAK as a bioactive compound capable of modulating pathways relevant to tumor development and progression. A structured literature search identified studies examining its molecular activity, pharmacological profile, and effects on breast cancer cells and stem cells. Results show that BAK influences oxidative stress regulation, mitochondrial function, apoptosis and estrogen receptor signaling while also affecting PI3K/AKT, MAPK, NF-κB, and EMT-related pathways. In breast cancer models, BAK acts as a selective phytoestrogen, induces S-phase arrest, activates the ATM/ATR–Chk1/Chk2 axis, and triggers mitochondrial apoptosis, particularly in ERα-positive cells. It also suppresses breast cancer stem-cell renewal, promotes BNIP3- and DAPK2-mediated apoptosis, reduces metabolic and transcriptional drivers of metastasis, and shows enhanced anticancer activity in derivative forms. These findings suggest that BAK may provide therapeutic benefit across several mechanisms central to breast cancer biology. In this review, the inclusion criteria encompassed publications describing the action of bakuchiol, its chemical and pharmacological properties, as well as its role in the treatment of various conditions, including cancers. Exclusion criteria included works not related to BAK or its therapeutic use in breast cancer, as well as publications that did not meet basic scientific standards, such as lacking methodological rigor or presenting a low level of scientific evidence. However, current evidence is predominantly in vitro, and limitations such as poor bioavailability and lack of clinical validation underscore the need for further in vivo and translational studies before therapeutic application can be established. Full article