Search Results (340)

Background: Adipose tissue is increasingly recognized as a highly dynamic endocrine and immunometabolic organ with marked functional heterogeneity. It serves as a reservoir for the active form of vitamin D₃, 1α,25-dihydroxyvitamin D₃ or calcitriol (1α,25-D₃), since it expresses enzymes responsible for its activation and inactivation and contains the vitamin D receptor (VDR). Through both classical and non-classical mechanisms, calcitriol modulates adipocyte proliferation and differentiation, protein expression and energy metabolism. This review aims to explore the signal transduction mechanisms of calcitriol in adipocytes, detailing the classical pathways mediated by the nuclear VDR (VDRn), as well as non-classical pathways involving membrane-associated VDR (VDRm), microRNAs, AMP-activated protein kinase (AMPK), and sirtuin 1 (SIRT1). Methods: A literature search was conducted using PubMed, ScienceDirect, and MDPI-indexed journals, prioritizing studies published within the last 10 years to ensure the inclusion of up-to-date evidence. Results: This review summarizes current knowledge on both classical and non-classical signaling pathways that are activated by calcitriol and highlights key molecular targets with potential relevance for drug development and therapeutic intervention. Through VDRn, calcitriol regulates the expression of proteins involved in inflammation and energy metabolism. Additionally, it modulates cellular processes such as energy production and secretion via the AMPK/SIRT1 axis and microRNA-mediated pathways, contributing to mitochondrial function and metabolic homeostasis. Conclusions: Calcitriol plays a central role in adipocyte biology by integrating multiple signaling pathways that regulate metabolic and inflammatory responses. These mechanisms highlight its potential as a therapeutic target and biomarker in metabolic diseases. Moreover, microRNAs emerge as critical posttranscriptional regulators in these processes, reinforcing their relevance as both biomarkers and targets for future interventions. Full article

Associated with high morbidity and mortality, cisplatin-induced acute kidney injury (AKI) is a common clinical complication characterized by oxidative stress, inflammation, and mitochondria-associated signaling. Although multiple signaling pathways have been implicated in AKI progression, effective interventions targeting these complex mechanisms are still lacking. As a medicinal fungus with antioxidant and anti-inflammatory properties, Schizophyllum commune (SC) has shown potential biological activities; however, its renoprotective effects in cisplatin-induced AKI remain unclear. Therefore, this study aimed to investigate SC’s protective effects and underlying mechanisms in a cisplatin-induced AKI mouse model. SC treatment improved renal function and attenuated histopathological damage. It reduced oxidative stress and inflammatory responses, as evidenced by the modulation of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), and pro-inflammatory cytokines. Mechanistically, SC regulated multiple signaling pathways, including mitogen-activated protein kinase (MAPK), toll-like receptor 4/nuclear factor kappa B (TLR4/ NF-κB), PI3K/AKT, nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1), and the calcium/calmodulin-dependent protein kinase kinase–AMP-activated protein kinase–sirtuin 1 (CaMKK–AMPK–Sirt1) axis. In addition, SC modulated apoptosis, autophagy, and PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy, suggesting improved mitochondrial homeostasis. These findings indicate that SC exerts renoprotective effects and may contribute to cisplatin-induced nephrotoxicity mitigation strategies. Full article

This study investigated the effects of different doses of ranolazine in a middle cerebral artery occlusion/reperfusion (MCAO-I/R) model by evaluating histopathological changes and serum Sirtuin 1 (SIRT1), Apela peptide (APELA), and Apelin-13 (APL13) levels. A total of 47 male Sprague Dawley rats (250 ± 20 g) were randomly assigned to five groups: Sham (n = 7), MCAO (n = 10), MCAO+RAN10 (n = 10), MCAO+RAN30 (n = 10), and MCAO+RAN50 (n = 10). MCAO-I/R was induced by transient filament occlusion of the right middle cerebral artery for 90 min followed by reperfusion. Ranolazine was administered intraperitoneally once daily for 21 days in the treatment groups. Serum SIRT1, APELA, and APL13 levels were measured using enzyme-linked immunosorbent assay (ELISA), and brain tissues were evaluated histopathologically for neuronal degeneration and apoptotic cell counts. Histopathological analysis revealed significant neuronal degeneration and increased apoptosis in the MCAO group compared with the Sham group. Ranolazine treatment did not demonstrate significant histopathological improvement compared with the untreated MCAO group. Among the treatment groups, the MCAO+RAN50 group showed higher apoptotic cell counts and lower serum biomarker levels than the other ranolazine-treated groups. Serum SIRT1, APELA, and APL13 levels were lowest in the MCAO+RAN50 group, with selected pairwise differences reaching statistical significance. Under the present experimental conditions, clear evidence of neuroprotection could not be demonstrated. None of the ranolazine-treated groups showed significant histopathological improvement compared with the untreated MCAO group. These findings indicate that higher-dose ranolazine was not associated with neuroprotection under the conditions of this study. However, given the limited sample size, absence of infarct volume analysis, lack of neurological functional assessment, and absence of tissue-level molecular validation, further studies are required to clarify the biological significance and potential clinical relevance of the observed biomarker changes. Full article

Lung cancer remains a leading cause of cancer-related mortality and is frequently complicated by respiratory infections, supporting interest in agents with both antitumoral and antimicrobial potential. This study evaluated two standardized thyme-derived, carvacrol-based formulations, Vacrol and S-Mix, in lung cancer-associated experimental models. A549 lung adenocarcinoma and BEAS-2B bronchial epithelial cells were treated with the formulations, and cell viability, clonogenic capacity, SIRT1–SIRT7 protein expression, in ovo tumor growth, histopathological changes, and antimicrobial activity against pneumonia-associated reference strains were assessed. S-Mix showed stronger short-term cytotoxicity in A549 cells, reaching an IC₅₀ of 1 mM after 72 h, whereas Vacrol produced more pronounced modulation of selected sirtuin proteins, particularly SIRT1, SIRT4, and SIRT5. Both formulations suppressed colony formation under prolonged exposure. In the CAM model, Vacrol was associated with greater macroscopic suppression of tumor growth and vascularization, while S-Mix produced more prominent histopathological cellular injury. Vacrol also showed antimicrobial activity against tested respiratory pathogens, with MIC values ranging from 0.5 to 4 mg/mL, MBC values ranging from 1 to 4 mg/mL and volatile-phase activity against Streptococcus pneumoniae as well as Klebsiella pneumoniae. These findings suggest that carvacrol-based formulations exert distinct cytotoxic, sirtuin-modulatory, antitumoral, and antimicrobial effects, warranting further mechanistic and translational validation. Full article

This study investigated the synergistic potential of mulberry leaf extract and Trolox against hydrogen peroxide (H₂O₂)-induced oxidative stress in SH-SY5Y cells. Cells were treated with the combination for 24 h prior to exposure to 200 µM H₂O₂. Cell viability was assessed using the MTT assay, while oxidative status was evaluated through measurements of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Sirtuin 1 (SIRT1) and apoptosis-related proteins, including p53, cyclic AMP response element-binding protein (CREB), Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), were determined by Western blot analysis. The combination treatment markedly upregulated SIRT1 expression, which was associated with increased CREB and Bcl-2 expression alongside reduced p53 and Bax levels. Increased SIRT1 expression was also accompanied by significant reductions in ROS and MDA levels and restoration of antioxidant enzyme activities. Collectively, these effects contributed to attenuation of oxidative stress and apoptosis, resulting in improved cell viability. These findings may support the formulation as a promising functional food-based strategy against oxidative stress-induced neuronal damage. However, these results are based on an in vitro SH-SY5Y cell model and represent preliminary evidence, warranting further in vivo and clinical studies to confirm their translational potential. Full article

Myocardial infarction (MI) remains the leading cause of death globally. Current treatment strategies involve restoring blood flow to the coronary artery, but have shortcomings in that these procedures cannot reverse damage to the myocardium that has already occurred. Therefore, therapies that can decrease the severity of ischemic damage are needed. Oxidative stress is an early and major driver of cardiomyocyte death following MI. Rhynchophylline (RHY) is a natural alkaloid known for its antioxidant activity; however, whether it can protect against MI-induced ischemic injury, as well as its underlying mechanism of action, remains unexplored. We performed murine models of surgical MI and examined the effects and mechanisms of RHY in protecting against myocardial ischemic injury. A sirtuin 1 (SIRT1)-specific inhibitor, EX-527, was subsequently used to verify that the cardioprotective effects of RHY were dependent upon targeted SIRT1-activation. Mice administered with RHY significantly protected against ischemic injury following MI, with improved cardiac function, reduced infarct size, and decreased levels of oxidative and DNA damage. The cardioprotective effect of RHY is associated with activation of the SIRT1 and its downstream redox-sensitive transcription factors: nuclear factor erythroid 2-related factor 2 (NRF2) and forkhead-box protein O3 (FOXO3a). The cardioprotective and antioxidant effects of RHY were abolished by EX-527, a selective SIRT1 inhibitor. Our findings provide evidence for the robust antioxidant properties of RHY in protecting against MI injury via activating the SIRT1/NRF2/FOXO3a signaling axis. These findings provide new mechanistic insight into the preconditioning-like cardioprotective potential of RHY during myocardial infarction. Full article

Gestational diabetes mellitus (GDM) exposes the fetus to chronic hyperglycemia, promoting early cardiac remodeling and increasing the risk of diabetic cardiomyopathy later in life. Epigenetic regulators such as p53 tumor suppressor gene (p53), microRNA-34a (miR-34a), and the sirtuins 1 and 7 (SIRT1/SIRT7) may contribute to this programming process; however, their temporal dynamics during postnatal cardiac development remain unclear. This study aimed to characterize structural and molecular alterations in the hearts of offspring exposed to GDM and to determine the involvement of the p53–miR-34a–SIRT1/SIRT7 axis in early cardiac remodeling. Cardiac morphometry was assessed at birth (newborn [NB]) and at 8, 15, 25, and 35 days. Left ventricles were examined through hematoxylin/eosin staining. SIRT1, SIRT7, Bcl-2, and Bax were evaluated by immunofluorescence, while p53 and miR-34a were evaluated by RT-PCR. Molecular interactions were integrated using IPA software, version 159584291. Offspring exposed to GDM exhibited a reduced cardiac area and ventricular lumen, along with increased left ventricular wall thickness and fibrosis during early postnatal stages. The cardiomyocyte area was elevated at all ages. The level of miR-34a increased early, preceding p53 upregulation. SIRT1 presences decreased from NB to 35 days, whereas SIRT7 expression remained consistently elevated. These findings suggest that GDM induces early and sustained cardiac remodeling associated with dysregulation of the p53–miR-34a–SIRT1/SIRT7 axis, a pattern that could increase susceptibility to diabetic cardiomyopathy. Full article

Sirtuin 1 (SIRT1) is an important protein for maintaining cellular homeostasis, and targeting SIRT1 represents a promising strategy for alleviating osteoporosis. The discovery of highly potent and safe SIRT1 activators therefore holds significant translational value for clinical anti-osteoporosis therapies. In this study, we performed deep mining of high-throughput RNA-sequencing (RNA-seq) data from 576 young and aged skeletal stem/progenitor cells (SSPCs) and identified SIRT1 downregulation as a critical hallmark of SSPC ferroptosis during aging-related osteoporosis. In SIRT1 heterozygous deficiency (SIRT1^+/−) mice, we found that SIRT1 deficiency triggered SSPC ferroptosis and induced premature osteoporosis. Computer-aided drug design (CADD) was employed to screen 9634 compounds targeting the SIRT1 active site, leading to the identification of the natural compound Hydroxygenkwanin (HGK) as a novel SIRT1 activator. HGK treatment effectively restored SIRT1 activity, suppressed ferroptosis in SSPCs in vitro, and ameliorated osteoporosis in vivo. Through transcriptomic analysis and lactylation profiling, we further found that HGK can activate SIRT1 and reverse the lactylation-mediated suppression of the enzymatic activities of SOD1 and PRDX1. This mechanism may underlie the ability of HGK to reduce SSPC ferroptosis and alleviate osteoporosis. Overall, our findings suggest that HGK possesses translational potential for the treatment of osteoporosis through SIRT1 activation. Full article

Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent class III histone deacetylase, functions as a central metabolic sensor and stress-responsive regulator in the cardiovascular system. Unlike its well-characterized role in atherosclerosis, SIRT1 exerts multifaceted protective effects directly on cardiac tissue. This review synthesizes recent advances in understanding SIRT1-mediated cardioprotection across a spectrum of heart diseases, including myocardial ischemia/reperfusion (I/R) injury, heart failure (HF), diabetic cardiomyopathy (DCM), cardiac hypertrophy, aging-related cardiac dysfunction and circadian rhythm disruption. Mechanistically, SIRT1 orchestrates antioxidant defense through nuclear factor erythroid 2-related factor 2 (Nrf2) and Forkhead box O (FoxO) transcription factors activation, suppresses inflammatory signaling via nuclear factor kappa B (NF-κB) deacetylation, inhibits apoptosis by targeting p53, promotes autophagic flux and mitophagy, regulates mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and controls ferroptosis via the Nrf2/glutathione peroxidase 4 (GPX4) axis. Preclinical studies demonstrate that natural compounds (resveratrol, quercetin, curcumin, ginsenosides, tanshinone IIA, bergenin, swietenine) and synthetic SIRT1 activators (SRT1720, anilinopyridine derivatives) attenuate cardiac injury and improve function. Moreover, SIRT1 serves as a prognostic biomarker in HF and diabetic patients. However, context-dependent dual roles, where excessive SIRT1 expression may be detrimental, underscore the need for precise modulation. Challenges remain in achieving cardiac-specific targeting, optimizing NAD⁺ availability, and translating preclinical findings into clinical practice. Future research should integrate multi-omics approaches, single-cell transcriptomics, and precision medicine strategies to unlock the therapeutic potential of SIRT1 in cardiac diseases. Full article

Neuronal ferroptosis is a key contributor to secondary brain injury following cerebral ischemia, yet the metabolic mechanisms governing this process remain poorly understood. Enriched environment (EE) is a housing paradigm that provides enhanced sensory, cognitive, and social stimulation through complex physical surroundings and increased opportunities for voluntary activity. Our preliminary data indicate that EE confers cerebroprotection against ischemia-induced ferroptosis; however, whether this effect is associated with glycogen metabolic regulation and the underlying molecular pathways has not been elucidated. This study aimed to determine whether EE may influence ferroptosis-associated pathways, potentially via Sirtuin 1 (SIRT1)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β)-related mechanisms of glycogen metabolism. Using a mouse model of middle cerebral artery occlusion (MCAO) and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we performed behavioral assessments, molecular and biochemical analyses, and pharmacological interventions to elucidate mechanistic pathways. EE was associated with improved neurological outcomes and reduced infarct volume after ischemia. Mechanistically, EE appeared to activate the SIRT1/AKT pathway and increase the inhibitory phosphorylation of GSK3β and relieving its suppressive effect on glycogen synthase, which may underlie the observed increase in glycogen levels within ischemic brain tissue. Pharmacological inhibition of SIRT1 largely diminished these metabolic and neuroprotective benefits. Consistently, at the cellular level, SIRT1 overexpression contributed to the restoration of glycogen metabolism and robustly attenuated ferroptosis under ischemic conditions. Collectively, these findings suggest that EE may attenuate ferroptosis-related pathways possibly involving SIRT1/AKT/GSK3β-dependent glycogen metabolic remodeling, providing a novel metabolic perspective on EE-induced cerebroprotection and highlighting SIRT1-centered regulation of glycogen metabolism as a potential therapeutic target for ischemic stroke. Full article

T-2 toxin, a mycotoxin produced by the genus Fusarium, is widely prevalent in agricultural products and livestock feed, posing substantial health risks to livestock and humans. This toxin induces oxidative stress in testicular Sertoli cells, disrupts testicular architecture, and compromises spermatogenesis. Despite its widespread presence in contaminated feeds, effective therapeutic strategies to counteract T-2 toxin-induced reproductive toxicity in Sertoli cells remain elusive. This study evaluated the protective efficacy and molecular mechanisms of proanthocyanidins (PCs), a phytochemical with antioxidant properties, against T-2 toxin-induced damage in yak (Bos grunniens) Sertoli cells. The findings revealed that T-2 toxin markedly reduced the viability of yak Sertoli cells and stimulated the production of reactive oxygen species (ROS). Treatment with 10 μg/mL PCs significantly enhanced cell viability, decreased apoptosis, and preserved cellular functions. Furthermore, PCs reduced ROS levels in yak Sertoli cells exposed to T-2 toxin and improved antioxidant capacity by upregulating the nuclear factor erythroid derived 2-like (NRF2)/heme oxygenase-1 (HO-1) signaling pathway. Additionally, PCs inhibited mitochondria-mediated apoptosis, diminished the occurrence of malformed mitochondria, and enhanced the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathway associated with mitochondrial biogenesis in yak Sertoli cells exposed to T-2 toxin. This study provides novel insights into the prevention and treatment of T-2 toxin-induced reproductive damage in yaks and underscores the potential application of PCs in this context. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease worldwide with complex pathogenesis and no approved specific therapy. Siraitia grosvenorii is a widely used medicinal and edible herb, yet its efficacy and underlying mechanisms against MAFLD remain poorly defined. This study explored the protective effects and potential mechanisms of aqueous extract of Siraitia grosvenorii (AESG) on MAFLD. Based on ultra-high-performance liquid chromatography-linear trap quadrupole orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap-MS) analysis, 38 components in AESG were tentatively assigned, with tetracyclic triterpene saponins being the most abundant. In high-fat diet (HFD)-induced MAFLD mice, AESG significantly attenuated body weight gain, reduced plasma total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) levels, and dramatically decreased hepatic triglyceride (TG) accumulation from 0.0141 mmol/g in the model group to 0.0063 mmol/g in the low-dose AESG group, corresponding to a reduction of 55.00%. AESG also alleviated plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatocyte steatosis. Furthermore, AESG restored HFD-induced gut dysbiosis by enriching beneficial bacteria including Akkermansia and suppressing harmful bacteria such as Ruminococcus. In free fatty acids (FFA) stimulated HepG2 cells, AESG suppressed de novo lipogenesis via downregulating Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC) and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), and enhanced antioxidant capacity via activating the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase 1 (HO-1)/Sirtuin 1 (SIRT1) pathway, thereby attenuating lipid accumulation and oxidative stress. In conclusion, AESG ameliorates MAFLD by inhibiting lipogenesis, improving oxidative stress, and regulating gut microbiota. These findings support Siraitia grosvenorii as a promising natural dietary intervention for MAFLD prevention and adjuvant therapy. Full article

Cosmetic dermatology has largely focused on topical applications targeting the stratum corneum. However, emerging evidence suggests that visible aging is a systemic readout of internal “organ clocks” and molecular dysregulation across the epidermis and dermis. This review proposes an “inside–out strategy” that seeks to re-conceptualize aesthetic vitality as a measurable indicator of systemic physiological resilience. The author describes theoretically proposed organ–skin axes, including the role of molecular signaling of kidney-derived klotho (KL1 fragment) via FGFR1-α–klotho complexes and muscle-derived irisin through the AMPK/PGC-1-α pathway in modulating skin homeostasis. Drawing on recent breakthroughs in non-human primate models (2023–2025), this synthesis explores the potential of systemic interventions—including nicotinamide adenine dinucleotide (NAD+) precursors (sirtuin 1 SIRT1 activators), senolytics (targeting BCL-2/p16), and glucagon-like peptide-1 (GLP-1) receptor agonists—as candidates to potentially synchronize these internal clocks. Furthermore, the review identifies direct regenerative interventions, such as retinoids (RAR/RXR signaling), chemical peels (HIF-1-α induction), exosomes (miR-21/29 delivery), and poly-L-lactic acid PLLA (mechanotransduction via YAP/TAZ), positioning them as potential physical and chemical epigenetic modulators that may support the restoration of cellular transcriptional fidelity. This article proposes a new paradigm for regenerative aesthetics that focuses on restoring the youthful phenotype by optimizing systemic molecular crosstalk and epigenetic transcriptional fidelity. Full article

Atherosclerosis is a chronic inflammatory and metabolic disease driven by endothelial dysfunction, immune activation, vascular smooth muscle cell remodeling and aging-associated mitochondrial decline. Although lipid lowering remains the cornerstone of therapy, substantial residual inflammatory risk persists, highlighting the need for integrative regulatory targets. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, has emerged as a central metabolic sensor linking energy availability to transcriptional control of inflammation, oxidative stress, mitochondrial biogenesis and cellular senescence. Experimental studies across endothelial cells, macrophages and vascular smooth muscle cells consistently demonstrate that SIRT1 activation preserves nitric oxide bioavailability, suppresses ROS-dependent inflammasome signaling, modulates macrophage polarization, inhibits ferroptosis and maintains mitochondrial integrity. These cell-type-specific effects converge to reduce plaque progression and enhance fibrous cap stability in preclinical models. However, SIRT1 activity is hierarchically regulated by AMPK signaling and NAD⁺ availability and is influenced by aging, metabolic dysfunction and environmental stressors, underscoring its context-dependent function. Despite promising mechanistic data, clinical translation remains limited, suggesting that precision modulation strategies may be required. This review synthesizes current evidence and proposes that SIRT1 functions as a metabolic–inflammatory integrator within the atherosclerotic arterial wall, representing a potential but context-sensitive target for future cardiovascular therapies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming increasingly prevalent worldwide, particularly among individuals with obesity and type 2 diabetes (T2D). MASLD remains potentially reversible in the early phases but, without timely intervention, it can progress to metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis, which in turn may advance to cirrhosis and hepatocellular carcinoma over time. With no pharmacological treatments specifically indicated for MASLD, current therapeutic strategies include lifestyle modifications, including dietary modifications. Niacin and its molecular derivatives (collectively belonging to the vitamin B3 group) play a central role in metabolic processes, especially through their involvement in the biosynthesis of the oxidized form of nicotinamide adenine dinucleotide (NAD⁺). A growing body of preclinical evidence suggests that reduced NAD⁺ levels are a hallmark of MASLD, and that NAD⁺ precursors may help attenuate disease progression through multiple mechanisms, including sirtuin 1 (SIRT1)-mediated inhibition of hepatic lipogenesis. Although these findings from experimental models suggest a potential role for niacin and related molecular derivatives as a modulators of MASLD-related pathways, evidence from human studies remains limited and inconsistent. For instance, interventional studies evaluating niacin or molecular derivatives supplementation have reported variable findings, with several trials showing limited meaningful benefits on MASLD-related outcomes. Consequently, further well-designed, controlled trials are needed to clarify therapeutic efficacy, dose–response relationship, and the feasibility of integrating niacin derivatives into dietary or therapeutic strategies aimed at reducing liver fat and improving adverse metabolic outcomes. This review aims to (i) summarize mechanistic insights on the role of niacin as a source of NAD⁺ on experimental MASLD and (ii) critically evaluate the available human evidence on the effect of supplemental niacin and derivatives in the prevention of MASLD development and its progression to MASH and fibrosis. Full article