Search Results (273)

Staphylococcus aureus (S. aureus)-induced mastitis poses a significant threat to animal husbandry. This condition triggers sustained mammary inflammation, oxidative stress, and disrupts mitochondrial homeostasis, ultimately impairing mammary gland function and milk yield. Conjugated linoleic acid (CLA) is a long-chain fatty acid found in meat and dairy products derived from ruminants. It exhibits multiple biological activities, including anti-cancer, anti-inflammatory, and antioxidative stress-alleviating effects. Thus, this study sought to determine whether CLA alleviates S. aureus-induced mastitis in Hu sheep through the PPARG-UCP2 axis. Fifteen lactating Hu sheep were randomly allocated into three groups (n = 5): control group, model group, and CLA group. The CLA group received 1 mg/mammary gland of CLA via intramammary infusion for seven days, followed by S. aureus challenge (5 × 10⁷ cells/mL, 2 mL/mammary gland) in the model and CLA groups, while the control group received saline. Venous blood and mammary tissue samples were collected at two days post-infection. The results demonstrated that S. aureus infection significantly upregulated the expression of inflammatory factors (IL-1β, IL-6, and NF-κB) in the mammary tissue of Hu sheep, p < 0.01. Relative to the control, the model group showed increased ROS and MDA levels, a diminished NAD+/NADH ratio, and downregulated expression of the antioxidant factors SOD, Nrf2, HO-1, and SIRT3, p < 0.01. Furthermore, the expression of p-AMPK and mitophagy-related factors (PARKIN, PINK1, and LC3b) showed a statistically significant increase in the model group than in the control group, p < 0.01. S. aureus infection also suppressed the expression of PPARG and UCP2, p < 0.01. In contrast, the CLA group showed lower levels of inflammatory factors (IL-1β, IL-6, and NF-κB), ROS and MDA, while the NAD+/NADH ratio and the expression of antioxidant factors (SOD, p-Nrf2, HO-1, and SIRT3) were elevated compared with the model group, p < 0.01. Moreover, the expression of p-AMPK and mitophagy-related factors (PARKIN, PINK1, and LC3b) was reduced in the CLA group relative to the model group, p < 0.05. Concurrently, the expression of PPARG and UCP2 was higher in the CLA group than in the model group, p < 0.001. These findings demonstrated that S. aureus infection induced mastitis in Hu sheep mammary tissue, whereas CLA alleviated the infection by upregulating the PPARG-UCP2 pathway, thereby reducing inflammation, oxidative stress, and mitophagy levels. This study offers a novel perspective on mammary tissue repair during mastitis and expands the understanding of UCP2’s biological role. Full article

Mitochondrial dysfunction is a defining hallmark of aging that connects redox imbalance, metabolic decline, and inflammatory signaling across organ systems. The mitochondrial deacetylase SIRT3 preserves oxidative metabolism and proteostasis, yet its age-related decline transforms metabolically demanding organs into sources of pro-senescent cues. This review synthesizes evidence showing how SIRT3 loss in select “driver tissues”—notably liver, adipose tissue, vascular endothelium, bone-marrow macrophages, and ovary—initiates systemic aging through the release of cytokines, oxidized metabolites, and extracellular vesicles. We discuss molecular routes and mediators of senescence propagation, including the senescence-associated secretory phenotype (SASP), mitochondrial-derived vesicles, and circulating mitochondrial DNA, as well as sex-specific modulation of SIRT3 by hormonal and intrinsic factors. By integrating multi-tissue and sex-dependent data, we outline a framework in which SIRT3 activity defines the mitochondrial threshold separating local adaptation from systemic aging spread. Targeting SIRT3 and its NAD⁺-dependent network may offer a unified strategy to restore mitochondrial quality, dampen chronic inflammation, and therefore recalibrate the aging dynamics of an organism. Full article

Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2–KEAP1 antioxidant system, the cGAS–STING innate immune pathway, and the PINK1–Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD⁺ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases. Full article

Background/Objectives: Sirtuin 7 (SIRT7), a nuclear NAD⁺-dependent deacylase, plays multifaceted and sometimes opposing roles in tumorigenesis. By preserving chromatin architecture and genome integrity, SIRT7 protects against malignant transformation; however, once cancer is established, it can either sustain or restrain tumor growth through context-dependent signaling programs, albeit via largely unknown mechanisms. Recent findings have uncovered an additional—and previously underappreciated—dimension: SIRT7’s capacity to modulate anti-cancer immunity. This review revisits the current understanding of SIRT7 in cancer by emphasizing its emerging immunomodulatory functions and influence on the tumor microenvironment. Methods: We conducted a comprehensive literature review up to October 2025 using the PubMed database to identify both tumor-intrinsic and tumor-extrinsic mechanisms linking SIRT7 to anti-cancer immunity and to relate the established molecular functions of SIRT7—such as its roles in metabolism, genome maintenance, and inflammatory regulation—to immune regulation. Results: SIRT7 directly regulates immune checkpoint expression and T cell metabolic fitness, thereby positioning it as a key node connecting tumor-intrinsic programs with immune surveillance. Moreover, by controlling molecular pathways such as metabolism, genomic stability, and inflammatory responses—both within cancer cells and across other components of the tumor microenvironment—SIRT7 may more broadly influence the immune landscape, orchestrating immune evasion or recognition. Conclusions: Deciphering how SIRT7’s tumor-intrinsic and immunomodulatory functions intersect is essential for anticipating the consequences of its pharmacological targeting in cancer. A deeper understanding of this interplay will enable the rational design of combination strategies that integrate SIRT7 modulation with immunotherapy within a precision medicine framework. Full article

The human sirtuins (SIRT1–SIRT7) are NAD⁺-dependent protein deacylases that orchestrate key cellular events such as metabolism, stress response, DNA repair, and aging. Accumulating evidence highlights their central role in women’s health. This review integrates recent insights into the roles of sirtuins across the female lifespan and their involvement in reproductive, metabolic, oncologic, and age-related disorders. Sirtuins regulate reproductive function, pregnancy outcomes, and hormone-dependent cancers. Their decline with aging contributes to menopausal and metabolic complications. Pharmacological interventions that enhance sirtuin activity, such as NAD⁺ precursors and SIRT1 activators, show promise in mitigating these conditions. Collectively, understanding the isoform- and tissue-specific roles of sirtuins provides a foundation for developing therapeutics to improve the lifespan and healthspan of women. Full article

Sirtuin 6 (SIRT6), a (Nicotinamide adenine dinucleotide) NAD⁺-dependent deacylase and mono- (adenosine diphosphate) ADP-ribosyltransferase, is increasingly recognized as a pivotal regulator of genomic stability, metabolic reprogramming, and epigenetic remodeling. This review synthesizes current evidence on the dual roles of SIRT6 in cancer, highlighting its context-dependent functions as both a tumor suppressor and promoter across various malignancies. We detail its involvement in DNA damage sensing, repair coordination, glycolytic regulation, and chromatin modification, and discuss how these mechanisms contribute to tumor initiation, progression, and therapy resistance. Emerging therapeutic strategies targeting SIRT6, including small-molecule modulators, genetic interventions, and combination therapies, are critically evaluated. Our analysis underscores the necessity for context-specific therapeutic targeting, and pharmacological modulation of SIRT6 represents a promising avenue for precision oncology. Full article

Background and Objectives: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet its molecular basis remains unclear. Nicotinamide adenine dinucleotide (NAD⁺) metabolism is crucial for energy regulation, redox balance, and inflammation. This study investigated the dysregulation of key NAD⁺ salvage enzymes (CD38, NAMPT, and SIRT1) across albuminuria stages in type 2 diabetes (T2D). Materials and Methods: A cross-sectional study was conducted on 225 participants: healthy controls (n = 45), T2D with normoalbuminuria (n = 60), microalbuminuria (n = 60), and macroalbuminuria (n = 60). Serum CD38, NAMPT, and SIRT1 were measured by ELISA, while CD38 and SIRT1 gene expression in peripheral blood mononuclear cells was analyzed by qPCR. Results: CD38 and NAMPT levels increased progressively with albuminuria, whereas SIRT1 levels declined significantly. CD38 and NAMPT correlated positively with HbA1c, creatinine, and urinary albumin-to-creatinine ratio (UACR), while SIRT1 showed inverse correlations and a positive association with eGFR. Regression analysis identified CD38 and NAMPT as independent positive predictors of albuminuria, and SIRT1 as a negative predictor. ROC analysis revealed strong diagnostic performance for CD38 (AUC = 0.89) and SIRT1 (AUC = 0.88). Conclusions: These findings highlight disrupted NAD⁺ salvage pathways in DN and suggest that restoring NAD⁺ balance, through CD38 inhibition, SIRT1 activation, or NAD⁺ precursor supplementation, may offer promising renoprotective strategies. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a major metabolic disorder associated with progressive microvascular complications such as nephropathy, retinopathy, and neuropathy. Early detection of diabetic nephropathy (DN) remains challenging, as conventional markers such as urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are influenced by non-renal factors and lack sensitivity for subclinical injury. Sirtuin 2 (SIRT2), a cytoplasmic NAD⁺-dependent deacetylase involved in oxidative stress and inflammatory regulation, has recently been implicated in renal pathophysiology. This study aimed to assess the relationship between serum SIRT2 levels and the presence of diabetic nephropathy and to evaluate its potential utility as a complementary biomarker reflecting early renal injury. Methods: In this single-center, cross-sectional study, 180 participants aged 18–80 years were enrolled: 60 healthy controls, 60 T2DM patients without nephropathy (T2DM − DN), and 60 T2DM patients with nephropathy (T2DM + DN). Serum SIRT2 concentrations were quantified using a validated ELISA. Group comparisons, multinomial logistic regression, and receiver operating characteristic (ROC) curve analyses were performed to assess associations between SIRT2 and renal indices (UACR and eGFR). Statistical significance was set at p < 0.05. Results: Serum SIRT2 concentrations showed a progressive elevation across study groups (p < 0.001), with median levels of 6.13 ng/mL in healthy controls, 8.53 ng/mL in T2DM − DN, and 33.19 ng/mL in T2DM + DN. ROC analysis revealed good diagnostic performance for differentiating DN from healthy controls (AUC = 0.813, sensitivity 75%, and specificity 78.3%). Multivariable regression analysis identified SIRT2 as an independent correlate of DN after adjusting for metabolic and renal covariates (adjusted OR = 1.22, 95% CI 1.11–1.35, p < 0.001). Conclusions: Serum SIRT2 levels were observed to increase in parallel with the presence and severity of diabetic nephropathy and remained independently associated with the condition after adjustment for conventional risk factors. These findings suggest that SIRT2 may serve as a feasible complementary biomarker reflecting renal injury processes not captured by traditional measures. Further longitudinal studies are warranted to clarify its prognostic significance and potential for clinical integration. Full article

Sirtuins are NAD⁺-dependent enzymes that are conserved in all domains of life, including mammals, metazoans, plasmodia, yeast, bacteria, and archaea. In humans, there are seven isoforms (SIRT1 to 7), and they function in cellular homeostasis, aging, DNA repair, survival, metabolism, and stress responses. Recent advances highlight the diverse functions of sirtuins in the pathogenesis and progression of cancer, metabolic diseases, and neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). To date, there is evidence that all seven isoforms contribute to cancer development, while SIRT1-3 and 6 contribute to metabolic and neurodegenerative diseases. Modulators of sirtuin activity are being actively explored to understand their biological and molecular mechanisms and potential for the treatment of various diseases. In this review, we begin with a broad discussion of post-translational modifications, protein deacetylation, and the mechanism of action of sirtuins. Next, we discuss the role of sirtuins in cancer, including inhibitors and activators of sirtuin activity as cancer therapies. In addition, we discuss the relationship of sirtuins to metabolic diseases and as possible treatment targets. Finally, we discuss the role of sirtuins in AD, PD, and HD, and sirtuin modulators for treating neurodegenerative diseases. Full article

Sirtuin 1 (SIRT1) is an NAD⁺-dependent deacetylase implicated in various physiological and pathological processes, including cardiovascular diseases. The lead compound for SIRT1, resveratrol (1), as well as natural-derived and synthetic SIRT1-activating compounds demonstrated to exert cardioprotective effects. In the present work, we evaluated a small series of diarylimidazoles, of which 4 emerged, in in vitro enzymatic assays, as an activator of SIRT1 endowed with a similar potency compared with that of 1. Therefore, 4 was subjected to pharmacological investigation, where it was proven to reduce myocardial damage induced by ischemia/reperfusion injury in isolated rat hearts, thus demonstrating its cardioprotective properties. An in silico study suggested the binding mode of this derivative within SIRT1 in the presence of the p53-AMC-peptide. These promising results could pave the way to further expand and optimize this chemical class of new SIRT1 activators as potential cardioprotective agents. Full article

Skin aging is primarily driven by oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. This study investigated the anti-senescence effects of fermented porcine placenta (FPP) and its dipeptides, leucine–glycine (LG) and proline–hydroxyproline (PH), in human epidermal keratinocytes (HEKs), using nicotinamide mononucleotide (NMN) as a reference for nicotinamide adenine dinucleotide (NAD⁺)-related pathways. FPP suppressed senescence-associated β-galactosidase (SA-β-gal) activity and Cyclin-dependent kinase inhibitor 2A (p16) expression while enhancing adenosine triphosphate (ATP) production and sirtuin 1 (SIRT1)–peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling. LG and PH exhibited distinct actions: LG improved redox balance by increasing the NAD⁺/NADH ratio and NAD(P)H quinone oxidoreductase 1 (NQO1) activity, whereas PH modulated cell cycle regulators and upregulated sirtuin 3 (SIRT3) expression. Although both peptides contributed to FPP’s effects, their combination did not fully replicate its overall activity, suggesting synergistic roles of multiple bioactive constituents. These findings highlight FPP as a multifactorial modulator of keratinocyte senescence, acting via mitochondrial and redox-related mechanisms. Full article

Sirtuin 3 (sirt3), a mitochondrial NAD⁺-dependent deacetylase, is an important enzyme in the maintenance of kidney functions, with critical roles in renal homeostasis, attenuation of oxidative stress, and preservation of mitochondrial homeostasis. This review aims to summarize the current literature on the mechanisms by which sirt3 impacts kidney health and disease, as well as highlight the therapeutic implications of sirt3 targeting. We conducted a PubMed search using the title word “sirt3” and the keyword “kidney” to generate our literature review sources. The animal studies that are explored in this review include cisplatin-induced acute kidney injury, cadmium-induced kidney injury, cecal ligation and puncture (CLP) and lipopolysaccharide-induced sepsis, diabetic kidney fibrosis, high-fat induced kidney disease, and ischemic kidney injury. Increasing evidence points towards a deficiency in sirt3 being an aggravator of mitochondrial dysfunction, promoting abnormal glycolysis, and contributing to the progression of diabetic kidney disease, renal fibrosis, and acute kidney injury. In contrast, pharmacological and dietary activation of sirt3 has been observed to enhance mitochondrial biogenesis, mitigate production of reactive oxygen species (ROS), and preserve the integrity of renal tubular cells under stressful conditions. Collectively, studies point towards sirt3 as a central metabolic and antioxidant regulator within the kidney, and link chronic kidney disease, as well as age-related decline in kidney function, to this enzyme. The conclusion of this review identifies future directions for translational research regarding sirt3 and NAD⁺-dependent regulation of mitochondrial homeostasis in renal medicine. Full article

Sirtuin 1 (SIRT1), an NAD⁺-dependent histone deacetylase, exerts complex and context-dependent effects in breast and gynecological cancers. By deacetylating histone and non-histone proteins such as p53, FOXO, and NF-κB, SIRT1 regulates essential processes including DNA repair, apoptosis, metabolism, and stress response. In breast cancer, SIRT1 may act as a tumor suppressor in early stages by maintaining genomic stability but promotes epithelial–mesenchymal transition, metastasis, and chemoresistance in aggressive subtypes such as triple-negative breast cancer. Similarly, in gynecological cancers, SIRT1 displays dual roles: promoting proliferation via estrogen signaling and p53/FOXO1 inhibition in Type I endometrial cancer yet potentially supporting DNA repair in high-grade Type II tumors. Its overexpression in ovarian and cervical cancers is linked to enhanced survival and drug resistance. Preclinical studies show that pharmacological inhibition of SIRT1 (e.g., with EX-527 or cambinol) restores chemosensitivity and reduces tumor cell viability, suggesting potential for SIRT1 inhibitors as adjuncts in cancer therapy. However, clinical trials specifically targeting SIRT1 in these cancers remain limited. Further investigation is needed to define therapeutic windows, molecular contexts, and combination strategies that could optimize SIRT1-targeted therapies. This review summarizes the current understanding of SIRT1’s roles in breast and gynecologic malignancies. Full article

Background/Objectives: Atherosclerosis remains a leading cause of morbidity and mortality worldwide, with an urgent need for novel preventive and therapeutic strategies. Sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, has emerged as a central regulator of vascular homeostasis, modulating oxidative stress, inflammation, lipid metabolism, and endothelial function. Increasing evidence highlights that some natural activators of SIRT1 may be interesting in mitigating the development of cardiovascular diseases. Methods: Searching in the main databases PubMed and Scopus, we made a literature revision, including studies from January 2000 to June 2025, of the major natural SIRT1 activators involved in vascular impairment in order to investigate their potential therapeutic use in atherosclerosis. Results: Among them, resveratrol, quercetin, naringenin, and hydroxytyrosol show the strongest evidence in activating SIRT1 and modulating the essential molecular pathways involved in atherosclerotic disease. These findings span from preclinical to clinical studies, with limited randomized clinical trial data for hard cardiovascular outcomes. Conclusions: This review synthesizes current knowledge on natural SIRT1 activators in the context of atherosclerosis, emphasizing their molecular mechanisms and clinical perspectives. The concept of using nutraceuticals-based interventions targeting SIRT1 may pave the way for innovative strategies in cardiovascular diseases. Full article

The fruits of Piper longum L. (long pepper), a spice and medicinal plant of the family Piperaceae, are widely used in South and Southeast Asian cuisine and traditional medicine, valued for their pungent flavor and aroma. The metabolomic profiling of P. longum using UPLC-qTOF-MS/MS provided a comprehensive chemical characterization of this traditional medicinal plant, revealing that lignans and amide alkaloids are the major classes of secondary metabolites. To further investigate its pharmacological potential, the bioactive ethyl acetate fraction was subjected to a SIRT1-targeted chemical investigation. This led to the isolation and structural elucidation of three previously undescribed compounds, a cadinene-type sesquiterpene (1) and two oxo-neolignan (2 and 5), along with four known compounds 3, 4, 6, and 7. Compounds (1–7) were evaluated for their ability to modulate p53-dependent transcriptional activity via SIRT1 activation using a luciferase reporter cell-based assay. SIRT1, a NAD⁺-dependent deacetylase, is a crucial regulator of longevity, metabolism, and cellular stress resistance, making it a key target for the treatment of age-related diseases. Compounds 2–7 exhibited significant SIRT1 activation, with compound 6 displaying particularly high efficacy, comparable to resveratrol, the most well-known natural SIRT1 activator. This study demonstrates that the discovery of novel chemical scaffolds through bioactivity-guided screening highlights the value of combining advanced metabolomics with pharmacological evaluation. The results support the traditional medicinal use of long pepper and its potential for development into functional foods or pharmaceuticals for healthy aging. Full article