We performed an integrated analysis of genome-wide DNA methylation and expression datasets in normal cells and healthy animals exposed to polyphenols with estrogenic activity (i.e. phytoestrogens). We identified that phytoestrogens target genes linked to disrupted cellular homeostasis, e.g. genes limiting DNA break repair (RNF169) or promoting ribosomal biogenesis (rDNA). Existing evidence suggests that DNA methylation may be governed by sirtuin 1 (SIRT1) deacetylase via interactions with DNA methylating enzymes, specifically DNMT3B. Since SIRT1 was reported to be regulated by phytoestrogens, we test whether phytoestrogens suppress genes related to disrupted homeostasis via SIRT1/DNMT3B-mediated transcriptional silencing. Human MCF10A mammary epithelial cells were treated with phytoestrogens, pterostilbene (PTS) or genistein (GEN), followed by analysis of cell growth, DNA methylation, gene expression, and SIRT1/DNMT3B binding. SIRT1 occupancy at the selected phytoestrogen-target genes, RNF169 and rDNA, was accompanied by consistent promoter hypermethylation and gene downregulation in response to GEN, but not PTS. GEN-mediated hypermethylation and SIRT1 binding were linked to a robust DNMT3B enrichment at RNF169 and rDNA promoters. This was not observed in cells exposed to PTS, suggesting a distinct mechanism of action. Although both SIRT1 and DNMT3B bind to RNF169 and rDNA promoters upon GEN, the two proteins do not co-occupy the regions. Depletion of SIRT1 abolishes GEN-mediated decrease in rDNA expression, suggesting SIRT1-dependent epigenetic suppression of rDNA by GEN. These findings enhance our understanding of the role of SIRT1-DNMT3B interplay in epigenetic mechanisms mediating the impact of phytoestrogens on cell biology and cellular homeostasis.

SIRT1 regulates gene transcription via various signaling pathways, mitigating oxidative stress damage in renal tubular epithelial cells, reducing renal inflammation, and decreasing apoptosis in tubular cells. This study explores the mechanisms of action of SIRT1 in sepsis-induced acute kidney injury (AKI), offering a theoretical foundation for future treatments. Experiments were carried out in a CLP mouse model and an in vitro model using LPS-stimulated HK-2 cells. Immunoblotting and ELISA were employed to assess the expression levels of inflammatory cytokines (p < 0.01), finding that SIRT1 effectively reduces the inflammatory response in sepsis-induced AKI. Moreover, the detection of cell apoptosis via multiple pathways showed that SIRT1 can reduce the rate of cell apoptosis and effectively decrease oxidative stress in the validation reaction. Transmission electron microscopy observations further supported these findings, demonstrating that SIRT1 expression induces the blockade of cell apoptosis processes. The biochemical experiments concluded that SIRT1 ameliorates sepsis-induced AKI. Consequently, SIRT1 may represent a novel therapeutic target for AKI.

Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition; this phenomenon is known as cerebral ischemia-reperfusion injury. Current studies have elucidated the neuroprotective role of the sirtuin protein family (Sirtuins) in modulating cerebral ischemia-reperfusion injury. However, the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration. In this review, the origin and research progress of Sirtuins are summarized, suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury, including inflammation, oxidative stress, blood-brain barrier damage, apoptosis, pyroptosis, and autophagy. The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways, such as nuclear factor-kappa B signaling, oxidative stress mediated by adenosine monophosphate-activated protein kinase, and the forkhead box O. This review also summarizes the potential of endogenous substances, such as RNA and hormones, drugs, dietary supplements, and emerging therapies that regulate Sirtuins expression. This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors. While Sirtuins show promise as a potential target for the treatment of cerebral ischemia-reperfusion injury, most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans, potentially influencing the efficacy of Sirtuins-targeting drug therapies. Overall, this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.

Periodontitis is a prevalent chronic inflammatory disease characterized by alveolar bone resorption. Its progression is closely linked to oxidative stress where reactive oxygen species (ROS) generated by mitochondria exacerbate inflammation in positive feedback loops. Strategies for mitochondrial regulation hold potential for therapeutic advances. Metal-organic frameworks (MOFs) have shown promise as nanozymes for ROS scavenging. However, inability to directly regulate cellular processes to prevent further ROS production from damaged mitochondria during persistent inflammation makes MOFs insufficient in treating periodontitis. This study synthesizes MnO2@UiO-66(Ce) by introducing MnO2 within nanoscale mesoporous UiO-66 type MOFs. MnO2 coupled with Ce clusters in MOF channels, forms a superoxide dismutase/catalase cascade catalytic system. More importantnly, manganese endows the MOFs with bioactive effects which enhances mitophagy, facilitating the removal of damaged mitochondria, thereby restoring long-term cellular homeostasis. The results demonstrate that this synergistic antioxidant solution MnO2@UiO-66 restores mitochondrial homeostasis and osteogenic activity of periodontal ligament cells in vitro and alleviates inflammatory bone resorption in a ligature-induced periodontitis model in vivo. The SIRT1-FOXO3-BNIP3 signaling axis plays a key role in this process. This study may provide a design strategy that combines a highly efficient cascade catalytic system with long-term regulation of cellular homeostasis to combat oxidative stress in chronic inflammation.

Intervertebral disc degeneration (IVDD) is a leading contributor to spinal degenerative diseases; however, its pathogenesis remains only partially elucidated. Recent studies have highlighted that the diminished activity of SIRT1 and the aberrant activation of the NF-κB signaling pathway are critical pathogenic factors in IVDD. DBC1 has been identified as a regulator of SIRT1 activity and the NF-κB signaling pathway. This study aimed to investigate the role of DBC1 in IVDD.

The expression levels of DBC1 in the nucleus pulposus of aging rats were quantified. Both overexpression and knockdown of DBC1 were utilized to explore their effects on the extracellular matrix (ECM) of the nucleus pulposus. Furthermore, the influence of DBC1 on cellular senescence, apoptosis, and ECM regulation in nucleus pulposus cells was assessed using Western blot (WB), cellular fluorescence assays, and histological staining techniques.

Our results demonstrate that DBC1 expression is significantly upregulated in IVDD. Moreover, DBC1 appears to contribute to IVDD by promoting apoptosis, senescence, and ECM degradation in nucleus pulposus cells. Mechanistic investigations revealed that DBC1 activates the NF-κB signaling pathway while suppressing SIRT1 expression in nucleus pulposus cells, suggesting that these two mechanisms underlie its effects on IVDD.

In summary, this study provides evidence that DBC1 may play a pivotal role in the pathogenesis of IVDD by inhibiting SIRT1 activity and activating the NF-κB signaling pathway. Consequently, targeting DBC1 suppression could represent a promising therapeutic strategy for managing IVDD.

Sirtuins (SIRTs) are multifunctional proteins that exhibit a wide range of substrate preferences and cellular localizations. They are reliant on NAD+ and are essential for the regulation of several cellular functions. The SIRT proteins play important role towards tumor survival and resistance mechanisms in tumor cells. Therefore, molecules targeting SIRT proteins gained significant recognition in cancer research. In this work, we explored the anticancer property, potential and mode of action of 2-(diarylalkyl)aminobenzothiazole derivatives on MCF7 human breast cancer cells. Our studies established that 2-(diarylalkyl)aminobenzothiazole derivatives 1-((6-chlorobenzo[d]thiazol-2-ylamino)(3,4-dichlorophenyl)methyl)naphthalen-2-ol (7ab) and 1-((6-chlorobenzo[d]thiazol-2-ylamino)(4-bromophenyl)methyl)naphthalen-2-ol (7ba) treatment in a dose dependent manner drastically lowered the cell proliferation in MCF7 cells and the IC50 values of 7ab and 7ba was found to be 11.4 µM and 9.6 µM at 24 hr in these cells. Docking and molecular dynamic simulation studies further revealed that 7ab and 7ba show significant binding with SIRT1 protein. Consistently, treatment with 7ab and 7ba reduced the expression levels of SIRT1 protein while increasing acetylation of p53, a known SIRT protein target in MCF-7 cells. We observed that SIRT1inhibition was associated with activation of p53, an essential protein for apoptotic cell death, in MCF-7 cell lines. Furthermore, 7ab and 7ba treatment induced LC3-II expression and vacuole formation in the cytoplasm leading to autophagic cell death. Our findings together reveal the plausible cellular targets and specificity of these new small molecules as SIRT inhibitors, which increase p53 acetylation and suppress the proliferation of MCF-7 human breast cancer cells by triggering autophagic and apoptotic cell death.

Globally, the incidence and prevalence rates of ulcerative colitis (UC) show a rising pattern. The limited efficacy and significant adverse effects associated with current treatment options underscore the need for novel therapeutic approaches. It has been found that linagliptin, a dipeptidyl peptidase-4 inhibitor, activates AMPK in different disease conditions. The main objective of the present work was to elucidate the potential implications of the AMPK/FOXO3a mediated by linagliptin in rats with chronic colitis. The findings of the current report revealed the first robust in-vivo evidence advocating the coloprotective effect of linagliptin against dextran sodium sulfate-induced chronic UC in rats. It has demonstrated potential beyond its antidiabetic effects by modulating FOXO3a localization. By shifting FOXO3a from the cytosol to the nucleus, linagliptin enhanced the transcription of genes involved in attenuation of pro-inflammatory events and restoration of redox homeostasis. Nuclear FOXO3a also impacted NFκB activity, reducing inflammation. This conclusion was fundamentally supported by the documented improvements in histopathological changes evidenced by reduced inflammation, edema, crypt atrophy, and submucosal fibrosis. Moreover, decreased colon weight/length ratio, as well as reduced scores of disease activity and macroscopic damage indices, were observed. Furthermore, it corrected body weight loss during the time frame of the experiment. These findings underscore the anti-inflammatory potential of therapies that promote the nuclear localization of FOXO3a in inflammatory conditions. Linagliptin's ability to modulate FOXO3a localization might be particularly useful for diabetic patients suffering from inflammatory bowel diseases. However, further molecular investigations are required to validate the findings and to assess the clinical application of this approach as a valid tool for alleviating UC.

The aim of the present work was to investigate some of the molecular mechanisms and targets of the anticancer action of the bioflavonoid fustin isolated from the heartwood of Cotinus coggygria Scop. in the triple-negative breast cancer cell line MDA-MB-231. For this purpose, we applied fluorescence microscopy analysis to evaluate apoptosis, necrosis, and mitochondrial integrity, wound healing assay to study fustin antimigratory potential and quantitative reverse transcription-polymerase chain reaction to analyze the expression of genes associated with cell cycle control, programmed cell death, metastasis, and epigenetic alterations. A complex network-based bioinformatic analysis was also employed for protein-protein network construction, hub genes identification, and functional enrichment. The results revealed a significant induction of early and late apoptotic and necrotic events, a slight alteration of the mitochondria-related fluorescence, and marked antimotility effect after fustin treatment. Of 34 analyzed genes, seven fustin targets were identified, of which CDKN1A, ATM, and MYC were significantly enriched in pathways such as cell cycle, intrinsic apoptotic signaling pathway in response to DNA damage and generic transcription pathway. Our findings outline some molecular mechanisms of the anticancer action of fustin pointing it out as a potential oncotherapeutic agent and provide directions for future in vivo research.

The fatty acid (FA) transporter CD36 (FA translocase/cluster of differentiation 36) is the gatekeeper of cardiac FA metabolism. Preferential localization of CD36 to the sarcolemma is one of the initiating cellular responses in the development of muscle insulin resistance and the type 2 diabetic heart. Posttranslational S-acylation controls protein trafficking, and in this study, we hypothesized that increased CD36 S-acylation may underpin the preferential sarcolemmal localization of CD36, driving metabolic and contractile dysfunction in diabetes.

Type 2 diabetes increased cardiac CD36 S-acylation, CD36 sarcolemmal localization, FA oxidation rates, and triglyceride storage in the diabetic heart. CD36 S-acylation was increased in diabetic rats, db/db mice, diabetic pigs, and insulin-resistant human iPSC-derived cardiomyocytes, demonstrating conservation between species. The enzyme responsible for S-acylating CD36, zDHHC4, was transcriptionally upregulated in the diabetic heart, and genetic silencing of zDHHC4 using siRNA or lentiviral shRNA decreased CD36 S-acylation. We identified that zDHHC4 expression is under the regulation of the transcription factor FoxO (forkhead box O) 1, as FoxO1 binds to the promotor of zDHHC4 and induces its transcription, as assessed using chromatin immunoprecipitation-seq, chromatin immunoprecipitation-quantitative PCR, luciferase assays, and siRNA silencing. Diabetic mice with cardiomyocyte-specific FoxO1 deletion had decreased cardiac zDHHC4 expression and decreased CD36 S-acylation, which was further confirmed using diabetic mice treated with the FoxO1 inhibitor AS1842856. Pharmacological inhibition of zDHHC enzymes in diabetic hearts decreased CD36 S-acylation, sarcolemmal CD36 content, FA oxidation rates, and triglyceride storage, culminating in improved cardiac function in diabetes. Conversely, inhibiting the deacylating enzymes in control hearts increased CD36 S-acylation, sarcolemmal CD36 content, and FA metabolic rates in control hearts, recapitulating the metabolic phenotype seen in diabetic hearts.

Activation of the FoxO1-zDHHC4-CD36 S-acylation axis in diabetes drives metabolic and contractile dysfunction in type 2 diabetic heart.

Nucleus pulposus cells (NPCs) undergo metabolic disorders and matrix pathological remodeling under the influence of various adverse factors during intervertebral disc degeneration (IVDD), whereas post-translational modifications (PTMs) can confer cells with the capacity to respond quickly and adapt to complex environmental changes. Here, SIRT1 protein, a key regulator within PTMs framework, was applied against the hostile degenerative microenvironment. Then, it was sequentially assembled with SOX9-expressing plasmid, an essential transcription factor to promote extracellular matrix (ECM) biosynthesis, onto a phenylboronic acid-functionalized G5-dendrimer to construct a multifunctional nanoplatform for IVDD therapy. In vitro, the nanoplatforms showed antioxidant capacity, and the ability to restore mitochondrial homeostasis and normal ECM metabolism, as well as to maintain cellular phenotypes. RNA sequencing suggested that inhibition of the Nod-like receptor signaling might be the mechanism behind their therapeutic effects. The nanoplatforms were then wrapped in a designed dynamic hydrogel, not only prolonging the retention time of the loaded cargoes, but also well maintaining the disc structure, height, and water content in vivo. Overall, this study presents a convenient assembled strategy to inhibit the multiple adverse factors, and hold promise for the IVDD treatment.

Annual bay scallops are commercially significant bivalve species for fisheries and aquaculture, but their small size and severe inbreeding depression impede the development of their industry. Some interspecific hybrids of bay scallops and peruvian scallops show longer lifespans and significantly greater sizes, which may result from the longevity genes in the latter (7-10 years). Sirtuins (SIRTs) play pivotal roles in the genetic control of aging in various model species and human beings. However, the role of SIRTs in longevity has not been systematically studied in aquatic animals. In this study, different gene numbers, sequences, structures and tandem duplications of SIRTs were first identified between the two scallops through genome-wide analysis. Cloning and characteristics of the SIRT1 and SIRT6 ORFs revealed dramatic variations in amino acids between the two scallops, which may cause intrinsic differences in function for longevity regulation. In particular, the amino acid variations in the N-terminus may auto-regulate conformations, causing intrinsic differences in catalytic activity for longevity regulation. The robust expression of SIRT1 and SIRT6-2 in peruvian scallops suggested they may exert a role in extending the lifespan. Nutrient restriction (NR) could promote lifespan in terrestrial model organisms, and the SIRTs and their related genes responded to NR for longevity in scallops; peruvian scallops showed a higher ability of autophagy. This study provides potential biomarkers for breeding long-lived larger scallop hybrids for the sustainability of aquaculture. Moreover, the genetic variation during evolution in the two scallops provides a foundation for further research on the longevity function of the SIRTs.

The online version contains supplementary material available at 10.1007/s42995-024-00269-3.

In response to stress stimuli, cells have evolved various mechanisms to integrate internal and external signals to achieve dynamic homeostasis. Lysine acetyltransferase (KATs) and deacetyltransferase (KDACs) are the key modulators of epigenetic modifications, enabling cells to modulate cellular responses through the acetylation and deacetylation of both histone and nonhistone proteins. Understanding the signaling pathways involved in cellular stress response, along with the roles of KATs and KDACs may pave the way for the development of novel therapeutic strategies. This review discusses the molecular mechanisms of acetylation and deacetylation in stress responses related to tumorigenesis, viral and bacterial infections. In tumorigenesis section, we focused on the tumor cells' intrinsic and external molecules and signaling pathways regulated by acetylation and deacetylation modification. In viral and bacterial infections, we summarized the update research on acetylation and deacetylation modification in viral and bacterial infections, which systematical introduction on this topic is not too much. Additionally, we provide an overview of current therapeutic interventions and clinical trials involving KAT and KDAC inhibitors in the treatment of cancer, as well as viral and bacterial infection-related diseases.

While obesity rates increase worldwide, physical activity levels are reduced. Obesity and physical inactivity may be inversely related to the production of reactive oxygen species (ROS) and cause oxidative stress in the central nervous system. In this study, we aimed to investigate the effects of aerobic physical exercise on the oxidative balance of the prefrontal cortex of rats subjected to overnutrition during lactation. For this, male Wistar rats were subjected to overnutrition during lactation between postnatal day 3 to 21. On postnatal day 23, the two groups of animals were subdivided into trained and untrained animals. Trained rats were subjected to a treadmill training protocol for four weeks, five days/week, 60 min/day, at 50% of maximum running capacity. Our findings demonstrate that overnutrition impairs REDOX balance in the prefrontal cortex through increased prooxidants and reduced antioxidant defenses. On the contrary, exercise tends to restore most of these measures to control levels, possibly due to the increase in mRNA levels of Sirt1 and reduction in Il-6 in the prefrontal cortex. Overnutrition causes oxidative stress in the prefrontal cortex, while exercise re-covers most of its adverse effects through activating anti-inflammatory mechanisms.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease closely related to aging with unclear pathogenic mechanisms. This study aims to identify the biomarkers in RA, aging and autophagy using bioinformatics and machine learning and explore the binding stability of taurine to target utilizing computer-aided drug design (CADD).

We identified differentially expressed genes (DEGs) for RA, then crossed with gene libraries for aging and autophagy to identify common genes (Co-genes). We performed Gene Ontology (GO), Kyoto Encyclopedia of the Genome (KEGG), and ClueGO analysis for Co-genes. The Co-genes were subjected to support vector machine-recursive feature elimination (SVM-RFE), Degree, and Betweenness algorithms to get hub genes, then verified by an artificial neural network (ANN). After continuing to perform least absolute shrinkage and selection operator (LASSO) and weighted gene co-expression network analysis (WGCNA) on Co-genes, the results were crossed with hub genes to obtain genes, which were imported into various validation sets for receiver operating characteristics (ROC) to identify key genes. We analyzed the microRNA/TF network, enriched pathways, and immune cell infiltration for key genes. The binding stability of taurine with the target protein was verified by CADD. Finally, we used Western blot for in vitro experimental verification.

We obtained 74 Co-genes enriched in RA, cellular senescence, and regulation of programmed cell death. The model prediction of hub genes works well in ANN. The key genes (MMP9, CXCL10, IL15, FOXO3) were tested in ROC with excellent efficacy. In RA, FOXO3 expression was down-regulated while MMP9, CXCL10, and IL15 expression were upregulated, and FOXO3 was negatively correlated with MMP9, CXCL10, and IL15. Two miRNAs (hsa-mir-21-5p, hsa-mir-129-2-3p) and four TFs (CTCF, KLF, FOXC1, TP53) were associated with key genes. The immune cells positively correlated with MMP9, CXCL10, and IL15 expression and negatively correlated with FOXO3 expression were Plasma cells, CD8 T cells, memory-activated CD4 T cells, and follicular helper T cells, aggregating in RA. The binding stability of taurine with FOXO3 was verified by molecular docking and molecular dynamics simulation. In vitro experiments have indicated that taurine can upregulate the expression of FOXO3 and treat RA through the FOXO3-Parkin signaling pathway.

MMP9, CXCL10, IL15, and FOXO3 are biomarkers of RA, cellular senescence, and autophagy. Taurine might be a promising drug against RA via targeting cellular senescence and autophagy through FOXO3.

Radiotherapy, a widely employed cancer treatment, often triggers diverse inflammatory responses such as radiation enteritis, pulmonary injury, pelvic inflammation, dermatitis, and osteitis. Dietary polyphenols have recently emerged as promising agents for mitigating radiation-induced inflammation. However, their clinical application faced challenges related to variable bioavailability, individual pharmacokinetics, optimal dosing, and limited clinical evidence. Current researches revealed the efficacy of bioactive small molecule polyphenols in addressing radiation-induced inflammation. In this review, along with a comprehensive examination of the etiology and categories of radiation-induced inflammatory conditions, the diversity of polyphenols and elucidating their anti-inflammatory mechanisms are explored. This study emphasizes the recent progresses in delivery systems for dietary polyphenols, aiming to enhance radioprotection effects. The optimized utilization of polyphenols, with a theoretical framework and reference guide, is of paramount relevance. Through diverse delivery mechanisms, the more effective and safer radioprotective strategies become achievable. This endeavor aspires to contribute to breakthroughs in the dietary polyphenols' application, significantly enhancing human health protection during radiotherapy. These comprehensive insights presented here also support (pre)-clinical practices in navigating the complexities of utilizing dietary polyphenols for radioprotection, fostering advancements in the field and improving patient outcomes.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder marked by a gradual decline in memory and cognitive functions. It is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal degeneration, affecting a significant portion of the human population. A key feature of various nervous system disorders, including AD, is extensive cellular death caused by apoptosis, which affects not only neurons but also glial cells. While apoptosis plays a vital role in eliminating certain cells and supporting normal development, alterations or disruptions in apoptotic pathways can lead to harmful neurodegenerative conditions such as AD. Thus, targeting apoptosis presents a promising therapeutic approach for these diseases. MicroRNAs (miRNAs), a class of non-coding RNA, play diverse roles in cellular functions, including proliferation, gene expression regulation, programmed cell death, intercellular communication, and angiogenesis. By modulating regulatory genes, miRNAs can influence apoptosis, either promoting or inhibiting it. Aberrant expression of miRNAs can impact multiple apoptotic pathways, potentially driving the progression of AD and related health issues. This review summarizes recent research on miRNAs and their dual role in exacerbating or protecting against neural cell damage in AD by altering apoptotic pathways. The regulation of apoptosis by miRNAs offers a prospective therapeutic strategy for Alzheimer's disease.

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a cluster of conditions characterized by accumulations of fat, metabolic factors such as obesity, diabetes and high cholesterol. MASLD is now the leading cause of chronic liver disease worldwide, with a rapidly increasing trend. We aimed to demonstrate that genetic variants of rs2802292 SNP can influence the development of MASLD even after many years. Methods: We studied 650 participants from the NUTRIHEP cohort, both at baseline (2005-2006) and at first recall (2014-2018), and genotyped rs2802292. The validated European Prospective Investigation into Cancer and Nutrition (EPIC) questionnaire was administered during the visit, and each single food was assigned to one of 33 groups. Results: Associations of food intake at baseline with MASLD were found in the first recall, for each genotype, GG, GT, and TT, and several covariates were used to adjust models. Dressing fats other than olive oil resulted protection against MASLD in GG subjects, whereas seed oil, juices, and spirits resulted in protection against MASLD for GT subjects. An increased risk of MASLD was found for subjects with the TT genotype for white meat intake (OR = 1.018, p = 0.031, 1.002 to 1.035 95% C.I.), ready-to-eat dishes (OR = 1.015, p = 0.033, 1.001 to 1.029 95% C.I.), processed meat (OR = 1.093, p = 0.003, 1.031 to 1.158 95% C.I.), and processed fish (OR = 1.085, p = 0.037, 1.005 to 1.172 95% C.I.). Conclusions: Subjects with the TT genotype had a higher risk of developing MASLD than subjects with other genotypes. A healthier lifestyle is important to counteract liver disease.

Heart failure-induced renal tubular epithelial cell fibrosis is an important pathological process that leads to chronic kidney disease. This study is to investigate the regulatory mechanism of over-expression or knock-down SIRT1 gene, alleviating hypoxia-induced HK2 cell fibrosis in heart failure. The focus is on the SIRT1-FoxO1-FoxO3-Autophagy pathway. In vitro experiments are performed by HK2cell line to simulate the normal oxygen state (Normoxia) and the hypoxia state (Hypoxia) caused by heart failure, SIRT1 gene over-expression by transfected vectors, knock-down and Rapamycin (RAPA)-induced cellular autophagy, and the cell models are divided into four subgroups, named control group, oeSIRT1, siSIRT1 and siSIRT1+RAPA. Western blotting (WB), real-time qPCR, immunofluorescence (IF), ELISA, and transmission electron microscopy are used to quantitatively or semi-quantitatively analyze the expression of FoxO1, FoxO3, SIRT1, Beclin1, LC-3, α-SMA, E- Cadherin, and collagen-I in cells or supernatants. It is demonstrated that activation of SIRT1 regulates the expression and activity of FoxO1 and FoxO3, thereby affecting autophagy. This modulation leads to a reduction in HK2 fibrosis markers (α-SMA and E-cadherin) and extracellular matrix deposition (collagen I), which ultimately attenuates renal tubular epithelial cell fibrosis. These findings provide new insights into potential therapeutic strategies for treating heart failure-induced renal tubular epithelial cell fibrosis by targeting the SIRT1-FoxO1-FoxO3-Autophagy pathway.

The transcription factor FoxO3a plays a crucial role in the process of cells adapting to various stress conditions. Multiple post - translational modifications and epigenetic mechanisms work together to precisely regulate the activity of FoxO3a, influencing its subcellular localization, stability, interactions with other proteins, DNA - binding affinity, and transcriptional regulatory capacity. Under different chemical signal stimuli and subcellular environments, the activation of FoxO3a triggered by oxidative stress can initiate diverse transcriptional programs, which are essential for the body to resist oxidative damage. In the development and progression of inflammatory diseases, FoxO3a exerts an important function by regulating the expression levels of antioxidant enzymes and participating in key physiological processes such as programmed cell death. This article comprehensively reviews the structural characteristics, mechanism of action of FoxO3a, as well as its functions in regulating antioxidant enzymes and programmed cell death. The aim is to deeply explore the potential of FoxO3a as a potential therapeutic target for preventing and treating damages such as inflammatory diseases caused by cellular stress.

Humans encounter ionizing radiation (IR) through various ways, such as medical applications, agricultural industry, and potential exposure from radioactive materials or acts of radiological terrorism. Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are crucial for maintaining the balance of blood cell lineages. The hematopoietic system, recognized as the most sensitive human tissue, is severely affected by IR, which can result in bone marrow (BM) failure, increased susceptibility to infections, hemorrhagic events, or anemia in affected individuals. Therefore, it is essential to develop radioprotective compounds to protect HSCs/HPCs. This review highlights several radioprotective agents that protect the hematopoietic system from IR-related damage to HSCs and HPCs and provides an overview of the mechanisms involved in damage and protection.

With advancing age, the decline in intestinal stem cell (ISC) function can lead to a series of degenerative changes in the intestinal epithelium, a critical factor that increases the risk of intestinal diseases in the elderly. Consequently, there is an urgent imperative to devise effective dietary intervention strategies that target the alterations in senescent ISCs to alleviate senescence-related intestinal dysfunction. The 28-month-old naturally aging mouse model was utilized to discover that the primary factor contributing to the compromised barrier function and digestive absorption of the small intestine was a decrease in both the number and regenerative capacity of ISCs. The underlying mechanism involves the degeneration of mitochondrial function in ISCs, resulting in insufficient energy supply and decreased metabolic capacity. Additionally, our findings indicate that fasting-refeeding can influence the mitochondrial metabolism of ISCs, and that alternate day fasting (ADF) can facilitate the restoration of both the quantity and regenerative capabilities of ISCs, thereby exhibiting a notable antiaging effect on the small intestine. In conclusion, this study provides new insights into the potential beneficial role of ADF in ameliorating intestinal aging, thereby establishing a foundation for future investigations into dietary interventions aimed at addressing age-related intestinal dysfunction.

Cells are susceptible to both oxidative and reductive stresses, with reductive stress being less studied and potentially therapeutic in cancer. Reductive stress, characterized by an excess of reducing equivalents exceeding the activity of endogenous oxidoreductases, can lead to an imbalance in homeostasis, causing an increase in reactive oxygen species induction, affecting cellular antioxidant load and flux. Unlike oxidative stress, reductive stress has been understudied and poorly understood, and there is still much to learn about its mechanisms in cancer, its therapeutic potential, and how cancer cells react to it. Changes in redox balance and interference with redox signaling are linked to cancer cell growth, metastasis, and resistance to chemotherapy and radiation. Overconsumption of reducing equivalents can reduce metabolism, alter protein disulfide bond formation, disrupt mitochondrial homeostasis, and disrupt cancer cell signaling pathways. Novel approaches to delivering or using cancer medicines and techniques to influence redox biology have been discovered. Under reductive stress, cancer cells may coordinate separate pools of redox pairs, potentially impacting biology.

Fatty liver hemorrhage syndrome (FLHS) has become one of the major factors leading to the death of laying hen in caged egg production. FLHS is commonly associated with lipid peroxidation, hepatocyte injury, decreased antioxidant capacity, and inflammation. However, there are limited evidences regarding the preventive effect of Lactiplantibacillus plantarum on FLHS in laying hens and its mechanisms. Our previous results showed that Lp. plantarum FRT4 alleviated FLHS by regulating lipid metabolism, but did not focus on its antioxidant and anti-inflammatory functions and mechanisms. Therefore, this study aimed to investigate the preventive mechanisms of Lp. plantarum FRT4 in alleviating FLHS, with a focus on its role in antioxidant activity and inflammation regulation.

Supplementation with Lp. plantarum FRT4 enhanced the levels of T-AOC, T-SOD, and GSH-Px, while reducing the levels of TNF-α, IL-1β, IL-8, and NLRP3 in the liver and ovary of laying hens. Additionally, Lp. plantarum FRT4 upregulated the mRNA expressions of SOD1, SOD2, CAT, and GPX1, downregulated the mRNA expressions of pro-inflammatory factors IL-1β, IL-6, and NLRP3, and upregulated the mRNA expressions of anti-inflammatory factors IL-4 and IL-10. Lp. plantarum FRT4 improved the structure and metabolic functions of gut microbiota, and regulated the relative abundances of dominant phyla (Bacteroidetes, Firmicute, and Proteobacteria) and genera (Prevotella and Alistipes). Additionally, it influenced key KEGG pathways, including tryptophan metabolism, amino sugar and nucleotide sugar metabolism, insulin signaling pathway, FoxO signaling pathway. Spearman analysis revealed that the abundance of microbiota at different taxonomic levels was closely related to antioxidant enzymes and inflammatory factors. Furthermore, Lp. plantarum FRT4 modulated the mRNA expressions of related factors in the FoxO/TLR-4/NF-κB signaling pathway by regulating gut microbiota. Moreover, the levels of E2, FSH, and VTG were significantly increased in the ovary after Lp. plantarum FRT4 intervention.

Lp. plantarum FRT4 effectively ameliorates FLHS in laying hens. This efficacy is attributed to its antioxidant and anti-inflammatory properties, which are mediated by modulating the structure and function of gut microbiota, and further intervening in the FoxO/TLR-4/NF-κB signaling pathway. These actions enhance hepatic and ovarian function and increase estrogen levels. Video Abstract.

In previous studies, we have shown that growth arrest and DNA damage (Gadd) 45α is required for the repair of nitric oxide-mediated DNA damage in β-cells. Gadd45α expression is stimulated by nitric oxide and requires forkhead box protein (Fox) O1 and NAD+-dependent deacetylase activity. Based on inhibitor studies, we attributed this activity to Sirtuin (SIRT)1; however, the inhibitors used in this previous study also attenuate the deacetylase activity of SIRT2, 3, and 6. We now provide experimental evidence that SIRT1 is dispensable for β-cell expression of Gadd45α and that the mitochondrial localized isoform SIRT3, is required for DNA repair in β-cells. We show that siRNA knockdown of Sirt3 attenuates nitric oxide-stimulated Gadd45α mRNA accumulation in both wildtype and Sirt1-/- INS 832/13 cells as well as isolated rat islets and that SIRT3 inhibition increases FoxO1 acetylation and attenuates DNA repair in response to nitric oxide. While SIRT3 is predominantly localized to mitochondria, a small fraction is localized in the nucleus of insulin-containing cells and functions to participate in the regulation of FoxO1-dependent, nitric oxide-stimulated DNA repair.

Ischemic stroke, the most prevalent form of stroke, is responsible for the highest disability rates globally and ranks as the primary cause of mortality worldwide. Sirt1, extensively investigated in neurodegenerative disorders, is the most well-known and earliest member of the sirtuins family. However, its mechanism of action during ischemic stroke remains ambiguous. The literature examination revealed the intricate involvement of Sirt1 in regulating both physiological and pathological mechanisms during ischemic stroke. Sirt1 demonstrates deacetylation effects on PGC-1α, HMGB1, FOXOs, and p53. It hinders the activation of NLRP3 inflammasome and NF-κB while also engaging with AMPK. It regulates inflammatory response, oxidative stress, mitochondrial dysfunction, autophagy, pro-death, and necrotic apoptosis. Therefore, the potential of Sirt1 as a therapeutic target for the management of ischemic stroke is promising.

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease. Ketogenic diets (KD) is a high-fat, low-carbohydrate diet. KD produces ketone bodies to supplement energy in the case of insufficient glucose in the body. β-Hydroxybutyrate (BHB) is the main component of ketone bodies. BHB serves as "ancillary fuel" substituting (but also inducing) anti-oxidative, anti-inflammatory, and cardio-protective features by binding to several target proteins, including histone acylation modification, or G protein-coupled receptors (GPCRs). KD have been used to treat epilepsy, obesity, type-2 diabetes mellitus, polycystic ovary syndrome, cancers, and other diseases. According to recent research, KD and the induced BHB delay DKD progression by improving the metabolism of glucose and lipids, regulating autophagy, as well as alleviating inflammation, oxidative stress and fibrosis. However, due to some side-effects, the role and mechanism of action of KD and BHB in the prevention and treatment of DKD are controversial. This review focuses on recent progress in the research of KD and BHB in clinical and preclinical studies of DKD, and provides new perspectives for DKD treatment.

NAD+ deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD+ enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD+ synthesis.

Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD+ levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.

NRH entered tissues unassisted and was rapidly metabolized for NAD+ biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD+ levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.

This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD+ enhancement.

Elevated levels of androgens in the brain accelerate tumor progression in patients with glioblastoma (GBM). Despite current research efforts concentrating on decreasing peripheral androgens to improve GBM prognosis, results have not met expectations. Herein, we aim to elucidate the source of increased androgen levels in the brains of GBM patients and investigate whether lowering it can improve the prognosis of GBM patients. The Elisa was employed to measure androgen levels. The effects of androgens on U87 cells were evaluated using CCK-8 assays, clone formation assays, wound healing assays, and migration/invasion assays. RNA sequencing, RT-qPCR and Western blotting were performed to assess the expression levels of steroid enzymes, tumor drug resistance, Sirt1, FOXO1genes and proteins. Co-immunoprecipitation (Co-IP) assays were conducted to investigate the interactions and acetylation levels between Sirt1 and FOXO1. Lentiviral transfection was utilized to establish stable cell lines. Furthermore, an in vivo murine subcutaneous tumor model was established to further confirm the role of Sirt1 in tumor progression. We found androgen levels in the cerebrospinal fluid of GBM patients were higher than in the periphery, contrasting with healthy individuals. Additionally, the steroid enzymes in GBM cells were upregulated. Reducing peripheral androgens compensatorily enhances GBM androgen synthesis capacity (CYP17A1, CYP11A1, SRD5A2) and chemo-resistance (ABCB11, BIRC3, FGF2, NRG1), while the levels of androgens in the brain remain consistently high. The above results indicate that the increased androgens in the brain of GBM patients are self-secreted. Further investigations demonstrate that the transcription factor FOXO1 in GBM is regulated by silent information regulator 1 (Sirt1) through deacetylation, leading to enhanced androgen synthesis capacity in vivo and in vitro. Overexpressing Sirt1 significantly lowers brain androgen levels and delays tumor progression in mouse models. Compared to conventional finasteran therapy, the targeted-Sirt1 results in lower brain androgen levels and smaller tumor volumes. Our findings provide evidence that the elevated androgens in the brain of GBM patients came from tumor autocrine. Overexpression of Sirt1 reduces FOXO1 acetylation, lowers androgen synthesis enzyme levels, and effectively decreases brain androgen levels, thereby delaying tumor progression.

Depression and coronary heart disease (CHD) are two interconnected diseases that profoundly impact global health. Depression is both a complex psychiatric disorder and an established risk factor for CHD. Sirtuin 1 (SIRT1) is an enzyme that requires the cofactor nicotinamide adenine dinucleotide (NAD+) to perform its deacetylation function, and its involvement is crucial in reducing cardiovascular risks that are associated with depression. SIRT1 exerts its cardioprotective effects via modulating oxidative stress, inflammation and metabolic processes, all of which are central to the pathogenesis of CHD in individuals with depression. Through influencing these pathways, SIRT1 helps to reduce endothelial dysfunction, prevent the formation of atherosclerotic plaques and stabilize existing plaques, thereby decreasing the overall risk of CHD. The present review underscores the important role of SIRT1 in serving as a therapeutic intervention molecule for tackling cardiovascular complications stemming from depression. Furthermore, it highlights the need for further studies to clarify how SIRT1 influences both depression and CHD at the molecular level. The ultimate goal of this research will be to translate these findings into practical clinical intervention strategies.

Aberrant expression of grainyhead-like transcription factor 3 (GRHL3) has been extensively reported in the development and progression of several squamous cell carcinomas, such as cutaneous, head and neck, and esophageal squamous cell carcinoma. However, the clinical significance and biological roles of GRHL3 in lung squamous cell (LUSC) carcinoma are largely unclear. Herein, we report that GRHL3 was significantly upregulated in lung squamous epithelium of LUSC tissues, bronchiole, and bronchus. Moreover, expression levels of GRHL3 were decreased with the advance of pathological grade, and low GRHL3 level presented poor overall survival and short progression-free and distant metastasis-free survival in LUSC patients but had no prognostic significance in LUAD patients. Functional experiments in vivo showed that downregulating GRHL3 promoted not only lung colonization and growth but also multiple organ distant metastasis of LUSC cells, including bone, brain, and liver. Moreover, silencing GRHL3 promoted anoikis resistance and cancer stem cell (CSCs) characteristics of LUSC cells in vitro. Mechanistically, silencing GRHL3 stabilized SOX2 via SIRT1-mediated decreasing acetylation and subsequent ubiquitination-dependent degradation in LUSC cells. Thus, in-depth understanding of the underlying mechanism of GRHL3 in the progression of LUSC will facilitate the development of prognostic biomarker and therapeutic avenues against LUSC, which will present favorable prospects in improving outcomes of LUSC patients. © 2025 The Pathological Society of Great Britain and Ireland.

Acute lung injury (ALI) is a continuum of lung changes caused by multiple lung injuries, often associated with severe complications and even death. In ALI, macrophages, alveolar epithelial cells and vascular endothelial cells in the lung are damaged to varying degrees and their function is impaired. Research in recent years has focused on the use of SIRT1 for the treatment of ALI. In this paper, we reviewed the role of SIRT1 in ALI in terms of its cellular and molecular mechanism, targeting of SIRT1 by non-coding RNAs and drug components, as well as pointing out the value of SIRT1 for clinical diagnosis and prognosis. Based on the current literature, SIRT1 exhibits diverse functionalities and possesses significant therapeutic potential. Targeting SIRT1 may provide new therapeutic ideas for the treatment of ALI.

The pathogenesis of alcohol-associated liver disease (ALD) involves ethanol-induced enhancement of gut permeability, bacterial products released from intestine and intrahepatic inflammation, and liver damage. Hepatic macrophages play a crucial role in mediating inflammatory response by alcohol. Sirtuin 7 (SIRT7), a NAD+-dependent type III histone deacetylase, is being recognized as a therapeutic target in various human diseases. Emerging evidence shows that SIRT7 participates in immune regulation, but whether it is involved in ALD remains elusive. In the present study, myeloid cell-specific Sirt7 knockout mice (Lyz2-Sirt7-/-) were used to show that knockout Sirt7 in myeloid cells significantly ameliorated alcohol-induced liver injury, inflammation, and cell infiltration, while only mildly affecting lipid metabolism pathways. Chemokine (C-C motif) ligand 2 (CCL2) was identified as the main target impaired by Sirt7 knockout after alcohol. In vitro studies confirmed that Sirt7 knockout impaired macrophages' ability of CCL2 secretion and monocyte recruiting, and exogenous CCL2 reversed this impairment. At the molecular level, knockout of Sirt7 significantly impaired lipopolysaccharide-induced p65 phosphorylation and nuclear localization. More importantly, the SIRT7 inhibitor 40569 sufficiently decreased alcohol-induced liver injury and hepatic inflammation via preventing CCL2 in vivo. The current data thus uncovered a previously undescribed role of myeloid SIRT7 in mediating ALD via promoting CCL2 secretion through the NF-κB signaling pathway. Targeting SIRT7 might offer novel mechanism-based therapeutic options for ALD.

Although 5-fluorouracil (5-FU) is widely utilized in cancer treatment, its side effects, including cardiotoxicity, limit its use. Taxifolin (TAX) is a bioactive anti-inflammatory and antioxidant flavonoid. This study aimed to elucidate the protective effect of TAX against 5-FU-induced cardiac injury in male mice. Mice were treated with TAX (25 and 50 mg/kg, orally) for 10 days and a single dose of 150 mg/kg 5-FU at day 8. Mice intoxicated with 5-FU showed increased creatine kinase-MB and lactate dehydrogenase activities and troponin I levels, with multiple cardiac histopathological changes. They also showed a significant increase in cardiac malondialdehyde (MDA) and nitric oxide (NO) and decreases in myocardial reduced glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities (P < 0.001). Pretreatment of 5-FU-injected mice with TAX suppressed cardiac injury, decreased MDA and NO contents (P < 0.001), and boosted antioxidant defenses in the myocardium. Moreover, TAX attenuated cardiac inflammatory response, as evidenced by the decreased expression levels of cardiac NF-κB p65, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines (P < 0.001). Largely, TAX ameliorated the decrease in Bcl-2 expression and the increase in BAX and caspase-3 in the heart. It also restored the cardiac Sirt1/Nrf2/HO-1 signaling pathway. In conclusion, TAX showed significant cardioprotective effects on 5-FU-induced cardiac injury and might represent a promising adjuvant in preventing cardiac injury associated with oxidative stress and inflammation.

Aging and metabolic disorders share intricate molecular pathways, with the Forkhead box O (FOXO)- Sirtuin 1 (SIRT1) axis emerging as a pivotal regulator of cellular stress adaptation, metabolic homeostasis, and longevity. This axis integrates nutrient signaling with oxidative stress defence, modulating glucose and lipid metabolism, mitochondrial function, and autophagy to maintain cellular stability. FOXO transcription factors, regulated by SIRT1 deacetylation, enhance antioxidant defence mechanisms, activating genes such as superoxide dismutase (SOD) and catalase, thereby counteracting oxidative stress and metabolic dysregulation. Recent evidence highlights the dynamic role of reactive oxygen species (ROS) as secondary messengers in redox signaling, influencing FOXO-SIRT1 activity in metabolic adaptation. Additionally, key redox-sensitive regulators such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) interact with this pathway, orchestrating mitochondrial biogenesis and adaptive stress responses. Pharmacological interventions, including alpha-lipoic acid (ALA), resveratrol, curcumin and NAD+ precursors, exhibit therapeutic potential by enhancing insulin sensitivity, reducing oxidative burden, and restoring metabolic balance. This review synthesizes current advancements in FOXO-SIRT1 regulation, its emerging role in redox homeostasis, and its therapeutic relevance, offering insights into future strategies for combating metabolic dysfunction and aging-related diseases.

Bone marrow mesenchymal stromal cells (BM-MSCs) are multipotent cells present in bone marrow; they play a crucial role in the process of bone formation. Cellular senescence is defined as a stable state of cell cycle arrest that impairs the functioning of cells. Research has shown that aging triggers a state of senescence in BM-MSCs, leading to a reduced capacity for osteogenic differentiation and the accumulation of senescent cells, which can accelerate the onset of various diseases. Therefore, it is essential to explore mechanisms and strategies for the rejuvenation of senescent BM-MSCs. Senile osteoporosis (SOP) is a metabolic bone disease characterized by reduced bone formation. The senescence of BM-MSCs is considered one of the most important factors in the occurrence and development of SOP. Therefore, the rejuvenation of BM-MSCs for the treatment of SOP represents a promising strategy. This work provides a summary of the functional alterations observed in senescent BM-MSCs and a systematic review of the mechanisms that facilitate the rejuvenation of senescent BM-MSCs. Additionally, we analyze the progress in and the limitations associated with the application of rejuvenated senescent BM-MSCs to treat SOP, with the aim of providing new insights for the prevention and treatment of SOP.

Adult stem cells maintain homeostasis and enable regeneration of most tissues. Quiescence, proliferation, and differentiation of stem cells and their progenitors are tightly regulated processes governed by dynamic transcriptional, epigenetic, and metabolic programs. Previously thought to merely reflect a cell's energy state, metabolism is now recognized for its critical regulatory functions, controlling not only energy and biomass production but also the cell's transcriptome and epigenome. In this review, we explore how metabolic pathways, metabolites, and transcriptional and epigenetic regulators are functionally interlinked in adult and aging skeletal muscle stem cells.