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.

Obesity is a global public health problem that can lead to mortality and morbidity. Studies on the pathophysiology of obesity for effective and safe treatments are focused on the mechanisms of adipogenesis. The association between boron treatment and weight loss has been reported, but its anti-adipogenic mechanisms and effects on preadipocytes remain unclear. This study aims to investigate the effects of boron compounds boric acid (BA) and calcium fructoborate (CaFB) on adipogenesis using the most widely used in vitro 3T3-L1 cellular model. In our study, cytotoxicity, Oil Red O (ORO), gene and protein expression analyses and cellular NAD measurements of boron compounds were performed. Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) transcription factors are the main regulators of adipogenesis, and boron compounds affect them at gene and protein levels by showing anti-obesity effects. This is the first study to show that CaFB has anti-obesity properties in mouse adipocytes. Sirtuins, known as the longevity genes, were also activated from boron treatment. Results of this research provide new basic knowledge and insights into the effect of boron-based compounds on obesity. It also offers potential prospects for the development of effective treatment and/or supportive treatment methods.

Pre-eclampsia (PE) globally impacts 2-8 % of pregnancies and is a leading cause of neonatal and maternal morbidity and mortality. Recent studies found the association between mitochondrial dysfunction and deficient motility of trophoblast cells in PE. Lower expressions of mitochondrial biogenesis related proteins (i.e. PGC1α, NRF1 and TFAM) and SIRT2 have recently been found. However, the regulative role of SIRT2 on the protein expression and acetylation of PGC1α and its influence on trophoblast migration and invasion in PE have never been investigated.

The alterations in protein expressions of SIRT2 and PGC1α/NRF1/TFAM were examined in the placenta from pregnant women with and without PE. The role of SIRT2 on mitochondrial biogenesis and mitochondrial morphology/function was explored in trophoblast cell, and the findings were confirmed in the LPS-induced PE mice with adeno-associated virus transfection system.

We demonstrated the lower protein expressions of SIRT2 and PGC1α/NRF1/TFAM and mitochondrial dysfunction in PE patients and mice compared with counterparts. Moreover, overexpression of SIRT2 enhanced the protein expressions of PGC1α and deacetylated PGC1α, and further facilitating mitochondrial function and motility of trophoblast cells. In vivo, overexpression of SIRT2 attenuated the PE-like symptoms and adverse pregnancy outcomes in LPS-induced PE mice via promoting mitochondrial biogenesis.

Above findings suggest that SIRT2 might be a potential interventive target against PE via improving deacetylation of PGC1α and mitochondrial biogenesis and function.

Maternal metabolic dysfunction adversely influences embryonic muscle oxidative capacity and mitochondrial biogenesis, increasing the child's long-term risks of developing obesity and metabolic syndrome in later life. This pilot study explored the mechanistic basis of embryonic muscle metabolic programming, employing non-invasive magnetic field exposures. Brief (10 min) exposure to low-energy (1.5 milliTesla at 50 Hertz) pulsing electromagnetic fields (PEMFs) has been shown in mammals to promote oxidative muscle development, associated with enhanced muscular mitochondriogenesis, augmented lipid metabolism, and attenuated inflammatory status. In this study, quail eggs were used as a model system to investigate the potential of analogous PEMF therapy to modulate embryonic muscle oxidative capacity independently of maternal influence. Quail eggs were administered five 10-min PEMF exposures to either upward-directed or downward-directed magnetic fields over 13 days. Embryos receiving magnetic treatment exhibited increased embryo weight, size, and survival compared to non-exposed controls. Upward exposure was associated with larger embryos, redder breast musculature, and upregulated levels of PPAR-α and PGC-1α, transcriptional regulators promoting oxidative muscle development, mitochondriogenesis, and angiogenesis, whereas downward exposure augmented collagen levels and reduced angiogenesis. Exposure to upward PEMFs may hence serve as a method to promote embryonic growth and oxidative muscle development and improve embryonic mortality.

Myocardial ischemia/reperfusion (I/R) injury has high morbidity and mortality rates, posing a significant burden on society. There is an urgent need to understand its pathogenesis and develop effective treatments. Reactive oxygen species (ROS) are crucial for the development of myocardial I/R injury, and inhibiting ROS overproduction is one of the most critical ways to delay myocardial I/R injury. Sirtuins are a group of nicotinic adenine dinucleotide ( +)-dependent histone deacetylases whose members can regulate ROS by modulating various biological processes. Numerous studies have shown that Sirtuins play an essential role in the progression of myocardial I/R injury by regulating ROS. This study focuses on the relationship between myocardial I/R injury and ROS, Sirtuins and ROS, discusses the role of Sirtuins in regulating ROS in myocardial I/R, and summarizes the therapeutic modalities aimed at targeting Sirtuins to modulate ROS in myocardial I/R injury, thereby guiding future research endeavors.

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are major contributors to the rise in metabolic disorders, particularly in developed countries. Despite the need for effective therapies, natural product-based interventions remain underexplored. This study investigated the therapeutic effects of Endarachne binghamiae, a type of brown algae, hot water extract (EB-WE) in ameliorating obesity and MASLD using high-fat diet (HFD)-induced ICR mice for an acute obesity model (4-week HFD feeding) and C57BL/6 mice for a long-term MASLD model (12-week HFD feeding). EB-WE administration significantly reduced body and organ weights and improved serum lipid markers, such as triglycerides (TG), total cholesterol (T-CHO), HDL (high-density lipoprotein), LDL (low-density lipoprotein), adiponectin, and apolipoprotein A1 (ApoA1). mRNA expression analysis of liver and skeletal muscle tissues revealed that EB-WE upregulated Ampkα and Cpt1 while downregulating Cebpα and Srebp1, suppressing lipogenic signaling. Additionally, EB-WE activated brown adipose tissue through Pgc1α and Ucp1, contributing to fatty liver alleviation. Western blot analysis of liver tissues demonstrated that EB-WE enhanced AMPK phosphorylation and modulated lipid metabolism by upregulating PGC-1α and UCP-1 and downregulating PPAR-γ, C/EBP-α, and FABP4 proteins. It also reduced oxidation markers, such as OxLDL (oxidized low-density lipoprotein) and ApoB (apolipoprotein B), while increasing ApoA1 levels. EB-WE suppressed lipid peroxidation by modulating oxidative stress markers, such as SOD (superoxide dismutase), CAT (catalase), GSH (glutathione), and MDA (malondialdehyde), in liver tissues. Furthermore, EB-WE regulated the glucose regulatory pathway in the liver and muscle by inhibiting the expression of Sirt1, Sirt4, Glut2, and Glut4 while increasing the expression of Nrf2 and Ho1. Tentative liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for EB-WE identified bioactive compounds, such as pyropheophorbide A and digiprolactone, which are known to have antioxidant or metabolic regulatory activities. These findings suggest that EB-WE improves obesity and MASLD through regulation of metabolic pathways, glucose homeostasis, and antioxidant activity, making it a promising candidate for natural product-based functional foods and pharmaceuticals targeting metabolic diseases.

Over the years, caloric intake has remained a subject of profound scrutiny. Within the scientific community, there has been rigorous debate to ascertain which path is most ideal for enhancing quality of life and extending the human lifespan. Caloric restriction has been shown to be a promising contributor towards longevity and delaying the onset of age-related diseases. This diet consists of a reduction in caloric intake while maintaining essential energy and nutritional requirements to achieve optimal health while avoiding malnutrition. However, the effects of this nutritional regimen on male reproductive health have not yet been comprehensively studied. Nevertheless, such a complex process will certainly be regulated by a variety of metabolic sensors, likely sirtuins. Evidence has been gathered regarding this group of enzymes, and their ability to regulate processes such as chromatin condensation, the cell cycle, insulin signaling, and glucose and lipid metabolism, among many others. Concerning testicular function and male fertility, sirtuins can modulate certain metabolic processes through their interaction with the hypothalamic-pituitary-gonadal axis and mitochondrial dynamics, among many others, which remain largely unexplored. This review explores the impact of caloric restriction on male fertility, highlighting the emerging role of sirtuins as key regulators of male reproductive health through their influence on cellular metabolism.

This review investigates the role of polyphenols, abundant natural compounds found in food, to influence the metabolic pathways involved in the thermogenesis and browning of white adipose tissue (WAT). Numerous proteins demonstrate altered expression patterns following prolonged polyphenol consumption, with peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) recognized as a key regulator, contributing to increased thermogenicity of adipose tissues. Polyphenols may enhance PGC-1α activity, stimulating WAT browning, and elevating brown adipose tissue (BAT) thermogenesis. Various classes of polyphenols are explored, along with extensive protein signaling and the physiological implications of these findings. A comprehensive understanding of the myriad proteins and pathways implicated in browning studies can provide readers with a broader perspective on the modulated response of adipose tissue to polyphenols and guide them to innovative therapeutic strategies for lipid metabolism, obesity, and associated metabolic disorders.

The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops, which modulates an approximately 24-hour cycle of endocrine and metabolic rhythms within cells and tissues. While circadian clocks regulate metabolic processes and related physiology, emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined. In this review, we highlight the concept of metabolites, including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake, as circadian pacemakers that drive changes in circadian rhythms, which in turn influence metabolism and aging. Furthermore, we discuss the roles of functional metabolites as circadian pacemakers, paving a new direction on potential intervention targets of circadian disruption, pathological aging, as well as metabolic diseases that are clinically important.

Preterm birth remains a significant global health concern despite advancements in neonatal care. While survival rates have increased, the long-term neurodevelopmental consequences of preterm birth persist. Notably, the profile of the preterm infant has shifted, with infants at earlier gestational ages surviving and decreased rates of gross structural injury secondary to intracranial hemorrhage. However, these infants are still vulnerable to insults, including hypoxia-ischemia, inflammation, and disrupted in utero development, impinging on critical developmental processes, which can lead to neuronal and oligodendrocyte injury and impaired brain function. Consequently, preterm infants often experience a range of neurodevelopmental disorders, such as cognitive impairment and behavioral problems. Here, we address mechanisms underlying preterm brain injury and explore existing and new investigational therapeutic strategies. We discuss how gestational age influences brain development and how interventions, including pharmacological and non-pharmacological approaches, mitigate the effects of preterm birth complications and improve the long-term outcomes of preterm infants.

Myocardial infarction (MI) has high morbidity and mortality, and the macrophage senescence-associated secretory phenotype (SASP) plays a central role in M1 healing. α-Lipoic acid (ALA) alleviates MI by regulating the function of macrophages, although the relationship between ALA and macrophage senescence remains unclear. To investigate macrophage SASP in MI, we performed single-cell RNA sequencing (scRNA-seq) on the GEO GSE163465 dataset, along with qPCR and western blot analyses to assess SASP expression in macrophages subjected to hypoxia and ALA treatment. Immunofluorescence was used to detect SASP distribution. Coculture and animal experiments were performed to assess the therapeutic effects of ALA on macrophage senescence and cardiomyocyte ischemic injury. scRNA-seq revealed an age-independent senescent propensity of macrophages in MI. Increased expression of H2A.X, CCL7, IL1β, and CDKN1A, along with decreased SOD2 expression, confirmed that macrophage SASP occurred after hypoxia, with oxidative stress and energy metabolism involved in the process. ALA inhibited the degradation of SIRT1 and promoted the Nrf2 nuclear translocation, alleviating macrophage senescence and myocardial ischemic injury. Age-independent macrophage SASP occurred during MI. Macrophage SASP was induced by ROS and mitochondrial dysfunction. ALA alleviated SASP by decreasing ROS generation and autophagy flux while increasing SIRT1 levels, and Nrf2 nuclear translocation. ALA ameliorated MI injury.

Prostate cancer (PCa) is the second most common cancer in men worldwide, and understanding its molecular mechanisms is crucial for developing effective treatment strategies. SIRT7, a NAD+-dependent histone deacetylase, has emerged as a key regulator in PCa progression due to its roles in chromatin remodeling, DNA repair, and transcriptional regulation. Analysis of 492 PCa samples from The Cancer Genome Atlas (TCGA) via cBioPortal revealed that high SIRT7 expression is associated with poor prognosis in PCa patients. Mechanistically, SIRT7 deacetylates histone H3 at lysine 18 (H3K18Ac), a marker associated with aggressive tumors, suppressing tumor suppressor genes and promoting cancer cell proliferation and survival. Epithelial-mesenchymal transition (EMT) is a cellular biological process in which epithelial cells undergo specific molecular and morphological changes to transform into cells with characteristics of mesenchymal cells. SIRT7 also regulates EMT, and inhibiting SIRT7 in PCa cell lines reduces cell migration and invasion, highlighting its potential as a therapeutic target. In summary, the clinical significance of SIRT7 expression in PCa requires further research to elucidate its mechanisms. Developing specific inhibitors targeting SIRT7's deacetylase activity is a promising therapeutic strategy. SIRT7 plays a crucial role in regulating biological processes such as cell proliferation, cell cycle, and apoptosis in PCa through its epigenetic control of gene expression and maintenance of genomic stability. Therefore, SIRT7 may be a potential therapeutic target for PCa, and its expression could have prognostic value for PCa patients, providing important guidance for clinical monitoring and diagnosis by physicians.

Atrial fibrillation (AF) is a prevalent and chronic cardiovascular disorder associated with various pathophysiological alterations, including atrial electrical and structural remodeling, disrupted calcium handling, autonomic nervous system dysfunction, aberrant energy metabolism, and immune dysregulation. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a significant role in the pathogenesis of AF.

This discussion aims to elucidate the involvement of AF-related lncRNAs, with a specific focus on their role as miRNA sponges that modulate crucial signaling pathways, contributing to the progression of AF. We also address current limitations in AF-related lncRNA research and explore potential future directions in this field. Additionally, we summarize feasible strategies and promising delivery systems for targeting lncRNAs in AF therapy.

In conclusion, targeting AF-related lncRNAs holds substantial promise for future investigations and represents a potential therapeutic avenue for managing AF.

Overweight and obesity are linked to mitochondrial alterations, impaired glucose tolerance and a high risk of type 2 diabetes. Time-restricted eating (TRE) may aid in facilitating weight loss to prevent diabetes. Here, we investigated if TRE in individuals with overweight and prediabetes or obesity affects mitochondrial bioenergetics of peripheral blood mononuclear cells (PBMCs) and platelets using the Seahorse extracellular flux technology. In a 3-month randomized controlled trial, PBMCs/platelets were analyzed from 52 participants before and after a TRE intervention with a 10-h eating window or habitual living. PBMC and platelet respiratory function was evaluated through sequential addition of substrates, uncouplers, and inhibitors in living cells. After 3 months, there were no statistically significant differences in mitochondrial respiration within or between the TRE and control groups. Association analyses between PBMC/platelet respiration and clinical parameters including body mass index and fat mass showed no significant effects. In conclusion, 3 months of 10-h TRE does not alter the mitochondrial bioenergetics of PBMCs and platelets in individuals with high risk of type 2 diabetes.

Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment.

The prevalence of type 2 diabetes (T2D) has increased significantly over the past three decades, with an estimated 30-40% of cases remaining undiagnosed. Brown and beige adipose tissues are known for their remarkable catabolic capacity, and their ability to diminish blood glucose plasma concentration. Beige adipose tissue can be differentiated from adipose-derived stem cells or through transdifferentiation from white adipocytes. However, the impact of T2D progression on beige adipocytes' functional capacity remains unclear. Transcriptomic profiling of subcutaneous adipose tissue biopsies from healthy normal-weight, obese, prediabetic obese, and obese subjects diagnosed with T2D, reveals a progressive alteration in cellular processes associated with catabolic metabolism, circadian rhythms, thermogenesis-related signaling pathways, cellular stress, and inflammation. MAX is a potential transcription factor that links inflammation with the circadian clock and thermogenesis during the progression of T2D. This study unveils an unrecognized transcriptional circuit that increasingly disrupts subcutaneous adipose tissue oxidative capacity during the progression of T2D. These findings could open new research venues for developing chrono-pharmaceutical strategies to treat and prevent T2D.

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.

Nicotinic acid (niacin, Vitamin B3) is one of the most effective medicines for improving high-density lipoprotein concentrations. Obesity and related diseases are life-threatening to dogs. This study investigated the niacin effect on triglyceride, cholesterol, lipoproteins, thyroid hormones, oxidative stress, and lipid peroxidation in intact adult dogs. Blood samples were taken from seven healthy, intact adult dogs as a control group (day 0). Then, the animals received 1000 mg/dog of oral nicotinic acid tab daily for 42 days, and blood sampling was performed on days 14, 28, 42, and 56.

The results showed an increasing trend in high-density lipoprotein (HDL) concentration. The highest HDL concentration (138.85 ± 43.72 mg/dl) was related to day 56; the HDL level followed a statistically significant increase between day 14 and 56. Unlike HDL, there was a decreasing trend in low-density lipoprotein (LDL) concentration. The lowest LDL concentration (21.85 ± 18.60 mg/dl) was related to day 56. The concentration of apolipoprotein A-I (apoA1) was significantly increased during the study. The highest concentration of apoA1 (1.66 ± 0.06 g/l) was on day 42. There was a significant increase in apoA1 concentrations between days 0 and 14, 42, and 56. The apoA1 was significantly increased between days 14 and 42 and 56. The apoA1 followed a statistically significant increase between days 28 and 42. Changes in thyroid hormone levels did not show any constant increasing or decreasing trend. On day 14, a decreasing trend in the concentrations of TT4, FT4, and T3 was observed. However, an increasing trend was detected in the concentrations of TT4, FT4, and T3 on days 28 and 42. However, the increase in the concentrations of TT4 and FT4 was less than that on day 0. After treatment (day 56), a decreasing trend was observed in thyroid hormone concentrations. The negative correlation was detected between apoA1 and triiodothyronine (T3), total thyroxine T4 (TT4)), and free T4 (FT4) concentrations on day 42. Furthermore, a significant negative relationship was observed between HDL and T4 on day 42. However, the relationship between triglyceride and T3 was statistically positive on day 14. There was an increasing trend in serum total antioxidant capacity (TAC). The highest TAC concentration (3.83 ± 0.62 µmol /l) was on day 56; however, the malondialdehyde (MDA) concentration was decreased during the study. The total antioxidant level followed a statistically significant increase between days 0 and 56 compared to days 14 and 42.

The study demonstrated the efficacy of nicotinic acid in improving serum HDL, apoA1, and TAC, as well as decreasing serum MDA and LDL concentrations.

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, nonalcoholic fatty liver diseases, and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency and fetal weight were significantly improved following three administrations of a nonviral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal liver tissue was collected near-term at gestational day 60. Fetal sex-specific differences in liver gene and protein expression of profibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. Increased plasma bilirubin, an indirect measure of hepatic activity, was also demonstrated with placental hIGF1 nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements.NEW & NOTEWORTHY A placenta-specific nonviral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later life. This knowledge may have implications toward removing predispositions that increase the risk of metabolic diseases, including diabetes, dyslipidemia, and nonalcoholic fatty liver disease in later life.

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.

Obesity, as a worldwide healthcare problem, has become more prevalent. ZFP36 is a well-known RNA-binding protein and involved in the posttranscriptional regulation of many physiological processes. Whether the adipose ZFP36 plays a role in obesity and insulin resistance remains unclear.

The expression levels of ZFP36 were analyzed in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. To determine whether adipose ZFP36 protects against the diet-induced obesity, we generated adipose-specific ZFP36 knockout (ZFP36AKO) mice, which were subjected to high-fat-diet (HFD) for 16 weeks. To explore the specific molecular mechanisms of ZFP36 regulating metabolic disorders, we used gene array assay of control and ZFP36-deficient adipose tissue, and assessed the pathways in vitro and vivo.

Western blotting and RT-PCR were performed to determine the downregulating level of ZFP36 in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. Relative to control mice, ZFP36AKO mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36AKO mice was attributed to hypertrophy of adipocytes in white adipose tissue via decreased expression of Perilipin1 (PLIN1), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). We discovered that ZFP36 oppositely regulated RNF128 expression by repressing the mRNA stability and translation of RNF128, a negative regulator of Sirt1 expression.

This study suggests that ZFP36 in adipose tissue plays an important role in diet-induced obesity, and identifies a novel molecular signaling pathway of ZFP36/RNF128/Sirt1 involved in obesity.

Calycosin‑7‑O‑β‑D‑glucoside (CG), a major active ingredient of Astragali Radix, exerts neuroprotective effects against cerebral ischemia; however, whether the effects of CG are associated with mitochondrial protection remains unclear. The present study explored the role of CG in improving mitochondrial function in a HT22 cell model of oxygen‑glucose deprivation/reperfusion (OGD/R). The Cell Counting Kit‑8 assay, flow cytometry, immunofluorescence and western blotting were performed to investigate the effects of CG on mitochondrial function. The results demonstrated that mitochondrial function was restored after treatment with CG, as indicated by reduced mitochondrial reactive oxygen species levels, increased mitochondrial membrane potential and improved mitochondrial morphology. Overactivated mitophagy was revealed to be inhibited by the regulation of proteins involved in fission [phosphorylated‑dynamin‑related protein 1 (Drp1) and Drp1] and mitophagy (LC3, p62 and translocase of outer mitochondrial membrane 20), and mitochondrial biogenesis was demonstrated to be enhanced by increased levels of sirtuin 1 (SIRT1) and peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α). In addition, neuronal apoptosis was ameliorated by CG, as determined by a decreased rate of apoptosis, and levels of caspase‑3 and Bcl‑2/Bax. In conclusion, the present study demonstrated that CG may alleviate OGD/R‑induced injury by upregulating SIRT1 and PGC‑1α protein expression, and reducing excessive mitochondrial fission and overactivation of mitophagy.

Sirtuins (SIRTs) are NAD+-dependent deacetylases that mediate post-translational modifications of proteins. Seven members of the SIRT family have been identified in mammals. Importantly, SIRTs interact with numerous metabolic and inflammatory pathways. Thus, researchers have investigated their role in metabolic and inflammatory disorders.

In this review, we comprehensively discuss the involvement of SIRTs in the processes of pancreatic β-cell dysfunction, glucose tolerance, insulin secretion, lipid metabolism, and adipocyte functions. In addition, we describe the current evidence regarding modulation of the expression and activity of SIRTs in diabetes, diabetic complications, and obesity.

The development of specific SIRT activators and inhibitors that exhibit high selectivity toward specific SIRT isoforms remains a major challenge. This involves the need to elucidate the physiological pathways involving SIRTs, as well as their important role in the development of metabolic disorders. Molecular modeling techniques will be helpful to develop new compounds that modulate the activity of SIRTs, which may contribute to the preparation of new drugs that selectively target specific SIRTs. SIRTs hold promise as potential targets in metabolic disease, but there is much to learn about specific modulators and the final answers will await clinical trials.

Mitochondria are multifaceted organelles with crucial roles in energy generation, cellular signalling and a range of synthesis pathways. The study of mitochondrial biology is complicated by its own small genome, which is matrilineally inherited and not subject to recombination, and present in multiple, possibly different, copies. Recent methodological developments have enabled the analysis of mitochondrial DNA (mtDNA) in large-scale cohorts and highlight the far-reaching impact of mitochondrial genetic variation. Genome-editing techniques have been adapted to target mtDNA, further propelling the functional analysis of mitochondrial genes. Mitochondria are finely tuned signalling hubs, a concept that has been expanded by advances in methodologies for studying the function of mitochondrial proteins and protein complexes. Mitochondrial respiratory complexes are of dual genetic origin, requiring close coordination between mitochondrial and nuclear gene-expression systems (transcription and translation) for proper assembly and function, and recent findings highlight the importance of the mitochondria in this bidirectional signalling.

Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

The complexity of the galaninergic system is still not fully understood, especially under specific pre-existing comorbidities related to metabolic dysfunction. A plant-derived triterpenoid celastrol was demonstrated to exert a complex effect on the galaninergic system and to have hepatoprotective and anti-obesity properties. However, the exact molecular mechanisms responsible for these effects remain unclear. Specifically, there are no data on the impact of celastrol on the heart and liver galaninergic system. Therefore, this study aimed to investigate the effects of celastrol on the galaninergic system expression in the heart and liver of mice suffering from diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH).

The male mice C57BL/6J were fed a Western-type high-fat diet for 16 and 20 weeks to induce obesity and MASLD/MASH. Celastrol was administered along with a specific diet for the last 4 weeks to evaluate its impact on the progression of these conditions. Moreover, the inhibitor of sterol regulatory element-binding protein 1/2 (SREBP1/2), fatostatin, was also tested to compare its influence on the galaninergic system with celastrol.

The study demonstrates that celastrol treatment was safe and led to a reduction in food and energy intake, body fat and liver weights, and MASLD-to-MASH progression and improved glucose tolerance, serum biochemistry markers, and hepatic lipid peroxidation in mice. Quantitative gene expression originally showed significant regulation of galanin and all three of its receptors (GalR1/2/3) in the heart ventricles and only GalR2 in the liver of obese mice. Celastrol influenced the gene expression of galanin receptors: it downregulated Galr1 in the heart and upregulated Galr2 in the liver and Galr3 in the heart ventricles, potentially affecting energy metabolism, oxidative stress, and inflammation. Fatostatin suppressed gene expression of all the detected members of the galaninergic system in the heart ventricles, depicting the role of SREBP in this process.

These findings suggest that celastrol may beneficially modulate the galaninergic system under obesity and MASLD-to-MASH progression, indicating its potential as a therapeutic agent for disorders associated with metabolic dysfunction.

Cigarette smoke (CS), an intricate blend comprising over 4000 compounds, induces abnormal cellular reactions that harm multiple tissues. Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease (CLD), encompassing non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Recently, the term NAFLD has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD), and NASH has been renamed metabolic dysfunction-associated steatohepatitis (MASH). A multitude of experiments have confirmed the association between CS and the incidence and progression of MASLD. However, the specific signaling pathways involved need to be updated with new scientific discoveries. CS exposure can disrupt lipid metabolism, induce inflammation and apoptosis, and stimulate liver fibrosis through multiple signaling pathways that promote the progression of MASLD. Currently, there is no officially approved efficacious pharmaceutical intervention in clinical practice. Therefore, lifestyle modifications have emerged as the primary therapeutic approach for managing MASLD. Smoking cessation and the application of a series of natural ingredients have been shown to ameliorate pathological changes in the liver induced by CS, potentially serving as an effective approach to decelerating MASLD development. This article aims to elucidate the specific signaling pathways through which smoking promotes MASLD, while summarizing the reversal factors identified in recent studies, thereby offering novel insights for future research on and the treatment of MASLD.

Nicotinamide adenine dinucleotide (NAD) is an essential regulator of cellular metabolism and redox processes. NAD levels and the dynamics of NAD metabolism change with increasing age but can be modulated via the diet or medication. Because NAD metabolism is complex and its regulation still insufficiently understood, achieving specific outcomes without perturbing delicate balances through targeted pharmacological interventions remains challenging. NAD metabolism is also highly sensitive to environmental conditions and can be influenced behaviorally, e.g., by exercise. Changes in oxygen availability directly and indirectly affect NAD levels and may result from exposure to ambient hypoxia, increased oxygen demand during exercise, ageing or disease. Cellular responses to hypoxic stress involve rapid alterations in NAD metabolism and depend on many factors, including age, glucose status, the dose of the hypoxic stress and occurrence of reoxygenation phases, and exhibit complex time-courses. Here we summarize the known determinants of NAD-regulation by hypoxia and evaluate the role of NAD in hypoxic stress. We define the specific NAD responses to hypoxia and identify a great potential of the modulation of NAD metabolism regarding hypoxic injuries. In conclusion, NAD metabolism and cellular hypoxia responses are strongly intertwined and together mediate protective processes against hypoxic insults. Their interactions likely contribute to age-related changes and vulnerabilities. Targeting NAD homeostasis presents a promising avenue to prevent/treat hypoxic insults and - conversely - controlled hypoxia is a potential tool to regulate NAD homeostasis.

Type 2 diabetes mellitus (T2DM) remains one of the major causes of morbidity and mortality worldwide, including Bangladesh. SIRT1, an NAD-dependent deacetylase, is involved in energy homeostasis and protects β-cells of the pancreas from oxidative stress. Single nucleotide polymorphisms (SNPs) in the SIRT1 gene have been found to be associated with T2DM in several populations, however, with conflicting results. The aim of this present case-control study, along with the meta-analysis, was to elucidate the association of rs3758391 polymorphism with the susceptibility to T2DM in Bangladeshi population.

72 T2DM patients and 90 healthy controls were enrolled in our study and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed for genotyping the SNP. Odds ratio (OR) with 95% confidence interval (95% CI) was used to represent the association of SIRT1 polymorphism with T2DM. For the meta-analysis six studies were included and pooled odds ratio with 95% CI were calculated for six genetic models using the random effects model. Heterogeneity and publication bias was also calculated for each study.

A significant association was found between rs3758391 polymorphism and increased risk of T2DM under codominant TT versus CC (OR = 3.88, 95% CI = 1.34-11.25, p = 0.012), recessive TT versus CC + CT (OR = 2.83, 95% CI = 1.12-7.09, p = 0.027) and allelic T versus C (OR = 1.67, 95% CI = 1.07-2.60, p = 0.024) genetic models. However, no significant association between rs3758391 and other biochemical and anthropometric parameters were found. Our meta-analysis showed no statistically significant association of this polymorphism.

We conclude that, polymorphism at rs3758391 of SIRT1 gene conferred an increased risk of T2DM in Bangladeshi population.

Hypoxia-inducible factor 1α (HIF-1α) is a crucial transcription factor that regulates cellular responses to low oxygen levels (hypoxia). In Alzheimer's disease (AD), emerging evidence suggests a significant involvement of HIF-1α in disease pathogenesis. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to neuronal dysfunction and cognitive decline. HIF-1α is implicated in AD through its multifaceted roles in various cellular processes. Firstly, in response to hypoxia, HIF-1α promotes the expression of genes involved in angiogenesis, which is crucial for maintaining cerebral blood flow and oxygen delivery to the brain. However, in the context of AD, dysregulated HIF-1α activation may exacerbate cerebral hypoperfusion, contributing to neuronal damage. Moreover, HIF-1α is implicated in the regulation of Aβ metabolism. It can influence the production and clearance of Aβ peptides, potentially modulating their accumulation and toxicity in the brain. Additionally, HIF-1α activation has been linked to neuroinflammation, a key feature of AD pathology. It can promote the expression of pro-inflammatory cytokines and exacerbate neuronal damage. Furthermore, HIF-1α may play a role in synaptic plasticity and neuronal survival, which are impaired in AD. Dysregulated HIF-1α signaling could disrupt these processes, contributing to cognitive decline and neurodegeneration. Overall, the involvement of HIF-1α in various aspects of AD pathophysiology highlights its potential as a therapeutic target. Modulating HIF-1α activity could offer novel strategies for mitigating neurodegeneration and preserving cognitive function in AD patients. However, further research is needed to elucidate the precise mechanisms underlying HIF-1α dysregulation in AD and to develop targeted interventions.

microRNA-22 (miR-22) plays a pivotal role in the regulation of metabolic processes and has emerged as a therapeutic target in metabolic disorders, including obesity, type 2 diabetes, and metabolic-associated liver diseases. While miR-22 exhibits context-dependent effects, promoting or inhibiting metabolic pathways depending on tissue and condition, current research highlights its therapeutic potential, particularly through inhibition strategies using chemically modified antisense oligonucleotides. This review examines the dual regulatory functions of miR-22 across key metabolic pathways, offering perspectives on its integration into next-generation diagnostic and therapeutic approaches while acknowledging the complexities of its roles in metabolic homeostasis.

Almost all organisms, from the simplest bacteria to advanced mammals, havea near 24 h circadian rhythm. Circadian rhythms are highly conserved across different life forms and are regulated by circadian genes as well as by related transcription factors. Transcription factors are fundamental to circadian rhythms, influencing gene expression, behavior in plants and animals, and human diseases. This review examines the foundational research on transcriptional regulation of circadian rhythms, emphasizing histone modifications, chromatin remodeling, and Pol II pausing control. These studies have enhanced our understanding of transcriptional regulation within biological circadian rhythms and the importance of circadian biology in human health. Finally, we summarize the progress and challenges in these three areas of regulation to move the field forward.

Microtia is a congenital malformation characterized by underdevelopment of the external ear. While chondrocyte dysfunction has been implicated in microtia, the specific cellular abnormalities remain poorly understood. This study aimed to investigate mitochondrial dysfunction in microtia chondrocytes using single-cell RNA sequencing. Cartilage samples were obtained from patients with unilateral, non-syndromic microtia and healthy controls. Single-cell RNA sequencing was performed using the 10 × Genomics platform. Bioinformatic analyses including cell type identification, trajectory analysis, and gene co-expression network analysis were conducted. Mitochondrial function was assessed through ROS levels, membrane potential, and transmission electron microscopy. Chondrocytes from microtia samples showed lower mitochondrial function scores compared to normal samples. Trajectory analysis revealed more disorganized differentiation patterns in microtia chondrocytes. Mitochondrial dysfunction in microtia chondrocytes was confirmed by increased ROS production, decreased membrane potential, and altered mitochondrial structure. Gene co-expression network analysis identified hub genes associated with mitochondrial function, including SDHA, SIRT1, and PGC1A, which showed reduced expression in microtia chondrocytes. This study provides evidence of mitochondrial dysfunction in microtia chondrocytes and identifies potential key genes involved in this process. These findings offer new insights into the pathogenesis of microtia and may guide future therapeutic strategies.

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.

Objective: Vitamin D insufficiency is a major contributor to osteoporosis. This study aimed to elucidate the mechanisms by which the vitamin D-Sirt1/PGC1α axis regulates bone metabolism and counteracts osteoporosis induced by active vitamin D insufficiency.

Mouse models including Sirt1 transgenic (Sirt1Tg), Cyp27b1+/- (active vitamin D deficient), and compound Sirt1TgCyp27b1+/- mice were utilized. Bone parameters were assessed by radiography, micro-CT, histology, and immunohistochemistry. In vitro studies used bone marrow-derived mesenchymal stem cells (BM-MSCs). Gene and protein expression were analyzed by RT-PCR and Western blotting. Chromatin immunoprecipitation and luciferase assays investigated transcriptional regulation. Effects of resveratrol supplementation were examined.

1,25-dihydroxyvitamin D (1,25(OH)2D) insufficiency caused downregulation of Sirt1 expression, leading to accelerated bone loss. Overexpression of Sirt1 in mesenchymal stem cells corrected bone loss by inhibiting oxidative stress, DNA damage, osteocyte senescence and senescence-associated secretory phenotype, promoting osteoblastic bone formation, and reducing osteoclastic bone resorption. 1,25(OH)2D3 transcriptionally upregulated Sirt1 expression in BM-MSCs through vitamin D receptor binding to the Sirt1 gene promoter. Resveratrol, a Sirt1 agonist, attenuated osteoporosis induced by 1,25(OH)2D insufficiency by modulating the Sirt1/PGC1α axis. Sirt1 interacted with and deacetylated PGC1α, a transcriptional coactivator involved in mitochondrial biogenesis and energy metabolism. Deacetylated PGC1α mediated the effects of Sirt1 on osteogenesis, oxidative stress, and cellular senescence in BM-MSCs.

This study elucidated the critical role of the vitamin D-Sirt1/PGC1α axis in regulating bone metabolism and counteracting osteoporosis induced by active vitamin D insufficiency. The findings highlight the potential of this axis as a therapeutic target for the prevention and treatment of osteoporosis.

Dietary restriction (DR) has been reported to be a significant intervention that influences lipid metabolism and potentially modulates the aging process in a wide range of organisms. Lipid metabolism plays a pivotal role in the regulation of aging and longevity. In this review, we summarize studies on the significant role of lipid metabolism in aging in relation to DR. As a potent intervention to slow down aging, DR has demonstrated promising effects on lipid metabolism, influencing the aging processes across various species. The current review focuses on the relationships among DR-related molecular signaling proteins such as the sirtuins, signaling pathways such as the target of rapamycin and the insulin/insulin-like growth factor (IGF)-1, lipid metabolism, and aging. Furthermore, the review presents research results on diet-associated changes in cell membrane lipids and alterations in lipid metabolism caused by commensal bacteria, highlighting the importance of lipid metabolism in aging. Overall, the review explores the interplay between diet, lipid metabolism, and aging, while presenting untapped areas for further understanding of the aging process.