Downregulation Of SIRT1 Research Articles

Protective Role of (-)-Epicatechin on Trimethylamine-N-Oxide (TMAO)-Induced Cardiac Hypertrophy via SP1/SIRT1/SUMO1 Signaling Pathway.

(-)-Epicatechin (EPI) is beneficial for cardiovascular health. Trimethylamine N-oxide (TMAO), a gut microbe-derived food metabolite, is strongly associated with the risk of cardiovascular diseases. However, the effects and underlying mechanisms of EPI on TMAO-induced cardiac hypertrophy remain unclear. This study aimed to determine whether EPI inhibits TMAO-induced cardiac hypertrophy. Plasma levels of TMAO in control participantsand patients with cardiac hypertrophy were measured and analyzed. Male C57BL/6 mice were randomly divided into control group, TMAO group, EPI group and TMAO + EPI group. According to the groups assignments, mice received intraperitoneal (i.p.) injection of normal saline or i.p. injection of TMAO (150mg/kg/day) for 14days. The EPI group was given intragastric (i.g.) administration of EPI alone (1mg/kg/day) for 21days, and TMAO + EPI group received i.g. administration of EPI for 7days before starting i.p. injection of TMAO, continuing until the end of the TMAO treatment. Histological analyses of the mice's hearts was accessed by H&E and Masson staining. In vitro, H9c2 cells were induced to hypertrophy by TMAO (10µM) for 24h and were pre-treated with or without EPI (10µM) for 1h. Protein level of cardiac hypertrophy markers and Sp1/SIRT1/SUMO1 pathway were determined by western blot. The plasma level of TMAO was 2.66 ± 1.59μmol/L in patients with cardiac hypertrophy and 0.62 ± 0.30μmol/L in control participants. EPI attenuated TMAO-induced hypertrophy in H9c2 cells. In vivo, TMAO induced cardiac hypertrophy and impaired the cardiac function of mice. Pathological staining showed that TMAO induced cardiac hypertrophy and collagen deposition in mice. EPI treatment improved the cardiac function, inhibited the myocardial hypertrophy induced by TMAO. EPI significantly attenuated the TMAO-induced upregulation of ANP and BNP and the downregulation of SP1, SIRT1 and SUMO1 in vivo and in vitro. EPI may suppress TMAO-induced cardiac hypertrophy by activating the Sp1/SIRT1/SUMO1 signaling pathway.

Study on the mechanism of activating SIRT1/Nrf2/p62 pathway to mediate autophagy-dependent ferroptosis to promote healing of diabetic foot ulcers.

Diabetic foot (DF), a prevalent and grave diabetes sequela, is considered as a notable clinical concern, with SIRT1 downregulation observed in DF patients' blood specimens. Nonetheless, the regulatory mechanisms of SIRT1 in diabetic foot ulcer (DFU) remain unclear. Thus, in the current study, we investigated the role and mechanisms of SIRT1 in alleviating DFU. Western blotting was used to detect the expression of autophagy and ferroptosis-related proteins, CCK8 assay was used to measure cell proliferation. Plate colony method was used to measure bacterial growth, and the inhibitory effect on intracellular and extracellular Staphylococcus aureus was observed after drug intervention. ELISA was used to detect inflammatory cytokines and oxidative stress markers levels. ROS, total iron, and Fe2+ levels were detected using corresponding assays. Additionally, HE staining detected the thickness of the epidermis and dermis of the rat wound tissue while the collagen deposition in the wound tissue was detected using Masson staining. In addition, Prussian blue staining was used to detect iron deposition, and C11 BODIPY 581/591 lipid peroxidation probe was used to detect lipid ROS. Our results suggested that the activation of SIRT1/Nrf2/p62 signaling affects cell proliferation, colony formation, ferroptosis, and the production of lipid ROS in DFU-infected cell model through autophagy. In vivo experiments indicated that activating SIRT1/Nrf2/p62 signaling affects oxidative stress, inflammation, and autophagy in wound tissue and promotes wound healing in DFU rats through mediating autophagy-dependent ferroptosis. Taken together, the activation of SIRT1/Nrf2/p62 pathway can promote DFU healing, which might be mediated by autophagy-dependent ferroptosis.

Deciphering avian hematopoietic stem cells by surface marker screening and gene expression profiling

BackgroundAvian species have played a pivotal role in developmental hematopoiesis research, leading to numerous critical discoveries. Avian influenza, particularly the H5N1 strain, poses a significant threat to poultry and has zoonotic potential for humans. Infections often result in abnormal hematologic profiles, highlighting the complex interplay between avian diseases and hematopoiesis. Many avian diseases can suppress immune cells in the bone marrow (BM), impacting immune responses. Studying hematopoietic stem cells (HSCs) in avian BM is crucial for understanding these processes and developing effective vaccines and protection strategies for both avian and human health. MethodsThis study adapted methods from mouse studies to isolate avian HSCs as Lineage-negative (Lin-) cells. These isolated cells were further identified as Lin-Sca1+c-Kit+ (LSK) and were found to be more prevalent than in control groups. RT-PCR analyses were conducted, showing that genes like MEIS1 and TSC1 were upregulated, while SIRT1, FOXO1, and AHR were downregulated in these stem cells. Screening for LSK markers revealed ten unique surface antigens in the Sca1+c-Kit+ cell populations, including highly enriched antigens such as CD178, CD227, and CD184. Additionally, studies on quail HSCs demonstrated that similar labeling techniques were effective in quail BM. ResultsThe research demonstrated that the identification of avian HSC-specific surface antigens provides valuable insights into the pathogenesis of avian influenza and other diseases, enhancing our understanding of how these diseases suppress HSC function. Notably, the upregulation of MEIS1 and TSC1 genes in LSK cells underscores their critical roles in regulating hematopoietic processes. Conversely, the downregulation of SIRT1, FOXO1, and AHR genes provides important clues about their roles in differentiation and immune response mechanisms. DiscussionThe findings of this study deepen our understanding of the effects of avian diseases on the immune system by identifying surface markers specific to avian HSCs. The suppression of HSC function by pathogens such as influenza highlights the importance of understanding these cells in developing targeted vaccines. These results represent a significant step towards improving global health security by mitigating risks associated with avian pathogens.

Occlusal disharmony promotes anxiety-like behaviours by suppressing Sirt1.

Previous studies have indicated that occlusal disharmony (OD) can promote anxiety-like behaviours. However, the specific molecules involved in the development of anxiety-like behaviours and their underlying mechanisms remain unknown. OD was produced by anterior crossbite of female mice. We measured the anxiety levels of mice in each group and screened the hippocampal mRNA expression profiles of mice in the control group and OD group. The role of target mRNA in OD-induced anxiety-like behaviours was evaluated and we preliminarily explored the possible downstream pathways. The results suggested that OD can induce and promote anxiety-like behaviours with/without chronic unpredictable mild stress. We found that Sirt1 was significantly downregulated within the hippocampus in OD mice. In addition, the downregulation of Sirt1 within the hippocampus in OD and control mice promoted anxiety-like behaviours, increased acetylated histone H3 expression and decreased Dnah12 transcription levels. In contrast, in OD mice subjected to an injection of resveratrol, there was a remission of anxiety-like behaviours and an upregulation of Sirt1 in the hippocampus, the effects of which were accompanied by decreased acetylated histone H3 expression and increased Dnah12 transcription levels. OD leads to increased sensitivity to chronic stress in mice, resulting in anxiety-like behaviours. During this process, Sirt1 acts as an effective factor in the regulation of OD-induced anxiety-like behaviours. OD, as a stressor, could induce anxiety-like behaviours. It investigates the impact of OD (a stressor) on the molecular genetic of the pathophysiology of major neuropsychiatric disorders.

Mulberroside A attenuates cigarette smoke-induced atherosclerosis in ApoE−/− mice via the Sirt1-HIF-1α axis

ObjectiveThis study investigated whether Mulberryside A (MBA) can attenuate cigarette smoke extract (CSE)-induced autophagy through a Sirt1-dependent pathway, thereby attenuating atherosclerosis in ApoE−/− mice. MethodsAfter treating human umbilical vein endothelial cells (HUVECs) with CSE and MBA, an MTT assay was performed to detect cell activity. Immunofluorescence and Western blotting were used to determine the expressions of autophagy-related proteins, Sirt1 and HIF-1α. Lentivirus and siRNA were used to construct overexpression and silencing (Sirt1 and HIF-1α) models. The in vivo inflammatory effects of CS on atherosclerosis in ApoE−/− mice were assessed by exposing mice to CS and MBA treatment. HE staining was used to detect atherosclerosis in mouse aortic tissue, and electron microscopy was used to detect autophagy of endothelial cells. ResultsCSE promoted autophagy in HUVECs, down-regulated Sirt1, and up-regulated HIF-1α expression. MBA treatment, overexpression of Sirt1, or silencing of HIF-1α attenuated CSE-induced autophagy, while MBA reversed CSE-induced downregulation of Sirt1 and upregulation of HIF-1α. However, overexpression of HIF-1α increased autophagy in HUVECs and attenuated the protective effect of Sirt1 overexpression or MBA on CSE-induced autophagy in HUVECs. In vivo experiments also demonstrated that MBA attenuates CS-induced aortic autophagy in ApoE−/− mice and up-regulates Sirt1 and downregulates HIF-1α expression. ConclusionsMBA attenuates CSE-induced autophagy through the Sirt1-HIF-1α axis, thereby attenuating atherosclerosis in ApoE−/− mice.

Melatonin Prevents Thioacetamide-Induced Gut Leakiness and Liver Fibrosis Through the Gut-Liver Axis via Modulating Sirt1-Related Deacetylation of Gut Junctional Complex and Hepatic Proteins.

Intestinal barrier dysfunction with high serum endotoxin is common in patients with liver fibrosis, but the mechanisms underlying liver fibrosis remain unclear. Melatonin is a well-recognized antioxidant and an anti-inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness-associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)-induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut-liver axis. Our results showed that gut leakiness markers, including decreased gut tight/adherens junction proteins (TJ/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ/AJs were hyper-acetylated, followed by ubiquitin-dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper-acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal Sirt1 deficiency greatly enhanced protein hyper-acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA-exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut-liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper-acetylation and gut leakiness.

Targeting POLD1 to suppress the proliferation and migration of breast cancer MDA-MB-231 cell lines by downregulation of SIRT1.

The resistant and aggressive nature of triple-negative breast cancer (TNBC) renders it mostly incurable even following extensive multimodal treatment. Therefore, more studies are required to understand the underlying molecular mechanisms of its pathogenesis. SIRT1 is a class III histone deacetylase NAD+-dependent enzyme that is interlinked in tumor progression, apoptosis, metastasis, and other mechanisms of tumorigenesis, while DNA polymerase delta 1 (POLD1) functions as a gene coding for p125, which plays an important role in genome stability and DNA replication. We aimed to investigate the downstream signaling pathway of EX-527, a potent and selective SIRT1 inhibitor, in MDA-MB-231 breast cancer cell lines, and the crosstalk between SIRT1 and POLD1, which is essential for the activities of polymerase δ. The antiproliferative and apoptotic effects of EX-527 on MDA-MB-231 cells were assessed by MTT and annexin V/PI double staining assays. Migration and invasion activity of MDA-MB-231 cells were assessed by wound-healing scratch and transwell assays. Protein expressions were examined using Western Blot analysis. MDA-MB-231 cells treatment with IC50 values of 45.3μM EX-527 significantly suppressed cell proliferation and induced apoptosis by down-regulating SIRT1. Also, it significantly repressed migration and invasion of MDA-MB-231 cells as evaluated by wound healing and transwell invasion assays. Western blot results showed that decreased expression of SIRT1 is positively correlated with expression of p53 along with down-regulating POLD1. SIRT1 could have an oncogenic role in breast cancer development and progression via activating POLD1. These conclusions present new insights into the underlying mechanisms of TNBC.

Hyperglycemia-induced Sirt3 downregulation increases microglial aerobic glycolysis and inflammation in diabetic neuropathic pain pathogenesis.

Hyperglycemia-induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear. To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia-induced neuroinflammation and DNP and to explore potential therapeutic interventions. Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA-sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia-induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis invivo and invitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high-glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy-lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia-induced inflammation. Metformin invivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia-induced Sirt3 downregulation. Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP.

IGFBP7 mediates oxLDL-induced human vascular endothelial cell injury by suppressing the expression of SIRT1

Endothelial cell injury plays an important role in initiating atherosclerotic lesion formation. Insulin-like growth factor binding protein 7 (IGFBP7) is known to modulate the behaviors of tumor-associated endothelial cells. This study was conducted to test whether IGFBP7 is involved in endothelial cell injury during atherosclerosis. Oxidized low-density lipoprotein (oxLDL) treatment was used to mimic atherosclerosis-related endothelial cell apoptosis and inflammation response. Small interfering RNA (siRNA) technology was employed to deplete IGFBP7 expression in human aortic endothelial cells (HAECs). HAECs were exposed to recombinant human IGFBP7 protein to evaluate the function of IGFBP7. Notably, IGFBP7 expression in HAECs was induced by oxLDL treatment. Knockdown of IGFBP7 or treatment with anti-IGFBP7 abolished oxLDL-induced apoptosis and inflammation in HAECs. Moreover, recombinant IGFBP7 (40 ng/mL but not 25 ng/mL) promoted apoptosis and inflammation in HAECs. IGFBP7 co-localized with CD93 on the surface of HAECs. A mechanistic investigation uncovered that IGFBP7 induced endothelial cell injury through interaction with CD93 and reduction of SIRT1 expression via an autocrine manner. Overexpression of SIRT1 rescued IGFBP7-induced phenotype in HAECs. Taken together, IGFBP7 is induced by oxLDL and mediates oxLDL-induced endothelial cell apoptosis and inflammation, likely through downregulation of SIRT1. These observations support a rationale to prevent atherosclerosis by targeting IGFBP7 activity.

Paricalcitol attenuates oxidative stress and inflammatory response in the liver of NAFLD rats by regulating FOXO3a and NFκB acetylation

The lack of therapeutics along with complex pathophysiology made non-alcoholic fatty liver disease (NAFLD) a research hotspot. Studies showed that the deficiency of Vitamin D plays a vital role in NAFLD pathogenesis. While several research studies focused on vitamin D supplementation in NAFLD, there is still a need to understand the regulatory mechanism of direct vitamin D receptor activation in NAFLD. In the present study, we explored the role of direct Vitamin D receptor activation using paricalcitol in choline-deficient high-fat diet-induced NAFLD rat liver and its modulation on protein acetylation. Our results showed that paricalcitol administration significantly reduced the fat accumulation in HepG2 cells and the liver of NAFLD rats. Paricalcitol attenuated the elevated serum level of alanine transaminase, aspartate transaminase, insulin, low-density lipoprotein, triglyceride, and increased high-density lipoprotein in NAFLD rats. Paricalcitol significantly decreased the increased total protein acetylation by enhancing the SIRT1 and SIRT3 expression in NAFLD liver. Further, the study revealed that paricalcitol reduced the acetylation of NFκB and FOXO3a in NAFLD liver along with a decrease in the mRNA expression of IL1β, NFκB, TNFα, and increased catalase and MnSOD. Moreover, total antioxidant activity, glutathione, and catalase were also elevated, whereas lipid peroxidation, myeloperoxidase, and reactive oxygen species levels were significantly decreased in the liver of NAFLD after paricalcitol administration. The study concludes that the downregulation of SIRT1 and SIRT3 in NAFLD liver was associated with an increased acetylated NFκB and FOXO3a. Paricalcitol effectively reversed hepatic inflammation and oxidative stress in NAFLD rats through transcriptional regulation of NFκB and FOXO3a, respectively, by inhibiting their acetylation.

Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review.

The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-β/Smad or Wnt/β-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.

Artesunate attenuates isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation

Cardiac Hypertrophy is an adaptive response of the body to physiological and pathological stimuli, which increases cardiomyocyte size, thickening of cardiac muscles and progresses to heart failure. Downregulation of SIRT1 in cardiomyocytes has been linked with the pathogenesis of cardiac hypertrophy. The present study aimed to investigate the effect of Artesunate against isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation. Experimental cardiac hypertrophy was induced in rats by subcutaneous administration of isoprenaline (5 mg/kg) for 14 days. Artesunate was administered simultaneously for 14 days at a dose of 25 mg/kg and 50 mg/kg. Artesunate administration showed significant dose dependent attenuation in mean arterial pressure, electrocardiogram, hypertrophy index and left ventricular wall thickness compared to the disease control group. It also alleviated cardiac injury biomarkers and oxidative stress. Histological observation showed amelioration of tissue injury in the artesunate treated groups compared to the disease control group. Further, artesunate treatment increased SIRT1 expression and decreased NF-kB expression in the heart. The results of the study show the cardioprotective effect of artesunate via SIRT1 inhibiting NF-κB activation in cardiomyocytes.

Intrauterine hyperglycemia induces SIRT3-mediated mitochondrial dysfunction: the fetal origin pathogenesis of precocious osteoarthritis

Diabetes and other metabolic and inflammatory comorbidities are highly associated with osteoarthritis (OA). However, whether early-life hyperglycemia exposure affects susceptibility to long-term OA is still unknown. The purpose of this study was to explore the fetal origins of OA and provide insights into early-life safeguarding for individual health. This study utilized streptozotocin to induce intrauterine hyperglycemia and performed destabilization of the medial meniscus surgery on the knee joints of the offspring mice to induce accelerated OA. Cartilage degeneration-related markers, as well as the expression levels of mitochondrial respiratory chain complexes and mitophagy genes in the adult offspring mice, were investigated. In vitro, mitochondrial function and mitophagy of chondrocyte C28/I2 cells stimulated under high glucose conditions were also evaluated. The methylation levels of the sirt3 gene promoter region in the articular cartilage of intrauterine hyperglycemia-exposed offspring mice were further analyzed. In this study, we found that the intrauterine hyperglycemic environment could lead to an increase in individual susceptibility to OA in late adulthood, mainly due to persistently low levels of Sirt3 expression. Downregulation of Sirt3 causes impaired mitophagy in chondrocytes and abnormal mitochondrial respiratory function due to a failure to clear aged and damaged mitochondria in a timely manner. Overexpressing Sirt3 at the cellular level or using Sirt3 agonists like Honokiol in mouse models can partially rescue mitophagy disorders caused by the hyperglycemic environment and thus alleviate the progression of OA. Our study revealed a significantly increased susceptibility to OA in the gestational diabetes mellitus offspring, which is partly attributed to exposure to adverse factors in utero and ultimately to the onset of disease via epigenetic modulation.

Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis

Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3−/− mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.

SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway.

High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

Gene expression patterns of Sirtuin family members (SIRT1 TO SIRT7): Insights into pathogenesis and prognostic of Myelodysplastic neoplasm

To assess and validate the gene expression profile of SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7) in relation to the pathogenesis and prognostic progression of Myelodysplastic neoplasm (MDS). Eighty bone marrow samples of patients with de novo MDS were diagnosed according to WHO 2022 and IPSS-R criteria. Ten bone marrow samples were obtained from elderly healthy volunteers and used as control samples. Gene expression levels of all SIRTs were assessed using RT-qPCR assays. Downregulation of SIRT2 (p = 0.009), SIRT3 (p = 0.048), SIRT4 (p = 0.049), SIRT5 (p = 0.046), SIRT6 (p = 0.043), and SIRT7 (p = 0.047) was identified in MDS patients compared to control individuals. Also, we identified that while SIRT2-7 genes are typically down-regulated in MDS patients compared to normal controls, there are relative expression variations among MDS patient subgroups. Specifically, SIRT4 (p = 0.029) showed increased expression in patients aged 60 or above, and both SIRT2 (p = 0.016) and SIRT3 (p = 0.036) were upregulated in patients with hemoglobin levels below 8 g/dL. SIRT2 (p = 0.045) and SIRT3 (p = 0.033) were highly expressed in patients with chromosomal abnormalities. Different SIRTs exhibited altered expression patterns concerning specific MDS clinical and prognostic characteristics. The downregulation in SIRTs genes (e.g., SIRT2 to SIRT7) expression in Brazilian MDS patients highlights their role in the disease's development. The upregulation of SIRT2 and SIRT3 in severe anemia patients suggests a potential link to manage iron overload-related complications in transfusion-dependent patients. Moreover, the association of SIRT2/SIRT3 with genomic instability and their role in MDS progression signify promising areas for future research and therapeutic targets. These findings underscore the importance of SIRT family in understanding and addressing MDS, offering novel clinical, prognostic, and therapeutic insights for patients with this condition.

Resolvin D4 mitigates lipopolysaccharide-induced lung injury in mice

Acute respiratory distress syndrome (ARDS) is a life-threatening condition involving severe lung inflammation. The excessive oxidative stress and persistent inflammation that occur in ARDS lead to decreased epithelial integrity and hypoxemia due to pulmonary edema via increased vascular permeability. Resolvin D4 (RvD4) is one of the lipid mediators that is biosynthesized from omega-3 polyunsaturated fatty acids. It plays a role in the resolution of inflammation and reduces oxidative stress and cell death. We investigated the therapeutic potential of the administration of RvD4 in a murine model of lipopolysaccharide (LPS)-induced ARDS. Concurrent with the intratracheal administration of LPS, RvD4 or saline was administered to mice via the caudal vein every 12 h. This treatment with RvD4 alleviated the LPS-induced infiltration of inflammatory cells in lungs, inhibited increased pulmonary vascular permeability, decreased the levels of IL-1β, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF), and suppressed the reduction of the expression levels of the tight junction protein, Zonula occludens-1 (Zo-1) and the NAD+-dependent deacetylase, Sirtuin-3 (Sirt3). In vitro experiments revealed that in LPS-stimulated BEAS-2B cells, treatment with RvD4 suppressed the increases in the expressions of pro-inflammatory cytokines and maintained the epithelial cell barrier function and cell viability. The silencing of SIRT3 abolished both the anti-inflammatory effect and the retention of cell integrity in BEAS-2B cells. Together these results indicate that treatment with RvD4 can (i) protect against LPS-induced lung injury by inhibiting inflammation, and (ii) maintain epithelial barrier function via a reduction in the downregulation of SIRT3.

Downregulation of SIRT1 and GADD45G genes and left atrial fibrosis induced by right ventricular dependent pacing in a complete atrioventricular block pig model.

The molecular and genetic mechanisms underlying left atrial (LA) enlargement and atrial fibrosis following right ventricular (RV) dependent pacing remain unclear. Our objective was to investigate genetic expressions in the LA of pigs subjected to RV pacing for atrioventricular block (AVB), as well as to identify the differential gene expressions affected by biventricular (BiV) pacing. We established an AVB pig model and divided the subjects into three groups: a sham control group, an RV pacing group, and a BiV pacing group. Differential expression genes (DEGs) analyses conducted through next-generation sequencing (NGS) and enrichment analyses were employed to identify genes with altered expression in the LA myocardium. The RV pacing group showed a significant increase in extracellular fibrosis in the LA myocardium compared to the control group. NGS analysis revealed suppressed expression of the sirtuin signaling pathway in the RV pacing group. Among the DEGs within this pathway, GADD45G was found to be downregulated in the RV pacing group and upregulated in the BiV pacing group. Remarkably, the BiV pacing group exhibited elevated levels of GADD45G protein. In our study, we observed significant downregulation of SIRT1 and GADD45G genes, which are associated with the sirtuin signaling pathway, in the LA myocardium of the RV pacing group when compared to the control group. Moreover, these genes, which were downregulated in the RV pacing group, displayed a noteworthy upregulation in the BiV pacing group when compared to the RV pacing group.

The role of Sirtuin 1 in regulation of fibrotic genes expression in pre-adipocytes.

Considering inhibition of pre-adipocyte cells differentiation in adipose tissue fibrosis, we aimed to explore whether Sirt1 and Hif-1α in pre-adipocytes have a significant effect on fibrotic gene expression. 3T3-L1 pre-adipocytes were transfected with SIRT1-specific siRNA, confirmed by real-time polymerase chain reaction (RT-PCR) and western blotting. Additionally, cells were treated with varying concentrations of resveratrol and sirtinol as the activator and inhibitor of Sirt1, respectively. Involvement of Hif-1α was evaluated by treatment with echinomycin. Subsequently, we assessed the gene and protein expressions related to fibrosis in the extracellular matrix of adipose tissue, including collagen VI (Col VI), lysyl oxidase (Lox), matrix metalloproteinase-2 (Mmp-2), Mmp-9, and osteopontin (Opn) in pre-adipocytes through RT-PCR and western blot. The current study demonstrated that Sirt1 knockdown and reduced enzyme activity significantly increased the expression of Col VI, Lox, Mmp-2, Mmp-9, and Opn genes in the treated 3T3-L1 cells compared to the control group. Interestingly, resveratrol significantly decreased the gene expression related to the fibrosis pathway. Inhibition of Hif-1α by echinomycin led to a significant reduction in Col VI, Mmp-2, and Mmp-9 gene expression in the treated group compared to the control. This study highlights that down-regulation of Sirt1 might be a predisposing factor in the emergence of adipose tissue fibrosis by enhancing the expression of extracellular matrix (ECM) components. Activation of Sirt1, similar to suppressing of Hif-1α in pre-adipocytes may be a beneficial approach for attenuating fibrotic gene expression. The online version contains supplementary material available at 10.1007/s40200-024-01389-4.

FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation

FBXO31, a member of F-box family to comprise of SCF complex, contributes to a pivotal role in cancer progression. However, the possible involvements of FBXO31 in PC are unelucidated. Here, we reported that FBXO31 was overexpressed in PC patients, which was negatively associated with survival in PC patients. Furthermore, FBXO31 significantly enhanced growth, migration and invasion of PC cells in vitro. Consistently, FBXO31 overexpression promoted tumor growth in nude mice. Mechanistically, SIRT2 was a target of FBXO31 and interacted with FBXO31. Protein half-life and ubiquitination analysis demonstrated that FBXO31 promoted proteasome-dependent degradation of SIRT2. In addition, FBXO31 binds to sirtuin-type domain of SIRT2. Moreover, SIRT2 is required for the oncogenic role of FBXO31 in PC progression. Impressively, METTL3 induced m6A modification of FBXO31 and up-regulated FBXO31 expression, subsequently leading to SIRT2 down-regulation in PC cells. The results showed that METTL3 enhanced FBXO31 mRNA translation in YTHDF1-dependent manner. Taken together, we suggest that METTL3–FBXO31–SIRT2 axis was involved in PC tumorigenesis, which could identify new targets for PC treatment.