Silent Information Regulator Factor Research Articles

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.

Anti-Aging Drugs and the Related Signal Pathways.

Aging is a multifactorial biological process involving chronic diseases that manifest from the molecular level to the systemic level. From its inception to 31 May 2022, this study searched the PubMed, Web of Science, EBSCO, and Cochrane library databases to identify relevant research from 15,983 articles. Multiple approaches have been employed to combat aging, such as dietary restriction (DR), exercise, exchanging circulating factors, gene therapy, and anti-aging drugs. Among them, anti-aging drugs are advantageous in their ease of adherence and wide prevalence. Despite a shared functional output of aging alleviation, the current anti-aging drugs target different signal pathways that frequently cross-talk with each other. At present, six important signal pathways were identified as being critical in the aging process, including pathways for the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), nutrient signal pathway, silent information regulator factor 2-related enzyme 1 (SIRT1), regulation of telomere length and glycogen synthase kinase-3 (GSK-3), and energy metabolism. These signal pathways could be targeted by many anti-aging drugs, with the corresponding representatives of rapamycin, metformin, acarbose, nicotinamide adenine dinucleotide (NAD+), lithium, and nonsteroidal anti-inflammatory drugs (NSAIDs), respectively. This review summarized these important aging-related signal pathways and their representative targeting drugs in attempts to obtain insights into and promote the development of mechanism-based anti-aging strategies.

Role of SIRT-1 as a Target for Treatment and Prevention of Diabetic Nephropathy: A Review.

Type-2 diabetes mellitus is a prime factor for the development of Diabetic Nephropathy (DN) that affects the vital organ namely the kidneys, and further alters the functions of the nephron system. DN is nowadays becoming a challenge for scientists towards the world because of its high pervasiveness and complexity of medication. Various risk factors are involved in the initiation of pathogenic DN, which are associated with different pathways against drug activity. Due to this DN becomes an unpredictable query to the researchers. SIRT1 is a silent information regulator factor 2 related enzyme 1 (SIRT1) is nicotinamide adenine dinucleotide (NAD+) dependent deacetylase that functions as an intracellular regulator of transcriptional activity. An activated version of SIRT-1 improves the metabolic diseased conditions associated with other molecular pathways. SIRT1 attenuates diabetic nephropathy in in vitro and in vivo experimental models of diabetes containing Podocytes, Mesangial cells, and Renal proximal tubular cells. SIRT1 shows nephroprotective effects in DN in part through deacetylation of transcription factors i.e., imply in the disease like p53, PTP1B, FOXO, RelA, NF- kβ, STAT-3, and PGC-1α/ PPARγ. It has been shown that some natural products like resveratrol and synthetic compounds are activating the SIRT1, this further involved the cascade pathways to prevent the DN. This review will help regarding the effectiveness of SIRT1as target in the prevention and treatment of DN.

Farnesol Exerts Protective Effects against Chronic Sleep Deprivation-Induced Cognitive Impairment via Activation SIRT1/Nrf2 Pathway in the Hippocampi of Adult Mice.

Sleep deprivation (SD) negatively affects all aspects of health, with one serious consequence being impaired cognition. Farnesol (FOL) is a sesquiterpene synthesized by plants and mammals that has antioxidant, anti-inflammatory, and neuroprotective properties. This study investigates the mechanism underlying the neuroprotective effectof FOL on SD-induced cognitive impairment. Administration of FOL dramatically ameliorates chronic sleep deprivation (CSD)-induced cognitive impairment. In addition, FOL notably attenuates oxidative stress damage, pro-inflammatory cytokines activation, and microglial activation in the hippocampi of the CSD-exposed mice. Further examination indicates that administration of FOL after the CSD significantly increases the protein expressions of silent information regulator factor 2-related enzyme 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (Gpx4) in the hippocampi. Sirt1 agonist resveratrol (RES) has a similar neuroprotective effect, indicating that FOL could exert neuroprotective effects through the activation of the Sirt1/Nrf2 signaling pathway. The results reveal that FOL could protect against CSD-induced cognitive impairment by activating the Sirt1/Nrf2 signaling pathway.

Linggui Zhugan Decoction activates the SIRT1-AMPK-PGC1α signaling pathway to improve mitochondrial and oxidative damage in rats with chronic heart failure caused by myocardial infarction.

Objective: To investigate the effects of Linggui Zhugan Decoction on mitochondrial and oxidative damage in rats with chronic heart failure after myocardial infarction and the related mechanisms. Methods: Chronic heart failure after myocardial infarction was established by coronary artery ligation. Heart failure rats were randomly divided into three groups: Model group (n = 11), Linggui Zhugan Decoction group (n = 12), and captopril group (n = 11). Rats whose coronary arteries were only threaded and not ligated were sham group (n = 11). Cardiac function, superoxide dismutase (SOD), malondialdehyde (MDA) contents, soluble growth-stimulating expression factor (ST2), and N-terminal B-type brain natriuretic peptide precursor (NTproBNP) levels were analyzed after treatment. Moreover, the level of mitochondrial membrane potential was detected by JC-1 staining, the ultrastructural of myocardial mitochondria were observed by transmission electron microscopy. The related signal pathway of silent information regulator factor 2-related enzyme 1 (SIRT1), adenylate activated protein kinase (AMPK), phosphorylated adenylate activated protein kinase (p-AMPK), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is an important pathway to regulate mitochondrial energy metabolism, and to initiate mitochondrial biogenesis. The expression level was detected by Western blot and reverse transcription to explore the mechanism of the decoction. Results: Compared with the model rats, Linggui Zhugan Decoction significantly improved cardiac function (p < 0.05), reduced MDA production (p < 0.01), increased SOD activity (p < 0.05), reduced ST-2(p < 0.01), and NT-proBNP(p < 0.05) levels, increased mitochondrial membrane potential, and improved mitochondria function. In addition, Linggui Zhugan Decoction upregulated the expression of SIRT1, p-AMPK, PGC-1α protein, and mRNA in cardiac myocytes. Conclusion: Linggui Zhugan Decoction can improve the cardiac function of heart failure rats by enhancing myocardial antioxidant capacity and protecting the mitochondrial function, the mechanism is related to activating SIRT1/AMPK/PGC-1α signaling pathway.

Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aβ25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aβ deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aβ25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

Ferroptosis contributes to hypoxic-ischemic brain injury in neonatal rats: Role of the SIRT1/Nrf2/GPx4 signaling pathway.

Hypoxic-ischemic brain injury (HIBI) often results in cognitive impairments. Herein, we investigated the roles of ferroptosis in HIBI and the underlying signaling pathways. Ferrostatin-1 (Fer-1) or resveratrol (Res) treatments were administered intracerebroventricularly 30 min before HIBI in 7-day-old rats. Glutathione peroxidase 4 (GPx4) expression, malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, and the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and nuclear factor erythroid-2-related factor 2 (Nrf2) were measured after HIBI. Additionally, the weight ratio of left/right hemisphere, brain morphology, Nissl staining, and the Morris water maze test were conducted to estimate brain damage. At 24-h post-HIBI, GPx4 expression was decreased, and MDA concentration and iron content were increased in the hippocampus. HIBI led to mitochondrial atrophy, brain atrophy/damage, and resultant learning and memory impairments, which were alleviated by Fer-1-mediated inhibition of ferroptosis. Furthermore, Res-mediated SIRT1 upregulation increased Nrf2 and GPx4 expression, thereby attenuating ferroptosis, reducing brain atrophy/damage, and improving learning and memory abilities. The results demonstrated that during HIBI, ferroptosis occurs via the SIRT1/Nrf2/GPx4 signaling pathway, suggesting it as a potential therapeutic target for inhibiting ferroptosis and ameliorating HIBI-induced cognitive impairments.

MiR-362-5p inhibits cartilage repair in osteoarthritis via targeting plexin B1.

Chondrogenesis of bone marrow mesenchymal stem cells (BMSCs) exerts great function during the pathogenesis of osteoarthritis (OA). Studies have reported the association of plexin B1 (PLXNB1) with OA pathogenesis. In this study, the upstream mechanism and function of PLXNB1 in this disease were explored. Flow cytometry was applied to test BMSC characterization. Chondrogenic differentiation of BMSCs was evaluated by Alcian blue staining. The expression of PLXNB1, miR-362-5p, miR-501-5p, miR-1827, miR-500-5p was measured using RT-qPCR analysis. The protein levels of PLXNB1, Aggrecan, and Silent information regulator factor 2-related enzyme 1 (SIRT1) were determined by western blotting. Binding relationship between miR-362-5p and PLXNB1 was confirmed using bioinformatics analysis and luciferase reporter assay. The in vivo model of OA was established in Sprague-Dawley rats which received medial meniscus instability surgery. For histopathological examination, cartilage tissues in the knee joint of rats were stained with hematoxylin and eosin. Micro-CT analysis was employed to observe the changes of morphometric indices including average trabecular separation, average trabecular thickness, and bone volume fraction. BMSCs were identified to possess the characteristics of mesenchymal stem cells. PLXNB1 was observed to be highly expressed during chondrogenic differentiation of BMSCs and PLXNB1 overexpression promoted BMSC chondrogenic differentiation. Mechanically, PLXNB1 was targeted by miR-362-5p. In rescue assays, miR-362-5p reversed the effects of PLXNB1 on chondrogenic differentiation of BMSCs. In the in vivo experiments, upregulated PLXNB1 expression alleviated joint injury of OA rats. Additionally, overexpressed miR-362-5p and downregulated PLXNB1 expression levels were detected in OA rats. MiR-362-5p promotes OA progression by suppressing PLXNB1.

SIRT1 ameliorated septic associated-lung injury and macrophages apoptosis via inhibiting endoplasmic reticulum stress

BackgroundThe inappropriate apoptosis of macrophages plays an important role in the pathogenesis of sepsis-induced acute lung injury, however, the detailed regulatory mechanisms remain largely unknown. As an endogenous apoptosis pathway, endoplasmic reticulum (ER) stress plays an important role in cell damage in patients with sepsis. Clarifying the ER stress response and its effect on macrophages during the development of sepsis is helpful to explore new strategies for the prevention and treatment of ALI in sepsis. MethodsThe mouse model and the RAW264.7 inflammation model were stimulated with LPS to establish in vivo and in vitro. We explored the effects of different expression levels of silent information regulator factor 2-related enzyme 1 (SIRT1) on the ER stress response and apoptosis of macrophages in the sepsis-related injury model. ResultsOur studies found that the increased expression of SIRT1 can significantly improve sepsis-related lung injury and relieve lung inflammation. SRT1720, a SIRT1 activator, can significantly inhibit the ER stress response of lung tissue and macrophages, inhibit the expression of pro-apoptotic proteins, promote the expression of anti-apoptotic proteins, and reduce macrophages of apoptosis. While the EX527, an inhibitor of SIRT1, had the opposite effect. ConclusionSIRT1 can significantly improve sepsis-associated lung injury and LPS-induced macrophage apoptosis. This protective effect is closely related to its inhibition of the ER stress response via the PERK/eIF2-α/ATF4/CHOP pathway.

NOX4 stimulates ANF secretion via activation of the Sirt1/Nrf2/ATF3/4 axis in hypoxic beating rat atria.

Silent information regulator factor 2-related enzyme 1 (Sirt1) is involved in the regulation of cell senescence, gene transcription, energy balance and oxidative stress. However, the effect of Sirt1 on atrial natriuretic factor (ANF) secretion, especially under hypoxic conditions is unclear. The present study aimed to investigate the effect of Sirt1, regulated by NADPH oxidase 4 (NOX4), on ANF secretion in isolated beating rat atria during hypoxia. ANF secretion was analyzed using radioimmunoassays and protein expression levels were determined by western blotting and immunofluorescence staining. Intra-atrial pressure was recorded using a physiograph. Hypoxia significantly upregulated Sirt1 and nuclear factor erythroid-2-related factor 2 (Nrf2) protein expression levels, together with significantly increased ANF secretion. Hypoxia-induced protein expression of Sirt1 was significantly blocked by a NOX4 inhibitor, GLX351322, and Nrf2 protein expression levels were significantly abolished using the Sirt1 inhibitor, EX527. Hypoxia also significantly elevated the protein expression levels of phosphorylated-Akt and sequestosome 1 and significantly downregulated Kelch-like ECH-associated protein 1 protein expression levels. These effects were significantly blocked by EX527, preventing hypoxia-induced Nrf2 expression. An Nrf2 inhibitor, ML385, significantly abolished the hypoxia-induced upregulation of activating transcription factor (ATF)3, ATF4, T cell factor (TCF)3 and TCF4/lymphoid enhancer factor 1 (LEF1) protein expression levels, and significantly attenuated hypoxia-induced ANF secretion. These results indicated that Sirt1 and Nrf2, regulated by NOX4, can potentially stimulate TCF3 and TCF4/LEF1 signaling via ATF3 and ATF4 activation, thereby potentially participating in the regulation of ANF secretion in beating rat atria during hypoxia. In conclusion, intervening with the Sirt1/Nrf2/ATF signaling pathway may be an effective strategy for resisting oxidative stress damage in the heart during hypoxia.

Evaluating the Effect of Circ-Sirt1 on the Expression of SIRT1 and Its Role in Pathology of Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a disease that plagues a major portion of the world’s population, and there is currently no effective cure for this ailment. The proliferation and migration of pulmonary artery smooth muscle cells (PASMC) are known to be the pathological basis of pulmonary vascular remodeling in pulmonary hypertension. Studies in the past have shown involvement of CircRNA in the pathology of pulmonary as well as cardiovascular diseases. However, there are very few studies that have analyzed the relationship between CircRNA and PAH. The aim of this study was to explore this relationship by using rat PAH model. A hypoxic, PAH rat model was constructed for this study and the subsequently produced hypoxia-induced rat PASMC cells were utilized to demonstrate the reduction in expression of circular RNA of Silent information regulator factor 2-related enzyme 1 (circ-Sirt1) and SIRT1 mRNA in response to hypoxia, through cell function tests, cell rescue tests, and physical tests. We found that the expression of circ-Sirt1 and SIRT1 decreased in the PAH rat model induced by hypoxia. It was also revealed that the overexpression of circ-SIRT1 increased SIRT1 levels, but inhibited the expression of transforming growth factor (TGF)-β1, Smad3, and Smad7, and weakened PASMC cell vitality, proliferation, and migration ability. The findings of the present study indicate that circ-Sirt1 regulates the expression of SIRT1 mRNA and inhibits TGF-β1/Smad3/Smad7 mediated proliferation and migration of PASMC. This provides a new insight into the molecular mechanism of pulmonary artery vascular remodeling in PAH and may aid in the development of novel therapeutic options for management of PAH.

Aerobic exercise ameliorates myocardial ischemia/reperfusion injury and thrombosis of diabetic rats via activation of AMPK/Sirt1/PGC-1α pathway.

This current work is aimed to make investigations for the action mechanism of aerobic exercise in rats with type 2 diabetes mellitus (T2DM) after myocardial ischemia/reperfusion injury (MI/RI). The high-fat diet was used to induce T2DM in male Wistar rats. After treatments, the rats in the exercise groups were underwent swimming training for 8 weeks. Two days later, all the rats were subjected to perform MI/RI experiments via left anterior descending artery ligation and reperfusion. The blood samples and myocardial tissues were collected for biochemistry analysis and histology assessment. The results demonstrated that aerobic exercise reduced the levels of serum glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and thrombosis in T2DM rats. In addition, aerobic exercise further decreased the levels of myocardial injury markers and also repressed inflammation responses. Furthermore, the AMP-activated protein kinase (AMPK)/silent information regulator factor 2-related enzyme 1 (Sirt1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathway could be activated by aerobic exercise. In a word, aerobic exercise may attenuate myocardial ischemia/reperfusion injury and repress thrombosis via activation of the AMPK/Sirt1/PGC-1α pathway in DM rats.

Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum stress-mediated apoptosis plays a vital role in the occurrence and development of heart failure. Dapagliflozin (DAPA), a new type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an oral hypoglycemic drug that reduces glucose reabsorption by the kidneys and increases glucose excretion in the urine. Studies have shown that DAPA may have the potential to treat heart failure in addition to controlling blood sugar. This study explored the effect of DAPA on endoplasmic reticulum stress-related apoptosis caused by heart failure. In vitro, we found that DAPA inhibited the expression of cleaved caspase3, Bax, C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the cardiomyoprotective protein Bcl-2 in angiotensin II (Ang II)-treated cardiomyocytes. In addition, DAPA promoted the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4) and the ratios p-PERK/PERK and p-eIF2α/eIF2α. Notably, the therapeutic effect of DAPA was weakened by pretreatment with the SIRT1 inhibitor EX527 (10 μM). Simultaneous administration of DAPA inhibited the Ang II-induced transformation of fibroblasts into myofibroblasts and inhibited fibroblast migration. In summary, our present findings first indicate that DAPA could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in Ang II-treated cardiomyocytes and ameliorate heart failure development in vivo.

Up-regulation of SIRT1 induced by 17beta-estradiol promotes autophagy and inhibits apoptosis in osteoblasts.

Osteoporosis is a common systemic skeletal metabolism disorder resulting in bone fragility and increased fracture risk. Silent information regulator factor 2 homolog 1 (SIRT1) is crucial in the regulation of several biological processes, including bone metabolism, autophagy, apoptosis, and aging. This study aimed to assess whether the up-regulation of SIRT1 induced by 17beta-estradiol (17β-E2) could promote autophagy and inhibit apoptosis in osteoblasts via the AMPK-mTOR and FOXO3a pathways, respectively. The study found that 17β-E2 (10-6 M) administration induced the up-regulation of SIRT1 in osteoblasts. Up-regulation of SIRT1 induced by 17β-E2 increased the expression level of LC3, Beclin-1, Bcl-2, p-AMPK, FOXO3a but decreased caspase-3 and p-mTOR expression, and then promoted autophagy and inhibited apoptosis. More autophagosomes were observed under a transmission electron microscope (TEM) in 17β-E2 and SRT1720 (a selective SIRT1 activator) co-treated group. When Ex527 (a SIRT1-specific inhibitor) was pretreated, the reversed changes were observed. Taken together, our findings demonstrated that the up-regulation of SIRT1 induced by 17β-E2 could promote autophagy via the AMPK-mTOR pathway and inhibit apoptosis via the FOXO3a activation in osteoblasts, and SIRT1 might become a more significant target in osteoporosis treatment.

Research Progress on Catalpol as Treatment for Atherosclerosis.

Coronary atherosclerotic heart disease, cerebrovascular disease, and peripheral artery disease are common diseases with high morbidity and mortality rates and must be addressed. Their most frequent complications, including myocardial infarction and stroke, are caused by spontaneous thrombotic occlusion and are the most frequent cause of death worldwide. Atherosclerosis (AS) is the most widespread underlying pathological change for the above diseases. Therefore, drugs that interfere with this pathophysiological process must be incorporated in the treatment. Chinese traditional and herbal drugs can effectively treat AS. With the development of traditional Chinese medicine, the active ingredients in common Chinese medicinal materials must be thoroughly purified prior to their application in western medicine. Various proprietary Chinese medicine preparations with remarkable effects have been used in AS treatment. Catalpol, the active component of Rehmannia glutinosa, belongs to iridoid terpene and has anti-inflammatory, antioxidant, insulin resistance improvement, and other related effects. Several reviews have been conducted on this compound and its actions against osteoporosis, neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and diabetes and its complications. The current review focused on catalpol’s effect on atherosclerotic plaque formation in different animal models. The potential mechanisms of catalpol to ameliorate AS were also summarized in terms of oxidative stress, inflammation, cell aging, apoptosis, and activation of the silent information regulator factor 2-related enzyme 1 (SIRT1) pathway.

Histidine ameliorates elastase- and lipopolysaccharide-induced lung inflammation by inhibiting the activation of the NLRP3 inflammasome.

Histidine treatment has anti-inflammatory effects on several diseases such as colitis and obesity. We revealed that histidine levels were decreased in the serum of patients with chronic obstructive pulmonary disease (COPD) in our previous study. However, whether histidine confers protection against COPD is unclear. In the present study, we evaluated the protective effects of histidine in a porcine pancreatic elastase- and lipopolysaccharide-induced COPD mouse model. We found that the serum histidine concentration was decreased in COPD mice. Histidine supplementation improved the COPD mouse lung function and reduced the inflammatory cell counts and production of cytokines in bronchoalveolar lavage fluid. In addition, histidine treatment ameliorated lung inflammation by inhibiting the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 inflammasome activation both in vivo and in vitro. Furthermore, we found that the potential anti-inflammatory mechanism involved the upregulation of silent information regulator factor 2-related enzyme 1. These results suggest that histidine may be a valuable therapeutic target for COPD.

Melatonin attenuates oxidative stress and inflammation of Müller cells in diabetic retinopathy via activating the Sirt1 pathway

Oxidative stress and inflammation are important pathogenic factors of diabetic retinopathy (DR). DR remains the most common ocular complication caused by diabetes mellitus (DM) and is the leading cause of visual impairment in working-aged people worldwide. Melatonin has attracted extensive attention due to its potent antioxidant and anti-inflammatory effects. In the present study, melatonin inhibited oxidative stress and inflammation by enhancing the expression and activity of silent information regulator factor 2-related enzyme 1 (Sirt1) both in in vitro and in vivo models of DR, and the Sirt1 inhibitor EX-527 counteracted melatonin-mediated antioxidant and anti-inflammatory effects on Müller cells. Moreover, melatonin enhanced Sirt1 activity through the maternally expressed gene 3 (MEG3)/miR-204 axis, leading to the deacetylation of the Sirt1 target genes forkhead box o1 (Foxo1) and nuclear factor kappa B (NF-κB) subunit p65, eventually contribute to the alleviation of oxidative stress and inflammation. The study revealed that melatonin promotes the Sirt1 pathway, thereby protecting the retina from DM-induced damage.

LncRNA-CRNDE regulates BMSC chondrogenic differentiation and promotes cartilage repair in osteoarthritis through SIRT1/SOX9.

Osteoarthritis (OA) is the most common chronic and degenerative joint disease. Although traditional OA medications can partially relieve pain, these medications cannot completely cure OA. Therefore, it is particularly important to find an effective treatment for OA. This study explored the function of long non-coding RNA (lncRNA)-colorectal neoplasia differentially expressed gene (CRNDE) in the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the underlying molecular mechanism, aiming to develop a new treatment method for osteoarthritis. BMSCs were isolated from rat bone marrow using the gradient centrifugation method. And BMSC chondrogenic differentiation was induced with chondrogenic medium. The expression of lncRNA-CRNDE was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Silent information regulator factor 2-related enzyme 1(SIRT1) and cartilage marker genes Aggrecan and collagen 2 (α1) protein expression were researched using western blot. Alcian blue staining was employed to examine the content of cartilage matrix proteoglycan glycosaminoglycan (GAG). The interaction between lncRNA-CRNDE and SIRT1 was detected by RNA pull-down and RNA immunoprecipitation (RIP) assay. Ubiquitination experiments were performed to measure the ubiquitination level of SIRT1. The combination between SMAD ubiquitination regulatory factor 2 (SMURF2) and SIRT1, as well as SRY-related high-mobility-group box 9 (SOX9) and collagen 2 (α1) promoter, was detected by Co-immunoprecipitation or ChIP. With the prolongation of induction time, the expression of lncRNA-CRNDE, SIRT1, cartilage marker genes Aggrecan and collagen 2 (α1) in BMSC osteogenic differentiation was gradually increased. Also, the content of cartilage matrix proteoglycan GAG was gradually elevated with the extension of the induction time. Further increase in the expression of SIRT1, cartilage marker genes Aggrecan and collagen 2 (α1) by overexpression of lncRNA-CRNDE also indicated elevated GAG content. RNA pull-down and RIP assay confirmed the binding between lncRNA-CRNDE and SIRT1. qRT-PCR and western blot showed that interference with lncRNA-CRNDE significantly inhibited the protein expression of SIRT1. BMSCs transfected with si-CRNDE increased ubiquitination levels of SIRT1 mediated by the E3 ligase SMURF2, leading to the reduced protein stability of SIRT1. However, overexpression of lncRNA-CRNDE increased the binding ability of SOX9 and collagen 2 (α1) promoter, which was reversed by the simultaneous transfection ofCRNDE overexpression (pcDNA-CRNDE) and SIRT1small interferingRNA (si-SIRT1). lncRNA-CRNDE regulates BMSC chondrogenic differentiation to promote cartilage repair in osteoarthritis through SIRT1/SOX9.

Effects of Macamide B on the Expression of SIRT1 in Brain Tissue of Neonatal Mice with Hypoxic-ischemic Brain Damage

Neonatal hypoxic-ischemic brain damage (HIBD) is the main cause of severe neurological diseases and death in newborns. Macamide B is an effective monomer extracted from Maca (Lepidium meyenii Walpers), which has important biological activities such as neuroprotection and neuromodulation. The purpose of this study was to investigate whether Macamide B can exert neuroprotective effects on HIBD in newborn mice by regulating Silent information regulator factor 2-related enzyme 1 (SIRT1). A modified Rice-Vannucci method was used to construct the HIBD model of newborn mice. The pups were divided into the following groups: sham group, HI group, and Macamide B group. On the first and third days after hypoxic-ischemic (HI), immunofluorescence and Western blot experiments were used to detect the expression level of SIRT1 in the brain tissue of infants. The results of the immunofluorescence experiment showed that compared with the sham group, the expression level of SIRT1 is significantly decreased in HI group pups, while the expression level of SIRT1 in pups pretreated with Macamide B increased significantly. The results of Western blot experiments are consistent with the results of immunofluorescence experiments. Our data indicate that Macamide B may exert a neuroprotective effect on HIBD in newborn mice by up-regulating the expression of SIRT1. Macamide B may become a new medicine effective in preventing and treating HIBD.

Hydrogen sulfide restores sevoflurane postconditioning mediated cardioprotection in diabetic rats: Role of SIRT1/Nrf2 signaling-modulated mitochondrial dysfunction and oxidative stress.

Diabetic hearts are vulnerable to myocardial ischemia/reperfusion injury (IRI), but are insensitive to sevoflurane postconditioning (SPC), activating peroxiredoxins that confer cardioprotection. Previous studies have demonstrated that hydrogen sulfide (H2 S) can suppress oxidative stress of diabetic rats through increasing the expression of silent information regulator factor 2-related enzyme 1 (SIRT1), but whether cardioprotection by SPC can be restored afterward remains unclear. Diabetic rat was subjected to IRI (30 min of ischemia followed by 120 min reperfusion). Postconditioning treatment with sevoflurane was administered for 15 min upon the onset of reperfusion. The diabetic rats were treated with GYY4137 (H2 S donor) 5 days before the experiment. Myocardial infarct size, mitochondrial structure and function, ATP content, activities of complex I-IV, marker of oxidative stress, SIRT1, nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADPH Oxidase-2 (Nox-2) protein expression were detected after reperfusion, and cardiac function was evaluated by echocardiography at 24 h after reperfusion. After H2 S activated SIRT1 in the impaired myocardium of diabetic rats, SPC significantly upregulated the expression of Nrf2 and its downstream mediator HO-1, thus reduced the expression of Nox-2. In addition, H2 S remarkably increased cytoplasmic and nuclear SIRT1 which was further enhanced by SPC. Furthermore, H2 S combined with SPC reduced the production of reactive oxygen species, increased the content of ATP, and maintained mitochondrial enzyme activity. Finally, myocardial infarct size and myocardium damage were decreased, and cardiac function was improved. Taken together, our study proved that H2 S could restore SPC-induced cardioprotection in diabetic rats by enhancing and promoting SIRT1/Nrf2 signaling pathway mediated mitochondrial dysfunction and oxidative stress.