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Background Subarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high mortality and disabilities. Retinoid X receptor (RXR) has been shown to be neuroprotective against ischemia/reperfusion injury. This study aimed to investigate the effects of the selective RXR agonist bexarotene on neuroinflammation in a rat model of SAH. Methods Two hundred male Sprague-Dawley rats were used. The endovascular perforation induced SAH. Bexarotene was administered intraperitoneally at 1 h after SAH induction. To investigate the underlying mechanism, the selective RXR antagonist UVI3003 and RXR siRNA or SIRT6 inhibitor OSS128167 was administered via intracerebroventricular 1 h before SAH induction. Post-SAH assessments including SAH grade, neurological score, brain water content, Western blot, and immunofluorescence were performed. Results The endogenous RXR and sirtuin 6 (SIRT6) protein levels were increased after SAH. Bexarotene treatment significantly reduced brain edema and improved the short-/long-term neurological deficit after SAH. Mechanistically, bexarotene increased the levels of PPARγ and SIRT6; decreased the expression of phosphorylated FoxO3a (p-FoxO3a), IL-6, IL-1β, and TNF-a; and inhibited the microglia activation and neutrophils infiltration at 24 h after SAH. Either UVI3003, OSS128167, or RXR siRNA abolished the neuroprotective effects of bexarotene and its regulation on protein levels of PPARγ/SIRT6/p-FoxO3a after SAH. Conclusions The activation of RXR by bexarotene attenuated neuroinflammation and improved neurological deficits after SAH. The anti-neuroinflammatory effect was at least partially through regulating PPARγ/SIRT6/FoxO3a pathway. Bexarotene may be a promising therapeutic strategy in the management of SAH patients.

Frailty, a common geriatric syndrome, is characterized by diminished physiological reserves and heightens the risk of adverse health events, including falls, hospitalizations, and mortality. Prevalence of frailty is increasing in populations by age. Sirtuin 6 (SIRT6) plays a pivotal role in energy metabolism, inflammation, DNA repair, oxidative stress, and fibrosis. Despite numerous studies investigating the functions of SIRT6, the role of its genetic variations in frailty remains poorly understood. The aim of this study was to investigate the association between SIRT6 SNP rs117385980 (C > T) and frailty syndrome. This study included samples from a cohort of older adults in Birjand, Iran, comprising 227 subjects, aged 60–90 years divided according to frailty status. Allele and genotype frequencies of the SIRT6 rs117385980 variant were analyzed in all participants. Results of the study indicated the increased presence of non-frail and pre-frail individuals compared to the frail group. Among individuals aged 60–69, 70–79, and 80–90 years, the frequency of the heterozygous CT genotype demonstrated a declining trend with advancing age ( p  = 0.07). Our findings suggest that the presence of rs117385980 T allele was decreased in older subjects but increased with robustness suggesting a diverse effect. Further studies with larger sample sizes and Dates of death data are warranted to confirm these preliminary findings.

Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.

Melanoma, the most aggressive human skin tumor, has a very short survival time, and there are currently no effective treatments. Alterations in cell metabolism, such as enhanced aerobic glycolysis, have been identified as hallmarks of cancer cells. In the present study, bioinformatics studies using online databases revealed that FOXO3a expression was lower in melanoma tissues compared with normal tissues and nevus. Additionally, Kaplan-Meier analysis showed that high expression of FOXO3a predicted an improved prognosis for patients with melanoma. Furthermore, Pearson correlation analysis indicated that the expression of FOXO3a was positively correlated with SIRT6 expression and negatively correlated with the expression levels of a number of glycolysis-associated genes. Chromatin immunoprecipitation and luciferase assays showed that FOXO3a was enriched in the SIRT6 promoter region and promoted its transcription. Then, SIRT6 was overexpressed in FOXO3a-knockdown MV3 cells and downregulated in FOXO3a-overexpressing MV3 cells by using lentivirus-mediated stable infection. The results showed that SIRT6 knockdown or overexpression rescued the effects of FOXO3a overexpression or knockdown, respectively, on glycolysis, as determined by glucose uptake, glucose consumption and lactate production assays, the expression of glycolytic genes and glucose stress flux tests. SIRT6 overexpression also suppressed FOXO3a knockdown-induced tumor growth in a mouse model. The present findings indicated that the FOXO3a-SIRT6 regulatory axis inhibited glucose metabolism and tumor cell proliferation in melanoma, and provided novel insight into potential therapeutic strategies to treat this disease.

Alzheimer’s disease (AD) is a neurodegenerative disease that is imposing an increasing burden on society. Currently, AD is the leading cause of senile dementia worldwide. Despite the long existence of AD, there is lack of therapies for AD, suggesting that new and effective treatment strategy must be explored. At present, sirtuin pathway has attracted attention from the researchers due to its promising results in laboratory models of aging. In addition, our understanding in the roles of sirtuin 6 in AD has expanded. It has been identified to be involved in telomere maintenance, DNA repair, genome integrity, energy metabolism, and inflammation, which ultimately regulate life span. Recent findings also demonstrate that sirtuin 6 is lacking in AD patients, proposing that it can be a new potential therapeutic target in AD. Therefore, exploring on how sirtuin 6 is related in AD manifestation may accelerate the research of AD further and benefits future AD patients. Keeping that in mind, this review aims to highlight the possible roles of sirtuin 6 in AD manifestation.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and exhibits a high mortality rate. Sirtuin (SIRT)6 is a member of the sirtuin family, which may be useful targets in the treatment of tumors. The present study aimed to explore the expression of SIRT6 in numerous HCC cell lines and investigate the role of SIRT6 in the proliferation and apoptosis of the HCC cells, and the underlying mechanisms. Overexpression and silencing of SIRT6 were performed by transfection of Huh-7 cells with synthetic overexpression and small interfering RNA (siRNA) plasmids. Cell proliferation was evaluated using a Cell Counting Kit-8 assay. The apoptosis rate was measured via flow cytometry. Cloning efficiency was assessed using plate clone formation assays. The expression of mRNAs and proteins were determined via reverse transcription-quantitative PCR and western blot analyses, respectively. SIRT6 was overexpressed in Hep3B, Huh-7, MHCC-97H, MHCC-97L, MHCC-LM6, MHCC-LM3, YY-8103 and SK-hep-1 cell lines, compared with MIHA and HL-7702 normal liver cell lines. Overexpression of SIRT6 increased the proliferation of Huh-7 cells, upregulated the expression of Bcl-2 and phosphorylation of extracellular-signal regulated protein kinase (ERK), and decreased the expression of cleaved-caspase-3 and Bcl-2-associated X protein (Bax) in Huh-7 cells. siRNA-mediated silencing of SIRT6 decreased the proliferation and increased the apoptosis of Huh-7 cells, downregulated the expression of Bcl-2 and phosphorylated-ERK, and promoted the expression of cleaved-caspase-3 and Bax. The proliferation of Huh-7 cells was decreased using the ERK1/2 inhibitor U0126. The results suggested that SIRT6 affected the proliferation and apoptosis of HCC cells via the regulation of the ERK1/2 pathway, altering the activation of the intrinsic apoptosis pathway. SIRT6 may be a potential target for the treatment of HCC; however, its role requires further investigation.

The sirtuin 6 (SIRT6) participates in regulating glucose and lipid homeostasis. However, the function of SIRT6 in the process of cardiac pathogenesis caused by obesity-associated lipotoxicity remains to be unveiled. This study was designed to elucidate the role of SIRT6 in the pathogenesis of cardiac injury due to nutrition overload-induced obesity and explore the downstream signaling pathways affecting oxidative stress in the heart. In this study, we used Sirt6 cardiac-specific knockout murine models treated with a high-fat diet (HFD) feeding to explore the function and mechanism of SIRT6 in the heart tissue during HFD-induced obesity. We also took advantage of neonatal cardiomyocytes to study the role and downstream molecules of SIRT6 during HFD-induced injury in vitro, in which intracellular oxidative stress and mitochondrial content were assessed. We observed that during HFD-induced obesity, Sirt6 loss-of-function aggravated cardiac injury including left ventricular hypertrophy and lipid accumulation. Our results evidenced that upon increased fatty acid uptake, SIRT6 positively regulated the expression of endonuclease G (ENDOG), which is a mitochondrial-resident molecule that plays an important role in mitochondrial biogenesis and redox homeostasis. Our results also showed that SIRT6 positively regulated superoxide dismutase 2 (SOD2) expression post-transcriptionally via ENDOG. Our study gives a new sight into SIRT6 beneficial role in mitochondrial biogenesis of cardiomyocytes. Our data also show that SIRT6 is required to reduce intracellular oxidative stress in the heart triggered by high-fat diet-induced obesity, involving the control of ENDOG/SOD2.

Pancreatic cancer (PC) is a malignant tumor with high mortality worldwide. SIRT6 plays versatile roles in human cancers. However, SIRT6 has rarely been studied in PC. The purpose of the present study was to explore the function and potential mechanism of SIRT6 in PC. The expression of SIRT6 in PC tissues and cells was detected by reverse transcription-quantitative PCR and western blotting. The overall survival time was analyzed through the Kaplan Meier method. Cell viability was measured by the Cell Counting Kit-8 assay. The Fe2+ content, glucose uptake, lactic acid and ATP production were detected through the corresponding kits. ROS was evaluated using the DCFH-DA detection kit. Protein expression was assessed by immunohistochemistry or western blot analysis. In the present study, SIRT6 was lowly expressed in PC tissues and cells compared with normal tissues and cells. Moreover, the low expression of SIRT6 was associated with a poor prognosis in patients with PC. Upregulation of SIRT6 significantly promoted the ferroptosis and inhibited the glycolysis in PC cells. However, knockdown of SIRT6 resisted ferroptosis and increased glycolysis in PC cells. Further studies found that the activation of NF-κB could reverse the effect of SIRT6 on PC cells. In addition, overexpression of SIRT6 restrained the growth of xenografted tumors and suppressed the nuclear transcription of NF-κB in vivo. Collectively, the present study indicated that SIRT6 promoted ferroptosis and inhibited glycolysis through inactivating the NF-κB signaling pathway in PC. These findings suggested that SIRT6 may become a therapeutic target for PC.

Sirtuin 6 (SIRT6) is a member of the nicotinamide adenine dinucleotide positivity-dependent class III deacetylase sirtuin family. The present study aimed to explore the expression and function of SIRT6 in colon cancer. Furthermore, the partial mechanism underlying the dysregulation of SIRT6 was investigated. The results of immunohistochemistry demonstrated that SIRT6 was markedly downregulated in colon cancer tissues, and patients with high SIRT6 expression had a better prognosis than those who did not. The proliferation and apoptotic assays demonstrated that SIRT6 was able to suppress colon cancer cell proliferation and induce apoptosis via the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. MicroRNAs (miRNAs/miRs) are important non-coding RNAs, which have a critical role in the negative regulation of their target genes. Through bioinformatics analysis and further experiments, the results demonstrated that miR-34c-5p was not only dysregulated in colon cancer tissues but may also regulate SIRT6 expression via interaction with the 3′-untranslated region of SIRT6 mRNA. The proliferation and apoptotic assays indicated that miR-34c-5p could directly promote cell growth and inhibit apoptosis via activation of the JAK2/STAT3 signaling pathway, which was similar to silencing SIRT6. In conclusion, the results of the present study demonstrated that miR-34c-5p promoted colon cancer cell proliferation by targeting SIRT6 via activation of the JAK2/STAT3 signaling pathway. It may be hypothesized that SIRT6 is a potential biomarker for colon cancer prognosis, and the miR-34c-5p/SIRT6/JAK2/STAT3 axis may provide novel insights into colon cancer treatment.

During an organism’s lifespan, two main phenomena are critical for the organism’s survival. These are (1) a proper embryonic development, which permits the new organism to function with high fitness, grow and reproduce, and (2) the aging process, which will progressively undermine its competence and fitness for survival, leading to its death. Interestingly these processes present various similarities at the molecular level. Notably, as organisms became more complex, regulation of these processes became coordinated by the brain, and failure in brain activity is detrimental in both development and aging. One of the critical processes regulating brain health is the capacity to keep its genomic integrity and epigenetic regulation—deficiency in DNA repair results in neurodevelopmental and neurodegenerative diseases. As the brain becomes more complex, this effect becomes more evident. In this perspective, we will analyze how the brain evolved and became critical for human survival and the role Sirt6 plays in brain health. Sirt6 belongs to the Sirtuin family of histone deacetylases that control several cellular processes; among them, Sirt6 has been associated with the proper embryonic development and is associated with the aging process. In humans, Sirt6 has a pivotal role during brain aging, and its loss of function is correlated with the appearance of neurodegenerative diseases such as Alzheimer’s disease. However, Sirt6 roles during brain development and aging, especially the last one, are not observed in all species. It appears that during the brain organ evolution, Sirt6 has gained more relevance as the brain becomes bigger and more complex, observing the most detrimental effect in the brains of Homo sapiens . In this perspective, we part from the evolution of the brain in metazoans, the biological similarities between brain development and aging, and the relevant functions of Sirt6 in these similar phenomena to conclude with the evidence suggesting a more relevant role of Sirt6 gained in the brain evolution.