To explore the effects and underlying mechanisms of Mdivi-1 on three common clinical models of acute kidney injury (AKI). Three common AKI cell models were constructed, classified into the control group (human renal tubular epithelial cells [HK-2] cells), the Iohexol group (HK-2 cells treated with Iohexol), the Genta group (HK-2 cells treated with Gentamicin), and the Cis group (HK-2 cells treated with Cisplatin). To explore the optimal protective concentration of Mdivi-1 for each AKI cell model, the experimental design consisted of the following seven groups: the control group (HK-2 cells cultured in medium), three injury groups (HK-2 cells subjected to Iohexol, Gentamicin, or Cisplatin), and the corresponding protection groups (with a certain concentration of Mdivi-1 added to each injury group). Cellular survival and apoptosis, reactive oxygen species (ROS) levels, and the expression of recombinant Sirtuin 3 (SIRT3) in each group were measured. Mitochondrial fission and fusion dynamics in cells were observed under an electron microscope. To explore relevant pathways, the changes in relevant pathway proteins were analyzed through Western blotting. The half maximal inhibitory concentration (IC50) values were 150.06 mgI/ml at 6 h in the Iohexol group, 37.88 mg/ml at 24 h in the Gentamicin group, and 13.48 microM at 24 h in the Cisplatin group. Compared with the control group, the three injury groups showed increased cell apoptosis rates and higher expressions of apoptotic proteins in HK-2 cells, with an accompanying decrease in cell migration. After the addition of corresponding concentrations of Mdivi-1, the optimal concentrations were 3 μM in the Iohexo-3 group, 1 microM in the Genta-1 group, and 5 μM in the Cis-5 group, HK-2 cells showed the highest survival rate, reduced apoptosis, decreased mitochondrial ROS and SIRT3 expression, and reduced mitochondrial fission and autophagy when compared with each injury group. Further verification with Western blot analysis after the addition of Mdivi-1 revealed a reduction in the expressions of mitochondrial fission proteins DRP1, Nrf2, SIRT3, Caspase-3, Jun N-terminal Kinase (JNK)/P-JNK, NF-kappaB, Bcl2, and autophagic protein P62, as well as reduced ROS levels. Mdivi-1 had protective effects on the three common AKI cell models by potentially reducing mitochondrial fission in cells and inhibiting the production of ROS through the mediation of the NF- B/JNK/SIRT3 signaling pathway, thereby exerting protective effects. Key words AKI, Cisplatin, Gentamicin, Iohexol, Mdivi-1.
- MeSH
- Acute Kidney Injury * metabolism pathology drug therapy MeSH
- Apoptosis drug effects MeSH
- Cell Line MeSH
- Humans MeSH
- MAP Kinase Signaling System drug effects physiology MeSH
- Mitochondrial Dynamics * drug effects physiology MeSH
- NF-kappa B * metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Signal Transduction * drug effects MeSH
- Sirtuin 3 * metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: Pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) syndrome is a rare disease, and part of the cluster histiocytosis-lymphadenopathy plus syndrome (H syndrome), which is associated with mutations in the SLC29A3 gene. Patients with PHID show clinical features of H syndrome but also have insulin-dependent diabetes mellitus. The PHID has previously been described as predominantly in absence of pancreatic autoantibodies. Case Series Presentation: Through an open call in two international diabetes registers, clinical and genetic characteristics of 7 PHID patients in 6 treatment centres were collected after informed consent. All of them had consanguinity in their families, and their origins were located in North-African and Middle Eastern regions. Four out of 7 patients had at least one positive pancreatic autoantibody. DISCUSSION AND CONCLUSION: Our case series reveals that PHID exhibits a wide range of clinical symptoms and signs. When consanguinity is present in a patient with newly diagnosed diabetes, and/or if other atypical symptoms such as dysmorphic features, skin lesions, haematological abnormalities, and developmental delay are present, threshold for genetic analysis should be low. Moreover, the presence of autoantibodies should not withhold genetic testing as our case series contradicts the previous observation of predominant autoantibody absence in PHID.
- MeSH
- Autoantibodies blood immunology MeSH
- Diabetes Mellitus, Type 1 * genetics complications MeSH
- Child MeSH
- Hypertrichosis * genetics MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation MeSH
- Consanguinity MeSH
- Child, Preschool MeSH
- Nucleoside Transport Proteins genetics MeSH
- Syndrome MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
AIMS/HYPOTHESIS: Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. METHODS: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. RESULTS: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. CONCLUSIONS/INTERPRETATION: This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.
- MeSH
- Diabetes Mellitus, Type 1 * epidemiology genetics MeSH
- Diabetes Mellitus, Type 2 * epidemiology genetics diagnosis MeSH
- Child MeSH
- Cohort Studies MeSH
- Humans MeSH
- Mutation genetics MeSH
- Infant, Newborn, Diseases * genetics MeSH
- Infant, Newborn MeSH
- Consanguinity MeSH
- Nucleoside Transport Proteins genetics MeSH
- Aged MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Iraq MeSH
Dynamic changes in maternal‒zygotic transition (MZT) require complex regulation of zygote formation, maternal transcript decay, embryonic genome activation (EGA), and cell cycle progression. Although these changes are well described, some key regulatory factors are still elusive. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, is a versatile driver of MZT via its epigenetic and nonepigenetic substrates. This study focused on the dynamics of SIRT1 in early embryos and its contribution to MZT. A conditional SIRT1-deficient knockout mouse model was used, accompanied by porcine and human embryos. Embryos across mammalian species showed the prominent localization of SIRT1 in the nucleus throughout early embryonic development. Accordingly, SIRT1 interacts with histone H4 on lysine K16 (H4K16) in both mouse and human blastocysts. While maternal SIRT1 is dispensable for MZT, at least one allele of embryonic Sirt1 is required for early embryonic development around the time of EGA. This role of SIRT1 is surprisingly mediated via a transcription-independent mode of action.
- MeSH
- Blastocyst metabolism MeSH
- Embryo, Mammalian metabolism MeSH
- Embryonic Development * genetics MeSH
- Histones metabolism MeSH
- Humans MeSH
- Mice, Knockout * MeSH
- Mice MeSH
- Swine MeSH
- Sirtuin 1 * metabolism genetics MeSH
- Gene Expression Regulation, Developmental MeSH
- Animals MeSH
- Zygote * metabolism MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Research shows that male body odor plays an important role in women's mate choice and that olfactory abilities are associated with women's sexual functioning. What remains unclear is what types of partner's odor actually shape women's experience during intimate activities. This study therefore explored women's experience associated with the partner's various odors and investigated how they affect women's intimate and sexual encounters. We performed semi-structured individual interviews with 20 single women and 20 women in a long-term relationship. Thematic analysis revealed four key natural odor types of the partner: body odor, sweat, genital odor, and semen odor. Further, we have identified three main types of fragrance odor (cologne, shower gel, and laundry agents) and investigated their perception in both intimate (hugging, kissing, cuddling, lying side by side) and sexual (intercourse, oral sex, ejaculation) contexts. Both partner's natural odor and fragrance affected women's emotional state (ranging from pleasant to unpleasant) and behavioral response (ranging from approach to avoidance of partner). Women's odor perception was frequently context-dependent, so that even mostly negatively perceived odors (e.g., semen, genital odor) were often accepted as part of sexual encounter. Finally, women's perception was negatively modified by partner's specific sweat (after workday, workout, or when the partner is ill) during intimate encounters. Our results highlight the complexity and interindividual variability of partner's odor perception.
- MeSH
- Smell physiology MeSH
- Olfactory Perception physiology MeSH
- Adult MeSH
- Interpersonal Relations MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Odorants * MeSH
- Sweat MeSH
- Sexual Behavior * psychology MeSH
- Sexual Partners * psychology MeSH
- Semen MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Obesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. METHODS: We analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches. RESULTS: Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner. CONCLUSIONS: SIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.
- MeSH
- Adipogenesis * genetics MeSH
- 3T3-L1 Cells * MeSH
- Epigenesis, Genetic * genetics MeSH
- Histones metabolism genetics MeSH
- Humans MeSH
- Mutation MeSH
- Mice MeSH
- Obesity genetics metabolism MeSH
- Protein Processing, Post-Translational genetics MeSH
- Sirtuins * genetics metabolism MeSH
- Adipocytes * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: Sepsis-induced acute kidney injury (AKI) remains a major challenge in intensive care, contributing significantly to morbidity and mortality. Tibolone, known for its neuroprotective and hormonal properties, has not been explored for its potential in AKI management. This study investigates the protective effects of Tibolone and its underlying mechanisms involving Sirtuin-1 (SIRT1) and Yes-Associated Protein (YAP) in a rat sepsis model. MATERIALS AND METHODS: Thirty-six female Wistar albino rats underwent cecal ligation and puncture (CLP) to induce sepsis. They were randomly assigned to control, CLP+Saline, and CLP+Tibolone groups. Tibolone was administered intraperitoneally. Biomarkers, including Sirtuin (SIRT1), Yes-associated protein (YAP), Tumor necrosis factor (TNF-α), High mobility group box 1 (HMGB1), malondialdehyde (MDA), creatinine, and urea, were assessed. Histopathological examination evaluated renal damage. RESULTS: Tibolone administration significantly reduced plasma TNF-α, HMGB1, MDA, creatinine, and urea levels compared to the CLP+Saline group. Moreover, Tibolone elevated SIRT1 and YAP levels in kidney tissues. Histopathological examination demonstrated a significant decrease in tubular epithelial necrosis, luminal debris, dilatation, hemorrhage, and interstitial inflammation in Tibolone-treated rats. CONCLUSION: This study unveils the protective role of Tibolone against sepsis-induced AKI in rats. The improvements in inflammatory and oxidative biomarkers and histological evidence suggest Tibolone's potential as a therapeutic intervention in sepsis-associated kidney injury. The upregulation of SIRT1 and YAP indicates their involvement in Tibolone's renoprotective mechanisms. Further investigations are warranted to explore Tibolone's translational potential in human sepsis-induced AKI.
- MeSH
- Acute Kidney Injury * etiology prevention & control drug therapy MeSH
- Biomarkers MeSH
- Rats MeSH
- Kidney drug effects metabolism MeSH
- Disease Models, Animal MeSH
- Norpregnenes * therapeutic use pharmacology MeSH
- Rats, Wistar * MeSH
- HMGB1 Protein metabolism MeSH
- Sepsis * complications drug therapy MeSH
- Sirtuin 1 * metabolism MeSH
- Tumor Necrosis Factor-alpha metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Exercise can improve the cardiovascular health. However, the mechanism contributing to its beneficial effect on elderly patients with myocardial infarction is obscure. 20-month-old male Sprague-Dawley rats were used to establish myocardial infarction (MI) model by permanent ligation of the left anterior descending coronary artery (LAD) of the heart, followed by 4-week interval exercise training on a motor-driven rodent treadmill. The cardiac function, myocardial fibrosis, apoptosis, oxidative stress, and inflammatory responses were determined by using pressure transducer catheter, polygraph physiological data acquisition system, Masson's trichrome staining, and ELISA to evaluate the impact of post-MI exercise training on MI. Western blot were performed to detect the activation of AMPK/SIRT1/PGC-1alpha signaling in the hearts of aged rats. Exercise training significantly improved cardiac function and reduced the cardiac fibrosis. In infarcted heart, the apoptosis, oxidative stress, and inflammation were significantly reduced after 4-week exercise training. Mechanistically, AMPK/SIRT1/PGC-1alpha pathway was activated in the myocardial infarction area after exercise training, which might participate in the protection of cardiac function. Exercise training improves cardiac function in MI rats through reduction of apoptosis, oxidative stress, and inflammation, which may mediate by the activation of AMPK/SIRT1/PGC-1alpha signaling pathway.
- MeSH
- Myocardial Infarction * metabolism MeSH
- Physical Conditioning, Animal * physiology MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Myocardium metabolism MeSH
- Rats, Sprague-Dawley MeSH
- AMP-Activated Protein Kinases metabolism MeSH
- Sirtuin 1 metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome.
- MeSH
- Carcinoma, Hepatocellular * metabolism pathology MeSH
- Hepatocytes metabolism pathology MeSH
- Collagen metabolism MeSH
- Humans MeSH
- Liver Neoplasms * metabolism pathology MeSH
- Non-alcoholic Fatty Liver Disease * genetics metabolism pathology MeSH
- Aged, 80 and over MeSH
- Sirtuins * genetics metabolism MeSH
- Centenarians MeSH
- Check Tag
- Humans MeSH
- Aged, 80 and over MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
