A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate.

SIRT1, an NAD+-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD+ into nicotinamide and 2'-O-acetyl-ADP-ribose (OAADPr). Selective SIRT1 activators have potential clinical applications in atherosclerosis, acute renal injury, and Alzheimer's disease. Here, we found that the activity of the potent SIRT1 activator CWR is independent of the acetylated substrate. It adopts a novel mechanism to promote SIRT1 activity by covalently bonding to the anomeric C1' carbon of the ribose ring in OAADPr. In addition, CWR is highly selective for SIRT1, with no effect on SIRT2, SIRT3, SIRT5, or SIRT6. The longer distance between the anomeric C1' carbon of the ribose ring in OAADPr and Arg274 of SIRT1 (a conserved residue among sirtuins) than that between the anomeric C1' carbon in OAADPr and the Arg of SIRT2, SIRT3, SIRT5, and SIRT6, should be responsible for the high selectivity of CWR for SIRT1. This was confirmed by site-directed mutagenesis of SIRT3. Consistent with the in vitro assays, the activator also reduced the acetylation levels of p53 in a concentration-dependent manner via SIRT1 in cells. Our study provides a new perspective for designing SIRT1 activators that does not rely on the chemical moiety immediately C-terminal to the acetyl-lysine of the substrate.

[Effects of Xiangqin Jiere Granules on lipid metabolism and chronic inflammation in different obesity model mice].

This paper aims to study the effect of Xiangqin Jiere Granules(XQ) on lipid metabolism and chronic inflammation in different obesity model mice. The monosodium glutamate(MSG) obese mouse model was established by subcutaneous injection of MSG in newborn mice, and the high fat diet(HFD) obese mouse model was established by feeding adult mice with HFD. The normal mice were assigned into the control group; the MSG obese mice were assigned into MSG model group, XQ4.5 group(Xiangqin Jiere Granu-les, 4.5 g·kg~(-1)), XQ22.5 group(Xiangqin Jiere Granules, 22.5 g·kg~(-1)); the HFD obese mice were assigned into HFD model group, XQ4.5 group, and XQ22.5 group. The mice were intragastrically administrated with saline or XQ for 5 weeks. After that, the body weight, visceral fat mass, liver and thymus weight, and the organ indexes in each group were measured. The levels of triglyceride(TG), total cholesterol(TC), and low-density lipoprotein cholesterol(LDL-c) in serum and liver tissue were detected by the kits. The mRNA expression levels of acetyl CoA carboxylase 1(ACC1), fatty acid synthetase(FAS), diacylgycerol acyltransferase 1(DGAT1) and hepatic lipase(HTGL) involved in lipid metabolism in mouse liver tissue were detected by quantitative real-time PCR(qPCR). The protein levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) in serum were detected by ELISA, and the mRNA levels of TNF-α and IL-6 in liver tissue were detected by qPCR. Compared with the control group, MSG and HFD mice showed increased body weight, abdominal circumference, Lee index and visceral fat mass as well as elevated levels of TG, TC, and LDL-c in serum. The model mice had up-regulated gene levels of ACC1, FAS and DGAT1 while down-regulated gene level of HTGL in the liver. Furthermore, the mRNA and protein levels of IL-6 increased in the model mice. Compared with the model mice, XQ treatment decreased the body weight, abdominal circumference, Lee index, and visceral fat mass, lowered the levels of TG, TC, and LDL-c in se-rum, down-regulated the gene levels of ACC1, FAS, and DGAT1 in liver tissue, up-regulated the gene level of HTGL, and down-regulated the mRNA and protein levels of IL-6. To sum up, XQ has good therapeutic effect on different obesity model mice. It can improve lipid metabolism and reduce fat accumulation in obese mice by regulating the enzymes involved in lipid metabolism, and alleviate obesity-related chronic low-grade inflammation.

The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment.

Diabetic pregnancy, with ever increasing prevalence, adversely affects embryogenesis and increases vasculometabolic disorder risks in adult offspring. However, it remains poorly understood whether maternal diabetes increases the offspring's susceptibility to heart injuries in adulthood. In this study, we observed that cardiac function and structure were comparable between adult offspring born to diabetic mice and their counterparts born to nondiabetic mice at baseline. However, in response to myocardial ischemia/reperfusion (MIR), diabetic mother offspring exhibited augmented infarct size, cardiac dysfunction, and myocardial apoptosis compared with control, in association with exaggerated activation of mitochondria- and endoplasmic reticulum (ER) stress-mediated apoptosis pathways and oxidative stress. Molecular analysis showed that the impaired myocardial ischemic tolerance in diabetic mother offspring was mainly attributable to blunted cardiac insulin receptor substrate (IRS)-1/Akt signaling. Furthermore, the effect of maternal melatonin administration on offspring's response to MIR was determined, and the results indicated that melatonin treatment in diabetic dams during pregnancy significantly improved the tolerance to MIR injury in their offspring, via restoring cardiac IRS-1/Akt signaling. Taken together, these data suggest that maternal diabetes predisposes offspring to augmented MIR injury in adulthood, and maternal melatonin supplementation during diabetic pregnancy may hold promise for improving myocardial ischemic tolerance in the offspring.

Identification of transcriptional signature change and critical transcription factors involved during the differentiation of mouse trophoblast stem cell into maternal blood vessel associated trophoblast giant cell.

The placenta is essential organ for oxygen and nutrient exchange between the mother and the developing fetus. Trophoblast lineage differentiation is closely related to the normal function of the placenta. Trophoblast stem cells (TSCs) can differentiate into all placental trophoblast subtypes and are widely used as in vitro stem cell models to study placental development and trophoblast lineage differentiation. Although extensive research has been conducted on the differentiation of TSCs, the possible parallels between trophoblast giant cells (TGCs) that are differentiated from TSCs in vitro and the various subtypes of TGC lineages in vivo are still poorly understood. In this study, mouse TSCs (mTSCs) were induced to differentiate into TGCs, and our mRNA sequencing (RNA-seq) data revealed that mTSCs and TGCs have distinct transcriptional signatures. We conducted a comparison of mTSCs and TGCs transcriptomes with the published transcriptomes of TGC lineages in murine placenta detected by single-cell RNA-seq and found that mTSCs tend to differentiate into maternal blood vessel-associated TGCs in vitro. Moreover, we identified the transcription factor (TF) ZMAT1, which may be responsible for the differentiation of mTSCs into sinusoid TGCs, and the TFs EGR1 and MITF, which are likely involved in the differentiation of mTSCs into spiral artery-associated TGCs. Thus, our findings provide a valuable resource for the mechanisms of trophoblast lineage differentiation and placental deficiency-associated diseases development.

Is tumor necrosis factor-α monoclonal therapy with proactive therapeutic drug monitoring optimized for inflammatory bowel disease? Network meta-analysis.

BACKGROUND: The efficacy and safety of anti-tumor necrosis factor-α (TNF-α) monoclonal antibody therapy [adalimumab (ADA) and infliximab (IFX)] with therapeutic drug monitoring (TDM), which has been proposed for inflammatory bowel disease (IBD) patients, are still controversial. AIM: To determine the efficacy and safety of anti-TNF-α monoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions. METHODS: As of July 2023, we searched for randomized controlled trials (RCTs) and observational studies in PubMed, Embase, and the Cochrane Library to compare anti-TNF-α monoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy. Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery. RESULTS: This systematic review and meta-analysis yielded 13 studies after exclusion, and the baseline indicators were balanced. We found a significant increase in the number of patients who achieved clinical remission in the ADA [odds ratio (OR) = 1.416, 95% confidence interval (CI): 1.196-1.676] and RCT (OR = 1.393, 95%CI: 1.182-1.641) subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive (OR = 0.237, 95%CI: 0.101-0.558) and IFX + ADA (OR = 0.137, 95%CI: 0.032-0.588) subgroups, and the overall risk of adverse events was reduced (OR = 0.579, 95%CI: 0.391-0.858) according to the pairwise meta-analysis. Moreover, the network meta-analysis results suggested that patients with IBD treated with ADA (OR = 1.39, 95%CI: 1.19-1.63) were more likely to undergo TDM, especially in comparison with patients with reactive TDM (OR = 1.38, 95%CI: 1.07-1.77). CONCLUSION: Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM. We recommend proactive TDM in IBD patients who are treated with ADA.

Comparative efficacy and safety of glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes: A network meta-analysis.

INTRODUCTION: This study aimed to evaluate the clinical efficacy and safety of 4 weekly formulations of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on glycemic control, including glycemic control, by using a network meta-analysis (NMA). METHODS: PubMed, EMBASE, and Cochrane Library Central Register of Controlled Trials were searched from inception until June 10, 2022. Randomized clinical trials (RCTs) enrolling participants with diabetes mellitus type 2 and a follow-up of at least 12 weeks were included, for which 4 eligible GLP-1RAs Exenatide, Dulaglutide, Semaglutide, Loxenatide were compared with either each other or placebo. The primary outcome is the change of hemoglobin A1c level. Secondary outcomes including additional glycemic control indicators and adverse events (AE). Frequentist random-effect NMA were conducted for effect comparison. This meta-analysis was registered on PROSPERO, CRD42022342241. RESULTS: The NMA synthesized evidence from 12 studies covering 6213 patients and 10 GLP-1RA regimens. A pairwise comparison of glycosylated hemoglobin type A1C (HbA1c) lowering effects showed that once-weekly GLP-1 receptor agonists were significantly better than placebo, and their glucose-lowering intensity was Semaglutide 2.0mg, Semaglutide 1.0mg, Dulaglutide 4.5mg, and Semaglutide 0.5mg, Dulaglutide 3.0mg, PEX168 200ug, Dulaglutide 1.5mg, PEX168 100ug and Dulaglutide 0.75mg. The GLP-1RA regimen has a comparable safety profile for hypoglycemia. And with the exception of PEX168, all other long-acting GLP-1RA drugs had lower rates of diarrhea, nausea and vomiting than placebo. CONCLUSION: Regimens of GLP-1RAs had differential glycemic control. The efficacy and safety of Semaglutide 2.0mg in comprehensively lowering blood sugar showed the best performance.

Research on the cultivation of sustainable development ability of higher vocational students by creative thinking teaching method.

Education for sustainable development (ESD) is an important guideline for United Nations Sustainable Development Goals. Students' creative thinking can be applied to various disciplines, promoting sustainable learning. Most of Taiwan's beauty and hairdressing technical education teachers mainly teach students to imitate, and students' works lack creativity and thinking. A total of 43 higher vocational college students participated, 23 of whom were in the experimental group using the creative thinking teaching method and 20 of whom were in the control group using the traditional teaching method. The results show that the creative thinking teaching method can effectively improve students' learning outcomes in the multimedia material creation course, including breaking through the limitation of thinking, putting forward different ideas and answers, and constantly innovating, to make the presented results more creative and meaningful. The creative thinking teaching methods solve students' trouble in creative problem solving, enhance students' problem solving and critical thinking skills, and improve students' involvement in the study.

Research on Relevant Dimensions of Tourism Experience of Intangible Cultural Heritage Lantern Festival: Integrating Generic Learning Outcomes With the Technology Acceptance Model.

The lantern exhibition at the Lantern Festival is an important traditional festival in Taiwan. Visitors play an important role in the promotion and sustainable development of intangible cultural heritage (ICH). In recent years, the involvement of digital technology in traditional lantern design and shows has contributed to the protection, inheritance, and promotion of ICH, there remains less research on using augmented reality (AR) with ICH tourism. In this study, AR is used for ICH lantern exhibition to discuss the learning experience in lantern tourism and the relationship between technology acceptance and satisfaction from the perspective of visitors, as well as evaluate what AR has on improving visitors' awareness and learning experience. Then, primary variables of the technology acceptance model (TAM) are combined with generic learning outcomes (GLOs) to integrate ICH, education, and technology to expand TAM, building a new model to study the ICH learning experience. A questionnaire and observation are used. Respondents are visitors participating in the AR lantern exhibition in Taiwan, which is designed by the author. There is a total of 200 questionnaires collected in the end. The result shows that knowledge and understanding (KU), attitudes and values (AV), activity, behavior, and progression (ABP), and enjoyment, inspiration, and creativity (EIC) from GLOs have a positive effect on technology acceptance and actual use (AU). Therefore, visitors are satisfied with innovative and interesting technology learning experiences, enhancing learning interest and results. Besides, the interaction of the AR system improves visitors' learning motivation, which shows the combination of AR technology with ICH tourism helps improve cultural awareness.

[Characteristics of Soil Organic Carbon Components and Their Correlation with Other Soil Physical and Chemical Factors in Cotton Fields with Different Continuous Cropping Years in the Oasis on the Northern Edge of Tarim Basin].

The study of soil organic carbon components in continuous cropping cotton fields in oases is helpful to reveal the change characteristics of the soil organic carbon stability mechanism in arid areas under the effects of man-land relationships. In this study, the contents of soil organic carbon, easily oxidized organic carbon, dissolved organic carbon, and microbial biomass carbon in cotton fields with different continuous cropping years (2 a, 5 a, 12 a, 20 a, and 35 a) were collected and analyzed by using space instead of the time series method. Through redundancy analysis, the relationship between soil organic carbon components and other soil physical and chemical factors was discussed. The results showed that:① continuous cropping for different years had a significant impact on the content of soil organic carbon components in the study area. The contents of soil organic carbon, easily oxidized organic carbon, dissolved organic carbon, and microbial biomass carbon in continuous cropping cotton fields for 12 a, 20 a, and 35 a were higher than those in continuous cropping cotton fields and wasteland for 2 a and 5 a. ω(soil organic carbon) reached the peak value (7.06 g·kg-1) in the cotton field in 20 a, which was 76.91% higher than that in the wasteland. The content of soil organic carbon decreased with the deepening of the soil layer. ② Based on the redundancy analysis of soil organic carbon content and soil environmental factors, the results showed that the content of soil organic carbon was positively correlated with total nitrogen, available phosphorus, and water content and negatively correlated with pH value and bulk density. The importance of soil environmental factors on the interpretation of soil organic carbon content was as follows:total N>available P>pH value>bulk density>water content>available K>total salt.

Carbon-carbon bond activation of 2,2,6,6-tetramethyl-piperidine-1-oxyl by a Rh(II) metalloradical: a combined experimental and theoretical study.

Competitive major carbon-carbon bond activation (CCA) and minor carbon-hydrogen bond activation (CHA) channels are identified in the reaction between rhodium(II) meso-tetramesitylporphyrin [Rh(II)(tmp)] (1) and 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) (2). The CCA and CHA pathways lead to formation of [Rh(III)(tmp)Me] (3) and [Rh(III)(tmp)H] (5), respectively. In the presence of excess TEMPO, [Rh(II)(tmp)] is regenerated from [Rh(III)(tmp)H] with formation of 2,2,6,6-tetramethyl-piperidine-1-ol (TEMPOH) (4) via a subsequent hydrogen atom abstraction pathway. The yield of the CCA product [Rh(III)(tmp)Me] increased with higher temperature at the cost of the CHA product TEMPOH in the temperature range 50-80 degrees C. Both the CCA and CHA pathways follow second-order kinetics. The mechanism of the TEMPO carbon-carbon bond activation was studied by means of kinetic investigations and DFT calculations. Broken symmetry, unrestricted b3-lyp calculations along the open-shell singlet surface reveal a low-energy transition state (TS1) for direct TEMPO methyl radical abstraction by the Rh(II) radical (SH2 type mechanism). An alternative ionic pathway, with a somewhat higher barrier, was identified along the closed-shell singlet surface. This ionic pathway proceeds in two sequential steps: Electron transfer from TEMPO to [Rh(II)(por)] producing the [TEMPO]+ [RhI(por)]- cation-anion pair, followed by net CH3+ transfer from TEMPO+ to Rh(I) with formation of [Rh(III)(por)Me] and (DMPO-like) 2,2,6-trimethyl-2,3,4,5-tetrahydro-1-pyridiniumolate. The transition state for this process (TS2) is best described as an SN2-like nucleophilic substitution involving attack of the d(z)2 orbital of [Rh(I)(por)]- at one of the C(Me)-C(ring) sigma* orbitals of [TEMPO]+. Although the calculated barrier of the open-shell radical pathway is somewhat lower than the barrier for the ionic pathway, R-DFT and U-DFT are not likely comparatively accurate enough to reliably distinguish between these possible pathways. Both the radical (SH2) and the ionic (SN2) pathway have barriers which are low enough to explain the experimental kinetic data.

Prevalence of Prediabetes Risk in Offspring Born to Mothers with Hyperandrogenism.

BACKGROUND: Excessive androgen exposure during pregnancy has been suggested to induce diabetic phenotypes in offspring in animal models. The aim of this study was to investigate whether pregestational maternal hyperandrogenism in human influenced the glucose metabolism in offspring via epigenetic memory from mother's oocyte to child's somatic cells. METHODS: Of 1782 reproductive-aged women detected pregestational serum androgen, 1406 were pregnant between 2005 and 2010. Of 1198 women who delivered, 1116 eligible mothers (147 with hyperandrogenism and 969 normal) were recruited. 1216 children (156 children born to mothers with hyperandrogenism and 1060 born to normal mother) were followed up their glycometabolism in mean age of 5years. Imprinting genes of oocyte from mothers and lymphocytes from children were examined. A pregestational hyperandrogenism rat model was also established. FINDINGS: Children born to women with hyperandrogenism showed increased serum fasting glucose and insulin levels, and were more prone to prediabetes (adjusted RR: 3.98 (95%CI 1.16-13.58)). Oocytes from women with hyperandrogenism showed increased insulin-like growth factor 2 (IGF2) expression. Lymphocytes from their children also showed increased IGF2 expression and decreased IGF2 methylation. Treatment of human oocytes with dihydrotestosterone upregulated IGF2 and downregulated DNMT3a levels. In rat, pregestational hyperandrogenism induced diabetic phenotypes and impaired insulin secretion in offspring. In consistent with the findings in human, hyperandrogenism also increased Igf2 expression and decreased DNMT3a in rat oocytes. Importantly, the same altered methylation signatures of Igf2 were identified in the offspring pancreatic islets. INTERPRETATION: Pregestational hyperandrogenism may predispose offspring to glucose metabolism disorder via epigenetic oocyte inheritance. Clinical trial registry no.: ChiCTR-OCC-14004537; www.chictr.org.

[Expression of helicase DDX41 in human dental pulp tissues and cells].

OBJECTIVE: To detect the expression of D-E-A-D-box polypeptide 41 (DDX41) in human dental pulp tissues and cells. METHODS: The mRNA and protein expressions of DDX41 in human dental pulp cells were detected by RT-PCR and immunocytochemistry, and the expression of DDX41 in human dental pulp tissues was investigated by immunohistochemistry. RESULTS: Strong expressions of DDX41 mRNA and protein were detected in dental pulp cells. In dental pulp tissues, DDX41 was expressed in the cytoplasm and nucleus of odontoblasts. CONCLUSION: DDX41/STING-dependent TBK1-IRF3-IFN-ß signaling pathway may play a role in innate immune responses of the dental pulp to caries and pulpitis.

Anti-Helicobacter pylori compounds from the ethanol extracts of Geranium wilfordii.

UNLABELLED: ETHNOPHARMOCOLOGICAL RELEVANCE: Geranium wilfordii Maxim has been extensively used in Chinese Herbal Medicine for treating gastrointestinal disorders, diarrhea and dysentery. In the current study we aimed to investigate the anti-Helicobacter pylori activity of ethanol extracts of Geranium wilfordii Maxim and its main active compounds, corilagin and 1,2,3,6-tetra-O-galloyl-ß-D-glucose. MATERIALS AND METHODS: The plant materials were extracted three times with ethanol and the concentrated filtrate was successively fractioned into chloroform, ethyl acetate, and n-BuOH-soluble portions which were examined in vitro for the anti-Helicobacter. pylori activity. Employing a standard strain and five clinical isolates of Helicobacter pylori, the extract, fractions and compounds of Geranium wilfordii Maxim were assessed in vitro. RESULTS: The ethanol fraction, ethyl acetate fraction, corilagin, and 1,2,3,6-tetra-O-galloyl-ß-D-glucose were found to be strongly inhibitory to Helicobacter. pylori (MICs: 40, 30, 4, and 8µg/ml respectively). CONCLUSIONS: The results of the present study showed that the ethanol and the ethyl acetate extracts from Geranium wilfordii Maxim displayed as well the most significant inhibition to the growth of Helicobacter. pylori, of which corilagin and 1,2,3,6-tetra-O-galloyl-ß-D-glucose have been identified main anti-Helicobacter pylori active constituents.