InR and Pi3K maintain intestinal homeostasis through STAT/EGFR and Notch signaling in enteroblasts.

To maintain the integrity of the adult gut, the proliferation and differentiation of stem cells must be strictly controlled. Several signaling pathways control the proliferation and differentiation of Drosophila intestinal epithelial cells. Although the modulatory effects of insulin pathway components on cell proliferation have been characterized, their specific role in which cell type and how these components interact with other regulatory signaling pathways remain largely unclear. In this study, we found that InR/Pi3K has major functions in enteroblasts (EBs) that were not previously described. The absence of InR/Pi3K in progenitors leads to a decrease in the number of EBs, while it has no significant effect on intestinal stem cells (ISCs). In addition, we found that InR/Pi3K regulates Notch activity in ISCs and EBs in an opposite way. This is also the reason for the decrease in EB. On the one hand, aberrantly low levels of Notch signaling in ISCs inhibit their proper differentiation into EBs; on the other hand, the higher Notch levels in EBs promote their excessive differentiation into enterocytes (ECs), leading to marked increases in abnormal ECs and decreased proliferation. Moreover, we found that Upd/JAK/STAT signaling acts as an effector or modifier of InR/Pi3K function in the midgut and cooperates with EGFR signaling to regulate cell proliferation. Altogether, our results demonstrate that InR and Pi3K are essential for coordinating stem cell differentiation and proliferation to maintain intestinal homeostasis.

Hydrogen sulfide ameliorated endothelial dysfunction in hyperhomocysteinemia rats: Mechanism of IRE1α/JNK pathway-mediated autophagy.

Previous studies showed that hyperhomocysteinemia (HHcy) induced endothelial dysfunction by endoplasmic reticulum (ER) stress induction and autophagy stimulation. This study aimed to determine the effect of hydrogen sulfide (H2S) in homocysteine (Hcy)-induced endothelial dysfunction and observe the possible mechanism involved. Male Wistar rats (160-180g) were used and randomly divided into four groups: Control group, HHcy group, HHcy+Sodium hydrosulfide (NaHS) group and NaHS group. Rats were fed with 2% high methionine diet for 8 weeks to set up HHcy model. Plasma concentration of Hcy was measured by ELISA. Endothelium-dependent and non-endothelium-dependent vasodilation of rat renal arteries were determined by myograph. The protein expression of cystathionine-γ-lyase (CSE), ER stress- and autophagy-related proteins in renal arteries or human umbilical vein endothelial cells (HUVECs) were analyzed by western blotting. The endothelial function was impaired in HHcy rats and HUVECs. NaHS supplementation could improve the ACh-induced vasodilation, however it was eliminated by ER stress inducer Tunicamycin (TM) or autophagy inducer Rapamycin. Western blotting in renal arteries showed that Glucose-regulated protein 78 (GRP78) and three branches of ER stress (p-IRE1α, p-PERK, ATF6) , p-JNK1+p-JNK2 were downregulated, simultaneously the autophagy marker Beclin1, LC3BII/LC3BI ratio were decreased and p62 was increased with NaHS treatment in HHcy rats. In HUVECs, IRE1α-JNK induced autophagy was involved in HHcy-induced endothelial dysfunction, while NaHS stimulation reversed the protein expression in IRE1α/JNK-autophagy pathway with Hcy incubation. This study might suggest that endothelial dysfunction induced by HHcy might be correlated with IRE1α-JNK-autophagy axis pathway, which was suppressed by exogenous supplementation of H2S donor, NaHS.

H2S alleviated sepsis-induced acute kidney injury by inhibiting PERK/Bax-Bcl2 pathway.

To investigate the protective mechanisms of hydrogen sulfide (H2S) in sepsis-induced acute kidney injury (SAKI), we conducted an in vivo study using a SAKI mouse model induced by intraperitoneal lipopolysaccharide (LPS) injection. Following 6 h of LPS injection, levels of tumor necrosis factor-alpha (TNF-α) and blood urea nitrogen (Bun) were significantly elevated in mouse plasma. In the kidneys of SAKI mice, expression of H2S-generating enzymes cysteinyl-tRNA synthetase (CARS), cystathionine γ-lyase (CSE) and cystathionine ß-synthase (CBS) was markedly downregulated, while glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase (p-PERK/PERK), and B-cell lymphoma-2 recombinant protein X/B-cell lymphoma-2 (Bax/Bcl2) expression was significantly upregulated. H2S improved renal function and attenuated renal histopathological changes in SAKI mice, thereby alleviating LPS-induced endoplasmic reticulum stress (ERS). Additionally, it inhibited the expression of p-PERK/PERK and Bax/Bcl2. After inhibiting CSE activity with dl-propargylglycine (PPG i. p.), the renal tissue pathology in LPS-induced AKI mice was further exacerbated, leading to enhanced activation of the PERK/Bax-Bcl2 pathway. Our findings suggest that endogenous H2S influences the pathogenesis of SAKI, while exogenous H2S protects against LPS-induced AKI by inhibiting the PERK/Bax-Bcl2 pathway involved in ERS.

Hydrogen Sulfide Ameliorates Heart Aging by Downregulating Matrix Metalloproteinase-9.

PURPOSE: Aging contributes significantly to cardiovascular diseases and cardiac dysfunction, leading to the upregulation of matrix metalloproteinase-9 (MMP-9) in the heart and a significant decrease in hydrogen sulfide (H2S) content, coupled with impaired cardiac diastolic function. This study explores whether supplementing exogenous hydrogen sulfide during aging ameliorates the decline in H2S concentration in the heart, suppresses MMP-9 expression, and improves the age-associated impairment in cardiac morphology and function. METHODS: We collected plasma from healthy individuals of different ages to determine the relationship between aging and H2S and MMP-9 levels through Elisa detection and liquid chromatography-tandem mass spectrometry (LC/MC) detection of plasma H2S content. Three-month-old mice were selected as the young group, while 18-month-old mice were selected as the old group, and sodium hydrosulfide (NaHS) was injected intraperitoneally from 15 months old until 18 months old as the old + NaHS group. Plasma MMP-9 content was detected using Elisa, plasma H2S content, cardiac H2S content, and cystathionine gamma-lyase (CSE) activity were detected using LC/MC, and cardiac function was detected using echocardiography. Heart structure was assessed using hematoxylin and eosin staining, Masone staining was used to detect the degree of cardiac fibrosis, while western blot was used to detect the expression of MMP-9, CSE, and aging marker proteins. Knockdown of MMP-9 and CSE in H9c2 cells using small interfering RNA was carried out to determine the upstream-downstream relationship between MMP-9 and CSE. RESULTS: H2S content in the plasma of healthy individuals decreases with escalating age, whereas MMP-9 level rises with age progression. Aging leads to a decrease in H2S levels in the heart and plasma of mice, severe impairment of cardiac diastolic function, interstitial relaxation, and fibrosis of the heart. Supplementing with exogenous H2S can improve these phenomena. CONCLUSION: H2S maintains the structure and function of the heart by inhibiting the expression of MMP-9 during the aging process.

Association between screen time and physical activity on mental health among preschoolers: a cross-sectional study from Southwest China.

BACKGROUND: Screen time and physical activity behaviors undergo development during early childhood and impact mental health. However, there is limited knowledge regarding the associations between physical activity, screen time, and mental health problems (MHP) in preschoolers. This study examines these associations using a large sample size and brief measures. METHODS: A multistage cluster stratified sampling method was used to conduct an observational cross-sectional study of 19,015 Chinese preschoolers in 2020. Information on physical activity, and screen time was collected by a self-administered questionnaire; MHP was assessed by the parent-reported Strengths and Difficulties Questionnaire (SDQ). Logistic regression models were used to obtain the odds ratios (ORs) and 95% confidence intervals (95% CIs) of preschoolers' MHP associated with screen time, total physical activities, moderate to vigorous physical activity (MVPA), and outdoor physical activities. RESULTS: A total of 19,015 participants from the 19,548 recruited population were included in the analyses (missing rate: 2.73%), 52.60% were boys. 64.01%, 57.96%, 35.98%, and 82.64% of preschoolers were reported to meet total physical activities, MVPA, and outdoor activities with screen time recommendations level. The results of multivariable-adjusted ORs (95% CIs) of preschoolers' MHP for comparisons of different levels of screen time (< 2 h/day, 2-4 h/day,≥4 h/day) show that screen time positively associated with MHP after adjusting for confounders (P < 0.05), but the association was not significant among girls with screen time ≥ 4 h/day. In addition, increased engagement in physical activity was reversely linked to MHP (P < 0.05). A stronger association between MHP and MVPA was observed in boys, however, this association was weakened when the total time spent engaging in MVPA exceeded two hours per day (P < 0.05). CONCLUSION: Less physical activity and more screen time positively relate to MHP, but the relationship differs by type of physical activity, total time, and gender. These findings provide novel insights and evidence supporting for guidelines on physical activity, screen time, and improvement of mental health for preschoolers.

Butyrate attenuates sympathetic activation in rats with chronic heart failure by inhibiting microglial inflammation in the paraventricular nucleus.

Sympathetic activation is a hallmark of heart failure and the underlying mechanism remains elusive. Butyrate is generated by gut microbiota and influences numerous physiological and pathological processes in the host. The present study aims to investigate whether the intestinal metabolite butyrate reduces sympathetic activation in rats with heart failure (HF) and the underlying mechanisms involved. Sprague-Dawley rats (220‒250 g) are anaesthetized with isoflurane, and the left anterior descending artery is ligated to model HF. Then, the rats are treated with or without butyrate sodium (NaB, a donor of butyrate, 10 g/L in water) for 8 weeks. Blood pressure and renal sympathetic nerve activity (RSNA) are recorded to assess sympathetic outflow. Cardiac function is improved (mean ejection fraction, 22.6%±4.8% vs 38.3%±5.3%; P<0.05), and sympathetic activation is decreased (RSNA, 36.3%±7.9% vs 23.9%±7.6%; P<0.05) in HF rats treated with NaB compared with untreated HF rats. The plasma and cerebrospinal fluid levels of norepinephrine are decreased in HF rats treated with NaB. The infusion of N-methyl-D-aspartic acid (NMDA) into the paraventricular nucleus (PVN) of the hypothalamus of HF model rats increases sympathetic nervous activity by upregulating the NMDA receptor. Microglia polarized to the M2 phenotype and inflammation are markedly attenuated in the PVN of HF model rats after NaB administration. In addition, HF model rats treated with NaB exhibit enhanced intestinal barrier function and increased levels of GPR109A, zona occludens-1 and occludin, but decreased levels of lipopolysaccharide-binding protein and zonulin. In conclusion, butyrate attenuates sympathetic activation and improves cardiac function in rats with HF. The improvements in intestinal barrier function, reductions in microglia-mediated inflammation and decreases in NMDA receptor 1 expression in the PVN are all due to the protective effects of NaB.

Inonotus obliquus aqueous extract inhibits intestinal inflammation and insulin metabolism defects in Drosophila.

In biomedical research, the fruit fly (Drosophila melanogaster) is among the most effective and flexible model organisms. Through the use of the Drosophila model, molecular mechanisms of human diseases can be investigated and candidate pharmaceuticals can be screened. White rot fungus Inonotus obliquus is a member of the family Hymenochaetaceae. Due to its multifaceted pharmacological effects, this fungus has been the subject of scientific investigation. Nevertheless, the precise mechanisms by which Inonotus obliquus treats diseases remain unclear. In this study, we prepared an aqueous extract derived from Inonotus obliquus and demonstrated that it effectively prevented the negative impacts of inflammatory agents on flies, including overproliferation and overdifferentiation of intestinal progenitor cells and decreased survival rate. Furthermore, elevated reactive oxygen species levels and cell death were alleviated by Inonotus obliquus aqueous extract, suggesting that this extract inhibited intestinal inflammation. Additionally, Inonotus obliquus aqueous extract had an impact on the insulin pathway, as it alleviated growth defects in flies that were fed a high-sugar diet and in chico mutants. In addition, we determined the composition of Inonotus obliquus aqueous extract and conducted a network pharmacology analysis in order to identify prospective key compounds and targets. In brief, Inonotus obliquus aqueous extract exhibited considerable potential as a therapeutic intervention for human diseases. Our research has established a foundational framework that supports the potential clinical implementation of Inonotus obliquus.

Hydrogen sulfide ameliorates endothelial dysfunction in aging arteries by regulating ferroptosis.

Aging causes vascular endothelial dysfunction. We aimed to investigate the causes of vascular endothelial dysfunction during aging using plasma and renal arteries from patients who underwent nephrectomy and animal models. The results showed that the endogenous H2S-producing enzyme cystathione-γ-lyase (CSE) protein expression was downregulated in renal artery tissue, plasma H2S levels were reduced. Moreover, elevated lipid peroxidation and iron accumulation levels led to ferroptosis and endothelial diastolic function in the renal arteries was impaired in the elderly group. H2S enhanced the endogenous CSE expression in the elderly group, promoted endogenous H2S production, decreased lipid peroxide expression, and inhibited ferroptosis, which in turn improved vascular endothelial function in the elderly group. In animal models, we also observed the same results. In addition, we applied NaHS, Ferrostatin-1 (ferroptosis inhibitor) and erastin (ferroptosis inducer) to incubate renal arteries of SD rats. The results showed that NaHS enhanced ferroptosis related proteins expression, inhibited ferroptosis and improved vascular endothelial function. We demonstrated that endothelial dysfunction associated with aging is closely related to reduced endogenous H2S levels and ferroptosis in vascular endothelial cells. Notably, H2S reduced lipid peroxidation levels in vascular endothelial cells, inhibited ferroptosis in vascular endothelial cells, and improved endothelial dysfunction.

Hydrogen sulfide ameliorates senescence in vascular endothelial cells through ameliorating inflammation and activating PPARδ/SGLT2/STAT3 signaling pathway.

Mounting evidence demonstrates that hydrogen sulfide (H 2S) promotes anti-inflammatory molecules and inhibits pro-inflammatory cytokines in endothelial cells (ECs). This study aims to investigate the favorable action of H 2S on endothelial function in senescence by inhibiting the production of inflammatory molecules. Senescent ECs exhibit a reduction in H 2S, endothelial nitric oxide synthase (eNOS) and peroxisome proliferator-activated receptor δ (PPARδ), coupled with increased inflammatory molecules, sodium glucose transporter type 2 (SGLT2) and phosphorylation of STAT3, which could be reversed by the administration of a slow but sustained release agent of H 2S, GYY4137. Decreased production of eNOS and upregulated p-STAT3 and SGLT2 levels in senescent ECs are reversed by replenishment of the SGLT2 inhibitor EMPA and the PPARδ agonist GW501516. The PPARδ antagonist GSK0660 attenuates eNOS expression and increases the production of p-STAT3 and SGLT2. However, supplementation with GYY4137 has no beneficial effect on GSK0660-treated ECs. GYY4137, GW501516 and EMPA preserve endothelial-dependent relaxation (EDR) in D-gal-treated aortae, while GSK0660 destroys aortic relaxation even with GYY4137 supplementation. In summary, senescent ECs manifest aggravated the expressions of the inflammatory molecules SGLT2 and p-STAT3 and decreased the productions of PPARδ, eNOS and CSE. H 2S ameliorates endothelial dysfunction through the anti-inflammatory effect of the PPARδ/SGLT2/p-STAT3 signaling pathway in senescent ECs and may be a potential therapeutic target for anti-ageing treatment.

UAV Trajectory Design and Power Optimization for Terahertz Band-Integrated Sensing and Communications.

Sixth generation (6G) wireless networks require very low latency and an ultra-high data rate, which have become the main challenges for future wireless communications. To effectively balance the requirements of 6G and the extreme shortage of capacity within the existing wireless networks, sensing-assisted communications in the terahertz (THz) band with unmanned aerial vehicles (UAVs) is proposed. In this scenario, the THz-UAV acts as an aerial base station to provide information on users and sensing signals and detect the THz channel to assist UAV communication. However, communication and sensing signals that use the same resources can cause interference with each other. Therefore, we research a cooperative method of co-existence between sensing and communication signals in the same frequency and time allocation to reduce the interference. We then formulate an optimization problem to minimize the total delay by jointly optimizing the UAV trajectory, frequency association, and transmission power of each user. The resulting problem is a non-convex and mixed integer optimization problem, which is challenging to solve. By resorting to the Lagrange multiplier and proximal policy optimization (PPO) method, we propose an overall alternating optimization algorithm to solve this problem in an iterative way. Specifically, given the UAV location and frequency, the sub-problem of the sensing and communication transmission powers is transformed into a convex problem, which is solved by the Lagrange multiplier method. Second, in each iteration, for given sensing and communication transmission powers, we relax the discrete variable to a continuous variable and use the PPO algorithm to tackle the sub-problem of joint optimization of the UAV location and frequency. The results show that the proposed algorithm reduces the delay and improves the transmission rate when compared with the conventional greedy algorithm.

Validation of a novel nutrition risk screening tool in stroke patients.

BACKGROUND AND OBJECTIVES: We aimed to apply a novel nutrition screening tool to stroke patients and assess its reliability and validity. METHODS AND STUDY DESIGN: Cross-sectional data among 214 imaging-confirmed stroke patients were collected between 2015 and 2017 in two public hospitals in Hebei, China. Delphi consultation was conducted to evaluate the items in the NRS-S scale. Anthropometric indices including body mass index (BMI), triceps skin fold thickness (TSF), upper arm circumference (AMC) and mid-arm muscle circumference (MAMC) were measured. Internal consistency reliability, test-retest reliability, construct validity and content validity were assessed. In order to estimate content validity, two rounds Delphi consultation of fifteen experts were conducted to evaluate the items in the Nutrition Risk Screening Scale for Stroke (NRS-S). RESULTS: High internal consistency was indicated by Cronbach's alpha of 0.632 and a split-half reliability of 0.629; test-retest reliability of NRS-S items ranged from 0.728 to 1.000 (p<0.0001), except for loss of appetite (0.436, p<0.001) and gastrointestinal symptoms (0.213, p=0.042). Content validity index of 0.89 indicated robust validity of the items. Regarding construct validity, the Kaiser-Meyer-Olkin value was 0.579, and the result of the Bartlett test of sphericity was 166.790 (p<0.001). Three factors were extracted by exploratory factor analysis, which contributed to 63.079% of the variance. Confirmatory factor analysis was performed on the questionnaire, finding the p-value of the model to be 0.321, indicating a high model fitting index. CONCLUSIONS: A novel stroke-specific nutritional risk screening tool demonstrated a relatively high reliability and validity in its clinical application.

The association between maternal healthy lifestyle factors during pregnancy and the neonatal anthropometric indicators based on a prospective cohort study.

BACKGROUND AND OBJECTIVES: We aimed to evaluate the associations between a combined healthy lifestyle during the second and third trimesters and offspring anthropometric outcomes in China. METHODS AND STUDY DESIGN: We examined these associations among 548 participants from nine community health centers and three hospitals in the North China cohort. A pregnant women's healthy lifestyle score (HLS) was constructed based on six lifestyle factors: smoking, alcohol consumption, physical activity, sedentary behavior, diet, and gestational weight gain. Anthropometric indicators at birth like birth weight (BW), head circumference (HC), and birth length (BL) were collected, and weight to head circumference ratio (WHC, kg/m), body mass index (BMI, kg/m2) and Ponderal Index (PI, kg/m3) were calculated. Multivariate linear and logistic regression models were used to examine the effects of HLS during the second and third trimesters on anthropometric outcomes at birth, respectively. RESULTS: In fully adjusted models, we found a negative association between second and third-trimester HLS and offspring HC and a positive relationship between second-trimester HLS and BL (p<0.05). Neonates with mothers in the highest HLS tertile had a 5.6% relatively lower HC and 2.3% relatively longer body length than women in the lowest tertile. Each additional unit in third-trimester HLS had an associated decrease in HC by 0.96 cm. None of the associations between HLS and BW, WHC, BMI, and PI of offspring were observed. CONCLUSIONS: A healthy lifestyle score may significantly impact offspring head circumference and body length, supporting the important role of healthy lifestyles in improving the health of offspring.

Targeting IRE1α-JNK-c-Jun/AP-1-sEH Signaling Pathway Improves Myocardial and Coronary Endothelial Function Following Global Myocardial Ischemia/Reperfusion.

Objectives: Endoplasmic reticulum (ER) stress and soluble epoxide hydrolase (sEH) upregulation/activation have been implicated in myocardial ischemia/reperfusion (I/R) injury. We previously reported that ER stress mediates angiotensin II-induced sEH upregulation in coronary endothelium, whether and how ER stress regulates sEH expression to affect postischemic cardiac function remain unexplored. This study aimed to unravel the signaling linkage between ER stress and sEH in an ex vivo model of myocardial I/R injury. Methods: Hearts from male Wistar-Kyoto rats were mounted on a Langendorff apparatus and randomly allocated to 7 groups, including control, I/R (30-min ischemia and 60-min reperfusion), and I/R groups pretreated with one of the following inhibitors: 4-PBA (targeting: ER stress), GSK2850163 (IRE1α), SP600125 (JNK), SR11302 (AP-1), and DCU (sEH). The inhibitor was administered for 15 min before ischemia with a peristaltic pump. Hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximal velocity of contraction (+dp/dtmax) and relaxation (-dp/dtmax) of the left ventricle were continuously recorded using an intraventricular balloon. Endothelial dilator function of the left anterior descending artery was studied in a wire myograph upon completion of reperfusion. The expression of ER stress molecules, JNK, c-Jun, and sEH was determined by western-blot. Results: I/R decreased LVSP (105.5±6.4 vs. 146.9±13.4 mmHg), and increased LVEDP (71.4±3.0 vs. 6.0±2.7 mmHg), with a resultant decreased LVDP (34.1±9.2 vs. 140.9±13.1 mmHg). I/R attenuated +dp/dtmax (651.7±142.1 vs. 2806.6±480.6 mmHg/s) and -dp/dtmax (-580.0±109.6 vs. -2118.0±244.9 mmHg/s) (all ps<0.001). The I/R-induced cardiac dysfunction could be alleviated by 4-PBA (LVSP 119.5±15.6 mmHg, p<0.01; LVEDP 21.2±4.2 mmHg, LVDP 98.3±12.0 mmHg, +dp/dtmax 2166.7±208.4 mmHg/s, and -dp/dtmax -1350.9±99.8 mmHg/s, all ps<0.001), GSK2850163 (LVSP 113.4±10.9 mmHg, p<0.01; LVEDP 37.1±3.1 mmHg, LVDP 76.3±13.9 mmHg, +dp/dtmax 1586.5±263.3 mmHg/s, -dp/dtmax -1127.7±159.9 mmHg/s, all ps<0.001), SP600125 (LVSP 113.9±5.6 mmHg, LVDP 40.5±3.3 mmHg, +dp/dtmax 970.1±89.8 mmHg/s, all ps<0.01), SR11302 (LVSP 97.9±7.5 mmHg, p<0.01; LVEDP 52.7±8.6mmHg, p<0.001; LVDP 45.2±9.8mmHg, p<0.05; +dp/dtmax 1231.5±196.6 mmHg/s, p<0.01; -dp/dtmax -658.3±68.9 mmHg/s, p<0.05), or DCU (LVSP 109.9±4.1 mmHg, p<0.01; LVEDP 11.7±1.8 mmHg, LVDP 98.2±4.9 mmHg, +dp/dtmax 1869.8±121.9 mmHg/s, and -dp/dtmax -1492.3±30.8 mmHg/s, all ps<0.001). The relaxant response of the coronary artery to acetylcholine was decreased after I/R in terms of both magnitude and sensitivity (p<0.001). All inhibitors improved acetylcholine-induced relaxation. Global I/R increased sEH expression and induced ER stress in both myocardium and coronary artery. Inhibition of ER stress or IRE1α downregulated I/R-induced sEH expression and inhibited JNK and c-Jun phosphorylation. Both JNK and AP-1 inhibitors lowered sEH level in myocardium and coronary artery in I/R-injured hearts. Conclusions: This study deciphered the molecular linkage between ER stress and sEH regulation in global I/R insult by uncovering a novel signaling axis of IRE1α-JNK-c-Jun/AP-1-sEH, which provided basis for future research on the therapeutic potential of targeting the IRE1α-JNK-c-Jun/AP-1-sEH axis for ischemic myocardial injury.

Endoplasmic reticulum stress mediates homocysteine-induced hypertrophy of cardiac cells through activation of cyclic nucleotide phosphodiesterase 1C.

Although the association of elevated homocysteine level with cardiac hypertrophy has been reported, the molecular mechanisms by which homocysteine induces cardiac hypertrophy remain inadequately understood. In this study we aim to uncover the roles of cyclic nucleotide phosphodiesterase 1 (PDE1) and endoplasmic reticulum (ER) stress and their relationship to advance the mechanistic understanding of homocysteine-induced cardiac cell hypertrophy. H9c2 cells and primary neonatal rat cardiomyocytes are exposed to homocysteine with or without ER stress inhibitor TUDCA or PDE1-specific inhibitor Lu AF58027, or transfected with siRNAs targeting PDE1 isoforms prior to homocysteine-exposure. Cell surface area is measured and ultrastructure is examined by transmission electron microscopy. Hypertrophic markers, PDE1 isoforms, and ER stress molecules are detected by q-PCR and western blot analysis. Intracellular cGMP and cAMP are measured by ELISA. The results show that homocysteine causes the enlargement of H9c2 cells, increases the expressions of hypertrophic markers ß-MHC and ANP, upregulates PDE1A and PDE1C, promotes the expressions of ER stress molecules, and causes ER dilatation and degranulation. TUDCA and Lu AF58027 downregulate ß-MHC and ANP, and alleviate cell enlargement. TUDCA decreases PDE1A and PDE1C levels. Silencing of PDE1C inhibits homocysteine-induced hypertrophy, whereas PDE1A knockdown has minor effect. Both cAMP and cGMP are decreased after homocysteine-exposure, while only cAMP is restored by Lu AF58027 and TUDCA. TUDCA and Lu AF58027 also inhibit cell enlargement, downregulate ANP, ß-MHC and PDE1C, and enhance cAMP level in homocysteine-exposed primary cardiomyocytes. ER stress mediates homocysteine-induced hypertrophy of cardiac cells via upregulating PDE1C expression Cyclic nucleotide, especially cAMP, is the downstream mediator of the ER stress-PDE1C signaling axis in homocysteine-induced cell hypertrophy.

The overall diet quality in childhood is prospectively associated with the timing of puberty.

PURPOSE: The influences of nutrition in childhood on puberty onset could have sustained consequences for health and wellbeing later in life. The aim of this study was to investigate the prospective association of diet quality prior to puberty with the timing of puberty onset. METHODS: We considered data from 3983 SCCNG (Southwest China Childhood Nutrition and Growth) study participants with dietary data, anthropometric measurement, and information on potential confounders at their baseline assessment (mean age: 7.1 years for girls and 7.3 years for boys; mean length of follow-up was 4.2 years). Cox proportional hazard regression estimating hazard ratios (HRs) and 95% confidence intervals (CIs) were used to examine the relationship between diet quality and puberty onset. Dietary intake at baseline was assessed using a validated food frequency questionnaire. Diet quality was determined using the Chinese Children Dietary Index (CCDI) which measures adherence to current dietary recommendations (theoretical range: 0-160 points). Age at Tanner stage 2 for breast/genital development (B2/G2), menarche or voice break (M/VB) were used as pubertal markers. RESULTS: The CCDI score ranged from 56.2 to 136.3 for girls and 46.1-131.5 for boys. Pubertal markers consistently indicate that girls and boys with higher diet quality were more likely to enter their puberty later than their counterparts with lower CCDI scores (higher vs. lower CCDI tertiles: adjusted HR for age at B2: 0.85 (95% CI, 0.81-0.94), p for trend = 0.02; G2: 0.86 (95% CI,0.80-0.96), p for trend = 0.02; M: 0.86 (95% CI,0.80-0.95), p for trend = 0.02; VB: 0.86 (95% CI,0.79-0.98), p for trend = 0.03), after adjustment for paternal education level, baseline energy intake, and pre-pubertal body fat. CONCLUSIONS: Our data suggested a later puberty onset and later timing of progressed puberty stages in children with a high diet quality, which were independent of pre-pubertal body fat.

Beyond protein intake: does dietary fat intake in the year preceding pregnancy and during pregnancy have an impact on gestational diabetes mellitus?

PURPOSE: Studies regarding the association between dietary fat intake and gestational diabetes mellitus (GDM) are limited and provide conflicting findings. Thus, the study aims to examine the association of dietary fat intake in the year preceding pregnancy and during pregnancy with the risk of GDM, taking the relevance of dietary protein intake on GDM into consideration. METHODS: A prospective study was conducted in 6299 singleton pregnancies, using the data from the Nutrition in Pregnancy and Growth in Southwest China (NPGSC). A validated food frequency questionnaire was used to assess dietary fat intake in the year preceding pregnancy and during the first and second trimesters of pregnancy. Logistic regression analysis was used to assess the prospective associations of dietary fat intake and the type and source of dietary fats in different time windows with GDM risk. RESULTS: Higher intake of total fat [OR (95% CI): 2.21 (1.19-4.20), P = 0.02] during 12-22 weeks of gestation was associated with higher GDM risk. However, adjustment for animal protein intake greatly attenuated this association [OR (95% CI): 1.81 (0.93, 3.64), P = 0.11]. Total fat intake neither in the year preceding pregnancy nor during the early pregnancy was associated with GDM risk. Moreover, insignificant associations were observed between intakes of vegetable fat, animal fat, cholesterol, saturated fatty acid, monounsaturated fatty acid and polyunsaturated fatty acid one year before pregnancy and during the first and second trimesters and GDM risk. CONCLUSION: Our study indicated that dietary fat intake one year before pregnancy and across the two pregnancy trimesters preceding the diagnosis of GDM has no relevance on GDM risk among Chinese women, particularly those with normal BMI, low, or normal calorie intake.

Obesity is a risk factor for central precocious puberty: a case-control study.

BACKGROUND: Obesity is an important underlying cause of central precocious puberty (CPP), but previous large studies are flawed by using just age and breast examination to diagnose CPP. We aimed to determine whether overweight and obesity in childhood increases hormonally diagnosed CPP. METHODS: Our retrospective, case-control study recruited 846 children diagnosed as having CPP and randomly sampled 1650 healthy control subjects in Xingtai Third Hospital in China between November 2018 and March 2021. Information was obtained from an electronic medical record and questionnaire investigated in the outpatient visit. Observations were made before the a priori hypothesis. Unconditional logistic regression for analysis was used to determine whether overweight and obesity status and duration of overweight/obesity were associated with CPP. RESULTS: Overweight and obesity were significantly associated with increased odds of CPP among girls, even after adjusting for birth weight, exclusive breastfeeding for 6 month, household income, maternal overweight, paternal overweight, and maternal menarche age (overweight: the adjusted odds ratio (aOR) (95%CI): 1.92 (1.16, 3.24), p = 0.02; obesity: aOR (95%CI): 1.78 (1.13, 3.48), p = 0.03). Furthermore, the effects of overweight and obesity were significant when ongoing for 1 to 2 years, 2 to 3 years, and greater than 3 years, but not at less than 1 year. For boys, association between obesity and increased odds of CPP was observed (aOR (95%CI): 1.68 (1.09, 3.75), p = 0.03). The effects of overweight and/or obesity were only significant when ongoing for greater than 2 years. CONCLUSIONS: Prolonged overweight and obesity in early childhood may be risk factors for CPP, especially in girls. Weight loss might be an important approach for the prevention of precocious puberty in children.

The Relationship Between Protein S-Nitrosylation and Human Diseases: A Review.

S-nitrosylation (SNO) is a covalent post-translational oxidative modification. The reaction is the nitroso group (-NO) to a reactive cysteine thiol within a protein to form the SNO. In recent years, a variety of proteins in human body have been found to undergo thiol nitrosylation under specific conditions. Protein SNO, which is closely related to cardiovascular disease, Parkinson's syndrome, Alzheimer's disease and tumors, plays an important role in regulatory mechanism of protein function in both physiological and pathological pathways, such as in cellular homeostasis and metabolism. This review discusses possible molecular mechanisms protein SNO modification, such as the role of NO in vivo and the formation mechanism of SNO, with particular emphasis on mechanisms utilized by SNO to cause certain diseases of human. Importantly, the effect of SNO on diseases is multifaceted and multi-channel, and its critical value in vivo is not well defined. Intracellular redox environment is also a key factor affecting its level. Therefore, we should pay more attention to the equilibrium relationship between SNO and denitrosylation pathway in the future researches. These findings provide theoretical support for the improvement or treatment of diseases from the point of view of SNO.

Nutrition in Pregnancy and Growth in Southwest China (NPGSC) cohort: Design, implementation, and characteristics.

BACKGROUND: Pregnancy and birth cohorts addressing maternal nutrition and its impact on health outcomes have been rare in China, especially in Southwest China. OBJECTIVES: To describe the design, implementation, baseline characteristics, and initial results of the Nutrition in Pregnancy and Growth in Southwest China (NPGSC) cohort. POPULATION: Pregnant women with their children in Southwest China. DESIGN: NPGSC participants have been prospectively recruited since 2014. Pregnant women were invited to participate in the study at their first routine ultrasound examination in gestational weeks 9-11. Data were assessed three times during pregnancy (9-11, 20-22, and 33-35 gestation weeks), and eight times in infants and toddlers. METHODS: Pre-pregnancy body weight and height were self-reported; gestational weight gain was measured at regular intervals. Both food frequency questionnaires (FFQ) and 24-hour dietary recalls were used to collect dietary intakes during pregnancy, and FFQ for diet before pregnancy. Information on pregnancy outcomes was extracted from the medical birth registry. Anthropometry of children in the first 3 years of life was measured by trained investigators. Other child outcomes, including feeding practices (self-reported by mothers) and cognitive development (assessed by the Chinese version of Ages and Stages Questionnaire), were recorded. PRELIMINARY RESULTS: Between 2014 and 2018, 12 989 pregnant women were enrolled, and 2296 children completed the 3 years follow-up. Among them, 115 pregnancies ended in stillbirth. Mean maternal pre-pregnancy BMI was 21.1 kg/m2 and mean gestational weight gain was 13.5 kg 18.6% of mothers developed gestational diabetes and 1.5% of mothers were diagnosed with preeclampsia. Mean birthweight and birth length of children were, respectively, 3329 g and 49.4 cm. CONCLUSION: We built a prospective cohort in Southwest China, which can provide valuable data to investigate the relevance of nutrition for the health of mothers and children.

Monetary diet cost is positively associated with diet quality and obesity: an analysis of school-aged children in Southwest China.

BACKGROUND: Little is known about the relationships between diet cost, dietary intake and obesity in Chinese populations. This study explored how diet cost was related to diet quality and obesity among school-aged children in Southwest China. METHODS: Data from a cross-sectional study was analysed. Diet cost was estimated based on dietary intake assessed with 24-h dietary recalls and retail food prices. Diet quality was measured using the Chinese Children Dietary Index. Body height, weight, waist circumference and skinfold thicknesses were measured, and their body mass index standard deviation score (BMISDS), waist-to-height ratio (WHtR), fat mass index (FMI) and fat-free mass index (FFMI) were calculated. Multivariate regression models were used to explore the relevance of diet cost to diet quality and obesity. RESULTS: After adjustment for potential confounders, a positive association was observed between diet quality and energy-adjusted diet cost (ß = 0.143, 95% confidence interval, CI: 0.014-0.285, Pfor-trend = 0.0006). Energy-adjusted diet cost also showed a positive association with FMI (ß = 0.0354, 95% CI: 0.0001-0.0709, Pfor-trend = 0.01), BMISDS (ß = 0.0200, 95% CI: 0.0006-0.0394, Pfor-trend = 0.002) and WHtR (ß = 0.0010, 95% CI: 0.0003-0.0017, Pfor-trend = 0.02). CONCLUSIONS: Energy-adjusted diet cost was independently and positively associated with diet quality and obesity among Chinese school-aged children.