Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging cardiovascular risk factor; evidence-based blood pressure (BP) management strategies for this population remain limited. We aimed to evaluate the efficacy and safety of a multifaceted intervention anchored by intensive BP control (< 130/80 mmHg) in patients with MAFLD using data from the China Rural Hypertension Control Project (CRHCP) trial. This study is a post hoc analysis of the CRHCP trial, an open-label, cluster-randomized controlled trial conducted from 2018 to 2023 across 326 villages in China. Adults aged ≥ 40 years with hypertension were eligible. Participants were randomized in a 1:1 ratio to receive either intensive BP control (target < 130/80 mmHg) or usual care. MAFLD was diagnosed using the hepatic steatosis index (HSI ≥ 36) combined with metabolic criteria. The primary outcome was a composite of stroke, myocardial infarction, heart failure, or cardiovascular death; secondary outcomes included individual components of the primary outcome and all-cause death. The CRHCP trial is registered with ClinicalTrials.gov NCT03527719. A total of 29,624 participants (12,912 with MAFLD) were included in this analysis. The mean (SD) age was 63.2 (9.2) years, and 18,348 (61.9

The Chronic Liver Disease (CLivD) score is a non-invasive marker of advanced liver disease risk. We evaluated its associations with dementia, cardiovascular disease (CVD), cancer, and all-cause mortality. This prospective cohort study included UK Biobank participants with calculable CLivD scores at baseline (2006–2010). Two previously validated versions of the score were calculated: a laboratory-based CLivD (CLivDlab), incorporating age, sex, waist-hip ratio, alcohol consumption, diabetes, smoking, and gamma-glutamyltransferase (GGT), and a non-laboratory CLivD (CLivDnonlab), based on the same predictors without GGT. Data were analyzed using Cox proportional hazards models, Kaplan–Meier survival curves, and restricted cubic spline functions. Additional models adjusted for centered age and sex. This prospective cohort study included 88,449 UK Biobank participants with calculable CLivD scores (2006–2010) and a mean 9.76-year follow-up. During follow-up, 1,052 (1.19

Background The ClivD score, a non-invasive marker for liver disease risk, shows strong predictive value for advanced liver disease. Given emerging links between chronic liver diseases and systemic conditions, this study examines ClivD's association with risks of cardiovascular disease, dementia, cancer, and all-cause mortality. Methods This prospective cohort study included eligible adult participants from the UK Biobank who had calculable ClivD scores between 2006 and 2010. Data were analyzed using Cox proportional hazards models, Kaplan–Meier (KM) survival curves, and restricted cubic spline (RCS) functions. Results This prospective cohort study included 84,469 UK Biobank participants with calculable ClivD scores (2006–2010) and a mean 9.77-year follow-up. During follow-up, 4,664 participants died, and 966 developed dementia; 8,347 experienced CVD events, and 15,152 were diagnosed with cancer. Compared to the lowest ClivD quartile (Q1), the highest quartile (Q4) was associated with significantly elevated risks of dementia (HR = 4.30 for ClivDlab; 3.31 for ClivDnonlab), CVD (HR = 2.72 for ClivDlab; 2.36 for ClivDnonlab), cancer (HR = 2.05 for ClivDlab; 1.86 for ClivDnonlab), and mortality (HR = 3.91 for ClivDlab; 3.28 for ClivDnonlab), all p < 0.001. Associations with secondary outcomes (e.g., Alzheimer’s disease, vascular dementia, stroke, coronary heart disease, heart failure) were also significant. KM curves showed higher event incidence in high-risk groups; RCS analysis revealed mostly nonlinear associations, except for stroke in relation to ClivDnonlab (linear trend). Subgroup and sensitivity analyses supported the robustness of findings. Conclusions Higher ClivD scores are strongly associated with increased risks of dementia, CVD, cancer, and mortality in the general population. These findings support integrating ClivD into chronic disease risk stratification frameworks to enable earlier detection and liver-informed preventive strategies.

BACKGROUND:Although intensive blood pressure control is recommended by major guidelines, its overall benefit-harm balance remains uncertain. In particular, it is unclear how net clinical benefit varies by blood pressure target and patient characteristics. We aimed to quantify the benefit-harm trade-offs of intensive blood pressure control versus standard blood pressure control. METHODS:We conducted a post-hoc, pooled participant-level analysis of six randomised controlled trials (ACCORD BP, SPRINT, ESPRIT, BPROAD, STEP, and CRHCP). Trial selection was based on our collaborative framework, the Blood Pressure Reduction Union-Landmark Evidence, and a targeted literature search, guided by five predefined inclusion criteria: (1) comparison of intensive systolic blood pressure targets (<120 mm Hg or <130 mm Hg) versus standard treatment; (2) reporting of composite major cardiovascular outcomes; (3) enrolment of more than 2000 participants; (4) standardised reporting of treatment-related adverse events; and (5) availability of individual participant data. We also conducted a systematic review in which we searched PubMed for studies published from database inception up to June 15, 2025, with no language restrictions. We used search terms related to cardiovascular outcomes, hypertension, intensive blood pressure lowering, and randomised trials. Study screening and data extraction were independently conducted in pairs by ten reviewers, with discrepancies resolved by discussion or adjudication. Participants in the six trials were randomly assigned to intensive blood pressure treatment (systolic blood pressure target <120 mm Hg or <130 mm Hg) versus standard treatment (systolic blood pressure target <140 mm Hg, <150 mm Hg in older adults, or usual care), depending on the trial design. The primary benefit outcome was a composite of myocardial infarction, stroke, heart failure, and cardiovascular death. The primary harm outcomes were adverse events of interest (eg, hypotension and syncope) and renal-related events. Statistical analyses were performed on an intention-to-treat basis using Bayesian hierarchical models. FINDINGS:The initial dataset included 80 676 participants, of whom 80 220 were included in our analyses (intensive blood pressure control group n=40 503; standard blood pressure control group n=39 717). The median age was 64·0 years (IQR 59·0-70·0), 39 043 (48·7%) participants were male, and 41 177 (51·3%) were female. Most participants were Asian (66 290 [82·6%]) or White (8097 [10·1%]). During a median follow-up of 3·2 years (IQR 3·0-3·5), the composite cardiovascular disease outcome occurred in 2158 (5·3%) participants in the intensive blood pressure control group and 2811 (7·1%) participants in the standard blood pressure control group (hazard ratio 0·76, 95% credible interval [CrI] 0·72-0·81; p<0·0001). Compared with standard blood pressure control, intensive blood pressure control was associated with a 1·73% absolute risk reduction (95% CrI 1·65-1·81) in cardiovascular disease (number needed to treat 58 [95% CrI 55-61]) and a 1·82% absolute risk increase (95% CrI 1·63-2·01) for adverse events of interest (number needed to harm 55 [95% CrI 49-61]). Overall, intensive blood pressure control showed a favourable benefit-harm profile, with a net benefit of 1·14 (95% CrI 1·03-1·25), using adjudicated weighting. The net benefit remained positive when considering kidney-related adverse events (1·13 [95% CrI 1·01-1·24]). INTERPRETATION:Compared with standard blood pressure control, intensive blood pressure control provides a net benefit between the reduction in cardiovascular events and the increase in adverse events, including renal events. FUNDING:National Key Research and Development Program, the Ministry of Science and Technology of China; National Science and Technology Major Project; National Natural Science Foundation of China; China Academy of Chinese Medical Sciences Innovation Fund for Medical Science; and Science and Technology Program of Liaoning Province.

Autophagy is a common biological phenomenon in eukaryotes that has evolved and reshaped to maintain cellular homeostasis. Under the pressure of starvation, hypoxia, and immune damage, autophagy provides energy and nutrients to cells, which benefits cell survival. In mammals, autophagy is an early embryonic nutrient supply system involved in early embryonic development, implantation, and pregnancy maintenance. Recent studies have found that autophagy imbalance in placental tissue plays a key role in the occurrence and development of pregnancy complications, such as gestational hypertension, gestational obesity, premature birth, miscarriage, and intrauterine growth restriction. This mini-review summarizes the molecular mechanism of autophagy regulation, the autophagy pathways, and related factors involved in placental tissue and comprehensively describes the role of autophagy in pregnancy complications.

IntroductionIntrauterine malnutrition impairs embryo kidney development and leads to kidney disease and hypertension in adulthood, yet the underlying mechanism remains unclear.MethodsWith a maternal protein restriction (MPR) rat model, we investigated the critical ciliogenesis factors and β-catenin pathway in FGR fetal kidneys and analyzed the impact of aberrant primary cilia on renal tubular epithelium.ResultsThe data showed decreased nephron number and renal tubular dysgenesis in FGR fetus. FGR fetus showed deregulated expression of ciliogenesis factors including upregulation of IFT88 and downregulation of DYNLT1, accompanied with cilia elongation in renal tubular epithelial cells. Wnt7b, the key ligand for Wnt/β-catenin signaling, was downregulated and nuclear translocation of β-catenin was decreased. The proapoptotic protein was upregulated. In vitro study with HK-2 cells showed that overexpression of IFT88 lengthened the cilia, inhibited β-catenin signaling. Besides, IFT88 overexpression suppressed cell proliferation, activated autophagy, and induced cell apoptosis. Inhibition of autophagy partly restored the cilia length and cell viability. Likewise, knockdown of DYNLT1 led to cilia elongation, suppressed cell proliferation, and promoted apoptosis in HK-2 cell. However, the cilia elongation induced by DYNLT1 knockdown was not autophagy-dependent, but associated with reactive oxygen species (ROS) accumulation.DiscussionWe elucidated that intrauterine protein malnutrition led to deregulation of ciliogenesis factors and cilia elongation in renal tubular epithelial, inhibited β-catenin signaling, and induced cell apoptosis and ultimately, compromised kidney development.

目的:分析术前临床淋巴结阴性(CN0)甲状腺微小乳头状癌(PTMC)患者发生非小容量中央区淋巴结转移(NSVCLNM)的影响因素.方法:回顾性分析 2018 年 1 月至 2021 年 2 月该院收治的 538 例CN0 期PTMC患者的临床资料.统计CN0 期PTMC患者发生NSVCLNM情况,并采用Logistic回归分析CN0 期PTMC患者发生NSVCLNM的影响因素.结果:538 例CN0 期PTMC患者中,发生NSVCLNM 30 例,占 5.60%;未发生NSVCLNM 508 例,占 94.40%.单因素分析结果显示,不同本甲状腺炎情况、BRAFV600E基因情况、BMI、多灶性情况、被膜侵犯情况、AJCC 分期患者NSVCLNM发生率比较,差异均无统计学意义(P＞0.05);男性、年龄＜40岁、双侧癌灶、脉管侵犯、颈侧区淋巴结转移患者的NSVCLNM发生率更高,与其他类别比较,差异均有统计学意义(P＜0.05);Logistic回归分析结果显示,男性、年龄＜40岁、双侧癌灶、颈侧区淋巴结转移均为影响CN0 期PTMC患者发生NSVCLNM的危险因素(OR＞1,P＜0.05).结论:男性、年龄＜40 岁、双侧癌灶、颈侧区淋巴结转移均为影响CN0 期PTMC患者发生NSVCLNM的危险因素.

ObjectiveTo investigate the association between hypoproteinaemia with massive proteinuria and the incidence of small for gestational age in pre-eclampsia. DesignRetrospective cohort study using propensity score matching. SettingNorthwest Women's and Children's Hospital in Shaanxi Province, China, using data from January 2016 to December 2021. ParticipantsPatients diagnosed with pre-eclampsia were grouped into the massive proteinuria group if the maximum proteinuria was >3.5 g/day and the minimum serum albumin was <30 g/L; otherwise, they were placed in the control group. Outcome measuresThe primary outcome was the incidence of small for gestational age infants. Secondary outcomes included fetal death, admission to the neonatal intensive care unit, a 5 min APGAR score <7, severe small for gestational age, fetal growth restriction, birth weight, premature birth, and maternal outcomes such as eclampsia, encephalopathy, placental abruption, haemolysis, elevated liver enzymes and low platelet syndrome, heart failure and retinal detachment. ResultsIn total, 468 patients (234 from each group) were included, and the groups were well matched. The incidences of small for gestational age (33.76% vs 20.51%, OR 1.646, 95% CI 1.208 to 2.243, p=0.001), severe small for gestational age (14.70% vs 7.69%, OR 1.833, 95% CI 1.063 to 3.162, p=0.026), fetal growth restriction (23.93% vs 16.24%, OR 1.474, 95% CI 1.018 to 2.133, p=0.038), and the numbers of infants admitted to the neonatal intensive care unit (67.52% vs 58.55%, OR 1.153, 95% CI 1.003 to 1.326, p=0.044) were significantly higher in patients with hypoproteinaemia and massive proteinuria than in the control group. In addition, the median birth weight was significantly lower in the massive proteinuria group. There were no significant differences in maternal outcomes except for renal parameters, which were worse in the massive proteinuria group. ConclusionHypoproteinaemia with massive proteinuria was associated with fetal growth and a higher incidence of small for gestational age infants in pre-eclampsia.

Objective:Studies have shown a high incidence of subclinical hypothyroidism in pregnancy, but the adverse pregnancy outcomes caused by it are not clear. Therefore, we conducted a systematic review and meta-analysis to evaluate the relationship between subclinical hypothyroidism in pregnancy and hypertensive disorders of pregnancy(HDP) to guide clinical practice.Method:We searched the MEDLINE (PubMed), Cochrane Central, EMBASE, Web of Science, and SCOPUS databases and screened all studies evaluating the relationship between subclinical hypothyroidism in pregnancy and hypertensive disorders of pregnancy. Two researchers independently evaluated the quality of all eligible original studies using the Newcastle-Ottawa Scale (NOS). We also performed a meta-analysis using STATA15.1. Sensitivity analyses were also performed by examining the effects of individual studies as well as using different effect models and detecting any publication bias using the harbord test.Results:Twenty-two studies were included in the final meta-analysis. Our results indicated that pregnant women with subclinical hypothyroidism had an increased risk of HDP (OR = 1.54(95% CI: 1.21-1.96) I²=67.1%), compared with euthyroidism. Subclinical hypothyroidism in pregnancy was not associated with hypertensive disorders of pregnancy at TSH diagnostic cut-off of less than 3.0 mIU/L (P = 0.077). Curiously, the risk of HDP increases when the TSH diagnostic cut-off value is higher or lower than 4 mIU/L. Although only 9 studies were above the threshold, the risk of developing HDP was still 1.69 times, which was highest in all subgroup analyses. This is consistent with the newly recommended diagnostic cut-off value of 4 mIU/L for TSH by the ATA. Our results consider that the risk of hypertensive disorder complicating pregnancy is increased regardless of the diagnosis of subclinical hypothyroidism at any stage of pregnancy. Unfortunately, there is insufficient evidence to support that patients can benefit from treatment with levothyroxine.Conclusion:The results of this meta-analysis indicate that subclinical hypothyroidism in pregnancy is associated with an increased risk of developing HDP, and this association exists regardless of the gestational period. However, the available evidence cannot support these patients receiving thyroxine intervention can benefit from it, so routine screening is only recommended for pregnant women with risk factors for hypothyroidism. Further research is needed to validate more scientific and rigorous clinical studies to clarify the relationship between subclinical hypothyroidism and HDP to improve patient prognosis.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, PROSPERO (CRD42021286405).

Cigarette smoke (CS) disrupts placental development, and impairs fetal health and maternal fertility, thus resulting in low birth weight, premature delivery, and spontaneous abortion; however, the underlying mecha-nisms remain unclear. This study investigated the mechanism through which CS impairs placental trophoblast cell viability and function. An in vivo study in pregnant rats exposed to CS indicated that CS-exposure decreased antioxidant factors expression and blocked NRF2 activation in the placenta. Anti-ferroptosis regulators expres-sion was downregulated, and pro-ferroptosis regulators expression was upregulated in placentas from CS -exposed rats. Further analysis revealed that cigarette smoke extract (CSE) led to peroxins downregulation and decreased the number of peroxisomes. An in vitro study in HTR-8/SVneo(HTR-8) cells showed that CSE led to free iron and ROS accumulation, and subsequently induced lipid peroxidation and cell death. Ferroptosis in-hibitors and the antioxidant L-arginine (ARG) partially inhibited CSE-induced cell death. ARG partially alleviated the toxic effects of CSE by promoting antioxidant factors expression in placenta and suppressing HTR-8 cell ferroptosis. Knockdown of PEX14, a peroxisome biogenesis marker, led to the downregulation of multiple PEXs, thus increasing intracellular H2O2 levels and inducing HTR-8 cell ferroptosis. These findings demonstrated that ferroptosis is responsible for CSE-induced trophoblast cell death and suggest that peroxisome dysfunction is involved in CSE-induced ferroptosis. Therefore, CSE-induced ferroptosis may serve as a potential therapeutic target for preventing adverse pregnancy outcomes.

BACKGROUND:The prevalence of uncontrolled hypertension is high and increasing in low-income and middle-income countries. We tested the effectiveness of a multifaceted intervention for blood pressure control in rural China led by village doctors (community health workers on the front line of primary health care). METHODS:In this open, cluster randomised trial (China Rural Hypertension Control Project), 326 villages that had a regular village doctor and participated in the China New Rural Cooperative Medical Scheme were randomly assigned (1:1) to either village doctor-led multifaceted intervention or enhanced usual care (control), with stratification by provinces, counties, and townships. We recruited individuals aged 40 years or older with an untreated blood pressure of 140/90 mm Hg or higher (≥130/80 mm Hg among those with a history of cardiovascular disease, diabetes, or chronic kidney disease) or a treated blood pressure of 130/80 mm Hg or higher. In the intervention group, trained village doctors initiated and titrated antihypertensive medications according to a standard protocol with supervision from primary care physicians. Village doctors also conducted health coaching on home blood pressure monitoring, lifestyle changes, and medication adherence. The primary outcome (reported here) was the proportion of patients with a blood pressure of less than 130/80 mm Hg at 18 months. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03527719, and is ongoing. FINDINGS:Between May 8 and November 28, 2018, we enrolled 33 995 individuals from 163 intervention and 163 control villages. At 18 months, 8865 (57·0%) of 15 414 patients in the intervention group and 2895 (19·9%) of 14 500 patients in the control group had a blood pressure of less than 130/80 mm Hg, with a group difference of 37·0% (95% CI 34·9 to 39·1%; p<0·0001). Mean systolic blood pressure decreased by -26·3 mm Hg (95% CI -27·1 to -25·4) from baseline to 18 months in the intervention group and by -11·8 mm Hg (-12·6 to -11·0) in the control group, with a group difference of -14·5 mm Hg (95% CI -15·7 to -13·3 mm Hg; p<0·0001). Mean diastolic blood pressure decreased by -14·6 mm Hg (-15·1 to -14·2) from baseline to 18 months in the intervention group and by -7·5 mm Hg (-7·9 to -7·2) in the control group, with a group difference of -7·1 mm Hg (-7·7 to -6·5 mm Hg; p<0·0001). No treatment-related serious adverse events were reported in either group. INTERPRETATION:Compared with enhanced usual care, village doctor-led intervention resulted in statistically significant improvements in blood pressure control among rural residents in China. This feasible, effective, and sustainable implementation strategy could be scaled up in rural China and other low-income and middle-income countries for hypertension control. FUNDING:Ministry of Science and Technology of China.

Background Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants of GNAI3 have been identified associated with ACS so far. Here, we report a case of prenatal genetic diagnosis of ACS carrying a novel GNAI3 variant. Case presentation A woman with 30 weeks of gestation was referred to genetic counseling for polyhydramnios and fetal craniofacial anomaly. Severe micrognathia and mandibular hypoplasia were identified on ultrasonography. The mandibular length was 2.4 cm, which was markedly smaller than the 95th percentile. The ears were low-set with no cleft or notching between the lobe and helix. The face was round with prominent cheeks. Whole-exome sequencing identified a novel de novo missense variant of c.140G > A in the GNAI3 gene. This mutation caused an amino acid substitution of p.Ser47Asn in the highly conserved G1 motif, which was predicted to impair the guanine nucleotide-binding function. All ACS cases with GNAI3 mutations were literature reviewed, revealing female-dominated severe cases and right-side-prone deformities. Conclusion Severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios are prenatal indicators of ACS. We expanded the mutation spectrum of GNAI3 and summarized clinical features to promote awareness of ACS.

BACKGROUND In China, hypertension prevalence is high and increasing while the control rate is low, especially in rural areas. Traditionally, village doctors play an important role in infectious disease control and delivering essential health services to rural residents. We aim to test the effectiveness of a village doctor-led multifaceted intervention compared with usual care on blood pressure (BP) control and cardiovascular disease (CVD) among rural residents with hypertension in China. METHODS In the China Rural Hypertension Control Project (CRHCP), a cluster randomized trial, 163 villages were randomly assigned to the village doctor-led intervention and 163 villages to control. A total of 33,995 individuals aged ≥40 years with an untreated BP ≥140/90 mm Hg or treated BP ≥130/80 mm Hg or with an untreated BP ≥130/80 mm Hg and a history of clinical CVD were recruited into the study. The village doctor-led multifaceted intervention is designed to overcome barriers at the healthcare system, provider, patient, and community levels. Village doctors receive training on standard BP measurement, protocol-based hypertension treatment, and health coaching. They also receive technical support and supervision from hypertension specialists/primary care physicians and performance-based financial incentives. Study participants receive health coaching on home BP monitoring, lifestyle changes, and adherence to medications. The primary outcome is BP control (<130/80 mm Hg) at 18 months in phase 1 and CVD events over 36 months in phase 2. CONCLUSIONS The CRHCP will provide critically important data on the effectiveness, implementation, and sustainability of a hypertension control strategy in rural China for reducing the BP-related CVD burden. CLINICAL TRIALS REGISTRATION Trial Number NCT03527719.

Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition in utero on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2α were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.

Aims: The mechanisms underlying the fetal origin of renal disease remains unknown. This study aimed to investigate the profiles of ion channel and transporter proteins in the fetal kidney in fetal growth restriction (FGR) rats, and to explore their association with the fetal origin of renal disease. Main methods: An FGR rat model was developed by administration of a low-protein diet. Then 367 differentially expressed proteins (DEPs) from quantitative proteome analysis were subjected to Ingenuity Pathway Analysis. 22 DEPs associated with ion channels/transporters were evaluated in the fetal kidney. Na+/H+ exchanger1(NHE1) and its downstream unfolded protein response (UPR) pathway were investigated. Furthermore, overexpression of NHE1 were achieved via plasmid transfection to evaluate the potential influence on the UPR pathway and cell apoptosis in human proximal tubular epithelial cell line HK2 cells. Key findings: Findings were as follows: 1) In the FGR fetal kidney, aquaporin 2/4, solute carrier (SLC) 8a1, 33a1, etc. were downregulated, whereas other transporters including SLC 2a1, 4a1, 9a1, 29a3, etc. were upregulated. 2) NHE1 mRNA levels were markedly elevated in the FGR fetus. Further investigation revealed an increase in the UPR pathway regulators. 3) In vitro study showed that NHE1 overexpression in HK2 cells significantly induced expression of the endoplasmic reticulum stress (ERS) regulators and led to a decrease in the anti-apoptotic potential. Significance: We speculate that maternal protein malnutrition causes dysregulation of ion channels/transporters in the fetal kidney. Upregulated NHE1 may activate the UPR pathway and induce cell apoptosis thus leading to impairment of kidney function.

Aim. The objective of the present study was to identify differentially expressed proteins (DEPs) in the pancreas of a fetus with intrauterine growth restriction (IUGR) and to investigate the molecular mechanisms leading to adulthood diabetes in IUGR. Methods. The IUGR rat model was induced by maternal protein malnutrition. The fetal pancreas was collected at embryonic day 20 (E20). Protein was extracted, pooled, and subjected to label-free quantitative proteomic analysis. Bioinformatics analysis (GO and IPA) was performed to define the pathways and networks associated with DEPs. LC-MS results were confirmed by western blotting and/or quantitative PCR (q-PCR). The principal parameters of oxidative stress-superoxide dismutase (Sod) were determined in blood samples of fetal rats. Results. A total of 57 DEPs (27 upregulated, 30 downregulated) were identified with a 1.5-fold change threshold and a p value ≤ 0.05 between the IUGR and the control pancreas. Bioinformatics analysis revealed that these proteins play important roles in peroxisome biogenesis and fission, fatty acid beta-oxidation (FAO), mitotic cell cycle, and histone modification. The peroxin Pex14 was downregulated in the IUGR pancreas as confirmed by western blotting and q-PCR. Pmp70, a peroxisomal membrane protein involved in the transport of fatty acids, was upregulated. Hsd17b4 and Acox1/2, which catalyze different steps of peroxisomal FAO, were dysregulated. Sod plasma concentrations in the IUGR fetus were higher than those in the control, suggesting partial compensation for oxidative stress. Multiple DEPs were related to the regulation of the cell cycle, including reduced Cdk1, Mcm2, and Brd4. The histone acetylation regulators Hdac1/2 were downregulated, whereas Sirt1/3 and acetylated H3K56 were increased in the IUGR fetal pancreas. Conclusion. The present study identified DEPs in the fetal pancreas of IUGR rats by proteomic analysis. Downregulation of pancreas peroxins and dysregulation of enzymes involved in peroxisomal FAO may impair the biogenesis and function of the peroxisome and may underlie the development of T2 diabetes mellitus in adult IUGR rats. Disorders of cell cycle regulators may induce cell division arrest and lead to smaller islets. The present data provide new insight into the role of the peroxisome in the development of the pancreas and may be valuable in furthering our understanding of the pathogenesis of IUGR-induced diabetes.

Intrauterine growth restriction (IUGR) leads to the development of metabolic syndrome in adulthood. To explore the potential mechanisms of metabolic imprinting, we investigated the effect of malnutrition in utero on hepatic unfolded protein response (UPR)-related genes in IUGR offspring. An IUGR rat model was developed by feeding a low-protein diet to pregnant rats. The expression levels and activity of hepatic UPR genes were analysed by quantitative PCR (qPCR) arrays and western blotting. The hepatic UPR molecules heat-shock 70-kDa protein 4l (Hspa4l), mitogen-activated protein kinase 10 (Mapk10), and endoplasmic reticulum to nucleus signalling 2 (Ern2) were markedly downregulated in IUGR foetuses, but the expression of Mapk10 and Ern2 returned to normal levels at 3 weeks postnatal. In contrast, cAMP responsive element binding protein 3-like 3 (Creb3l3) was upregulated in hepatic tissues at embryo 20(E20), then restored to normal in adulthood (12 weeks). The protein levels of activating transcription factor 2 (Atf2) and Atf6, two key factors of the UPR pathway, were upregulated in the livers of IUGR foetuses, and the latter remained upregulated until 12 weeks. Combined with our previous findings showing an increase in hepatic gluconeogenesis enzymes in IUGR offspring, we speculated that aberrant intrauterine milieu impaired UPR signalling in hepatic tissues; these alterations early in life might contribute to the predisposition of IUGR foetuses to adult metabolic disorders.

Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often experience persistent respiratory tract disease. In experimental models, doxorubicin-induced developmental lung abnormalities may result from downregulation of branching morphogenesis factor fibroblast growth factor (Fgf10). This study investigated the temporospatial expression of Fgf10 pathway components and lung epithelial factors in an doxorubicin-induced EA-TEF model by quantitative polymerase chain reaction, immunohistochemistry, and immunoblotting. Epigenetic regulation of gene expression by histone deacetylation was also investigated. Bone morphogenetic protein (Bmp) 4 and Cathepsin H (Ctsh), downstream targets of Fgf10, were significantly downregulated in the EA-TEF model during the saccular stage, consistent with Fgf10 expression. The developmental expression pattern of P2x7 receptor (ATI-cell marker), Sftpa, and Sftpb in lung epithelial cells was not affected. Sftpc (ATII-cell Marker) and Scgb1a1 (Clara cell marker) were significantly downregulated at the canalicular stage. Meanwhile, histone deacetylase (Hdac) 1 was upregulated and subsequently decreased acetylation of histone H3 Lys56 in the EA-TEF model, which returned to a normal level at the saccular stage. In conclusion, disturbed molecular signaling involving Fgf10/Ctsh was associated with impaired airway branching and epithelial cell development in lung morphogenesis, as evidenced by downregulated Sftpc and Scgb1a1 protein expression. The influence of Hdac1 activity on gene and protein expression in lung epithelial cells deserves further study.

The present study investigated the potential role of UbiA prenyltransferase domain-containing 1 (UBIAD1) in the pathogenesis of hypertensive cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats at 8, 16 and 28 weeks of age were used. Blood pressure was measured using a non-invasive tail cut-off system. Cardiac functional index was assessed by arterial catheterization. Myocardial structure and cell apoptosis were evaluated by hematoxylin and eosin staining, and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assays, respectively. Myocardial expression of UBIAD1, coenzyme Q10 (CoQ10), endothelial nitric oxide synthase (eNOS) and atrial natriuretic peptide were evaluated by immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. Circulating and myocardial expression of nitric oxide (NO) were measured using the Griess method. SHRs exhibited increased blood pressure and cardiomyocyte apoptosis, as well as cardiac hypertrophy, compared with age-matched WKY rats. Myocardial expression of UBIAD1 was significantly decreased in SHRs in an age-dependent manner. Similarly, myocardial CoQ10 and eNOS expression were significantly reduced in SHR compared to age-matched WKY rats, and these expression levels additionally decreased further with aging. Serum and myocardial NO expression was additionally decreased in SHRs. Decreased UBIAD1 expression in SHR hearts was associated with decreased levels of CoQ10, eNOS and NO. Given the well-established role of UBIAD1 in the regulation of NO signaling, reduced expression of UBIAD1 in SHR hearts potentially contributed to the pathogenesis of hypertensive cardiac hypertrophy. Therefore, UBIAD1 may represent a potential therapeutic target for clinical treatment of hypertensive cardiac hypertrophy.