Genetic variations in ACE2 gene associated with metabolic syndrome in southern China: a case-control study.

Metabolic syndrome (MetS) is closely related to cardiovascular and cerebrovascular diseases, and genetic predisposition is one of the main triggers for its development. To identify the susceptibility genes for MetS, we investigated the relationship between angiotensin-converting enzyme 2 (ACE2) single nucleotide polymorphisms (SNPs) and MetS in southern China. In total, 339 MetS patients and 398 non-MetS hospitalized patients were recruited. Four ACE2 polymorphisms (rs2074192, rs2106809, rs879922, and rs4646155) were genotyped using the polymerase chain reaction-ligase detection method and tested for their potential association with MetS and its related components. ACE2 rs2074192 and rs2106809 minor alleles conferred 2.485-fold and 3.313-fold greater risks of MetS in women. ACE2 rs2074192 and rs2106809 variants were risk factors for obesity, diabetes, and low-high-density lipoprotein cholesterolemia. However, in men, the ACE2 rs2074192 minor allele was associated with an approximately 0.525-fold reduction in MetS prevalence. Further comparing the components of MetS, ACE2 rs2074192 and rs2106809 variants reduced the risk of obesity and high triglyceride levels. In conclusion, ACE2 rs2074192 and rs2106809 SNPs were independently associated with MetS in a southern Chinese population and showed gender heterogeneity, which can be partially explained by obesity. Thus, these SNPs may be utilized as predictive biomarkers and molecular targets for MetS. A limitation of this study is that environmental and lifestyle differences, as well as genetic heterogeneity among different populations, were not considered in the analysis.

Evaluation of Resistance Resources and Analysis of Resistance Mechanisms of Maize to Stalk Rot Caused by Fusarium graminearum.

Stalk rot is one of the most destructive and widely distributed diseases in maize plants worldwide. Research on the performance and resistance mechanisms of maize against stem rot is constantly improving. In this study, among 120 inbred maize lines infected by Fusarium graminearum using the injection method, 4 lines (3.33%) were highly resistant to stalk rot, 28 lines (23.33%) were resistant, 57 lines (47.50%) were susceptible, and 31 lines (25.84%) were highly susceptible. The inbred lines 18N10118 and 18N10370 were the most resistant and susceptible with disease indices of 7.5 and 75.6, respectively. Treatment of resistant and susceptible maize inbred seedlings with F. graminearum showed that root hair growth of the susceptible inbred lines was significantly inhibited, and a large number of hyphae attached and adsorbed multiple conidia near the root system. However, the resistant inbred lines were delayed and inconspicuous, with only a few hyphae and spores appearing near the root system. Compared with susceptible inbred lines, resistant maize inbred line seedlings treated with F. graminearum exhibited elevated activities of catalase, phenylalanine ammonia-lyase, polyphenol oxidase, and superoxide dismutase. We identified 153 genes related to disease resistance by transcriptome analysis. The mitogen-activated protein kinase signaling and peroxisome pathways mainly regulated the resistance mechanism of maize inbred lines to F. graminearum infection. These two pathways might play an important role in the disease resistance mechanism, and the function of genes in the two pathways must be further studied, which might provide a theoretical basis for further understanding the molecular resistance mechanism of stalk rot and resistance gene mining.

Functional reorganization of brain activity in children with attention-deficit/hyperactivity disorder: Evidence from the modulatory effect of cognitive demand during visuospatial attention task.

Previous studies reported that the inferior parietal lobule (IPL) had lower activation during visuospatial attention in children with attention-deficit/hyperactivity disorder (ADHD), while the functional connectivity (FC) between the IPL and other brain regions and how cognitive demand might modulate IPL's FC remain unclear. We performed a functional magnetic resonance imaging experiment recruiting two task conditions with relatively low and high cognitive demand of visuospatial attention. Forty-four children with ADHD and 36 age- and sex-matched healthy controls were included. IPL's regional activation and FC intensities were compared between groups and correlated with clinical measurements. We found that the IPL had significantly reduced activation in children with ADHD compared to healthy controls and this abnormal activation was not modulated by the cognitive demand of visuospatial attention. Importantly, further analysis revealed that the functional connectivity between IPL and inferior frontal gyrus was modulated by the cognitive demand of visuospatial attention in children with ADHD. These results revealed a modulatory effect of cognitive demand of visuospatial attention on IPL's functional connectivity but not IPL's activation in children with ADHD. More generally, these results highlight the functional reorganization of the brain activity as a possible compensatory strategy in response to the symptoms of ADHD.

Aberrant brain dynamics and spectral power in children with ADHD and its subtypes.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children, usually categorized as three subtypes, predominant inattention (ADHD-I), predominant hyperactivity-impulsivity (ADHD-HI), and a combined subtype (ADHD-C). Yet, common and unique abnormalities of electroencephalogram (EEG) across different subtypes remain poorly understood. Here, we leveraged microstate characteristics and power features to investigate temporal and frequency abnormalities in ADHD and its subtypes using high-density EEG on 161 participants (54 ADHD-Is and 53 ADHD-Cs and 54 healthy controls). Four EEG microstates were identified. The coverage of salience network (state C) were decreased in ADHD compared to HC (p = 1.46e-3), while the duration and contribution of frontal-parietal network (state D) were increased (p = 1.57e-3; p = 1.26e-4). Frequency power analysis also indicated that higher delta power in the fronto-central area (p = 6.75e-4) and higher power of theta/beta ratio in the bilateral fronto-temporal area (p = 3.05e-3) were observed in ADHD. By contrast, remarkable subtype differences were found primarily on the visual network (state B), of which ADHD-C have higher occurrence and coverage than ADHD-I (p = 9.35e-5; p = 1.51e-8), suggesting that children with ADHD-C might exhibit impulsivity of opening their eyes in an eye-closed experiment, leading to hyper-activated visual network. Moreover, the top discriminative features selected from support vector machine model with recursive feature elimination (SVM-RFE) well replicated the above results, which achieved an accuracy of 72.7% and 73.8% separately in classifying ADHD and two subtypes. To conclude, this study highlights EEG microstate dynamics and frequency features may serve as sensitive measurements to detect the subtle differences in ADHD and its subtypes, providing a new window for better diagnosis of ADHD.

Coupling Relationship Analysis between Quality Infrastructure and Ecological Environment Quality for Policy Implications.

Long-term improvement of ecological environment quality (EEQ) is a hotspot and urgent topic in the context of high-quality and sustainable development. It is urgent to look for methods that could support EEQ improvement in a high-quality and sustainable way. Owing to its natural supporting and guaranteeing functions for enhancing quality, quality infrastructure (QI) is a fundamental and critical element in promoting EEQ, but a neglected one. In this paper, we analyzed the coupling structure between QI and EEQ and applied an improved coupling model to recognize contributed and weakened indicators that affected the coupling relationship. We also examined this coupling relationship in the Yangtze River Delta (YRD) from 2012 to 2017, which proved the current situation where QI construction cannot satisfy the practical needs of EEQ improvement. Results showed that the important supporting role of QI in EEQ improvement should be valued for long-term sustainable development. Meanwhile, equilibrium and consistency of indicators in the QI and EEQ systems determined the coupling state. EEQ improvement countermeasures were also provided according to the coupling relationship analysis results. This study provided a scientific basis and guidance for EEQ improvement and sustainable development.

LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.

BACKGROUND: Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive. METHODS: The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. RESULTS: We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer. CONCLUSION: Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.

MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma.

BACKGROUND: By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear. METHODS: The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated. RESULTS: We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC. CONCLUSION: Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.

Glucagonoma and the glucagonoma syndrome.

Glucagonoma is an extremely rare pancreatic α-islet cell tumor and is often accompanied by certain clinical symptoms including necrotizing migratory erythema (NME), diabetes, weight loss and anemia. The objectives of the current review were to discern the clinical features, diagnosis, treatment and prognosis of glucagonoma by evaluating 623 reported cases. A 1998 study reviewed 407 cases and 216 cases were reported in studies published after 1998. The current review consisted of 268 males and 339 females, with an average age of 52.4 years. The male-to-female ratio was 0.79. The incidence of typical clinical findings were as follows: NME, 82.4% (350/425); diabetes, 68.5% (291/425); weight loss, 60.2% (256/425); anemia, 49.6% (211/425); and glossitis or stomatitis or cheilitis, 41.2% (175/425). A total of 499 cases reported the location of the tumor as the pancreas and 64.1% (320/499) involved the pancreatic tail. Tumor size was recorded in 58.3% (126/216) cases reported after 1998 and average tumor size was 5.0 cm. Metastasis was detected in 49.2% of patients (293/595 for whom metastasis or no metastasis were recorded) upon diagnosis. These patients were older than those without metastasis (average age, 54.0 years old vs. 50.8 years old). The average time between symptoms and diagnosis of glucagonoma was 31.4 months. Glucagonoma is a very rare disease. It is important for clinicians to learn more about this disease to be able to diagnose and treat it as early as possible, thus improving patient prognosis.

NF-κB in pancreatic cancer: Its key role in chemoresistance.

Pancreatic cancer is considered a lethal disease with a high mortality and an extremely low five-year survival rate. Chemotherapy plays a pivotal role in pancreatic cancer treatment both in an adjuvant setting after complete resection and in the case of unresectable metastatic disease. However, none of the available combination chemotherapy regimens has resulted in satisfactory survival outcomes. Recent studies have revealed that both constitutive and induced activation of nuclear factor kappa B (NF-κB) in pancreatic cancer cells are closely associated with cell proliferation, invasion, anti-apoptosis, inflammation, angiogenesis and chemotherapeutic resistance. Therefore, NF-κB inhibitors in combination with cytotoxic compounds have been reported as novel agents that improve chemotherapy sensitivity in pancreatic cancer. In this review, we outline recent developments in the understanding of the role of the NF-κB signaling pathway and its associated genes in the progression of pancreatic cancer and highlight some potentially effective strategies for pancreatic cancer treatment.

Extracellular vesicles as mediators of the progression and chemoresistance of pancreatic cancer and their potential clinical applications.

Pancreatic cancer is one of the most lethal cancers worldwide due to its insidious symptoms, early metastasis, and chemoresistance. Hence, the underlying mechanisms contributing to pancreatic cancer progression require further exploration. Based on accumulating evidence, extracellular vesicles, including exosomes and microvesicles, play a crucial role in pancreatic cancer progression and chemoresistance. Furthermore, they also possess the potential to be promising biomarkers, therapy targets and tools for treating pancreatic cancer. Therefore, in-depth studies on the role of extracellular vesicles in pancreatic cancer are meaningful. In this review, we focus on the regulatory effects of extracellular vesicles on pancreatic cancer progression, metastasis, cancer-related immunity and chemoresistance, particularly their potential roles as biomarkers and therapeutic targets.

PD-1/PD-L1 and immunotherapy for pancreatic cancer.

Therapy that targets programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), which are known as immune checkpoints, has been recently rapidly developing as oncotherapy for various carcinomas. However, this therapy has a poor effect on the treatment of pancreatic cancer with PD-1/PD-L1 blockade monotherapy. In this review, the development and limitations of anti-PD-1/PD-L1 monotherapy in pancreatic cancer are discussed. We then consider the underlying mechanism of anti-PD-1/PD-L1 monotherapy failure, combination strategies overcoming resistance to anti-PD-1/PD-L1 immunotherapy and the prospect of targeting PD-1/PD-L1 for the immunotherapy of pancreatic cancer.

The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer.

Pancreatic cancer, which is often asymptomatic, is currently one of the most common causes of cancer-related death. This phenomenon is most likely due to a lack of early diagnosis, a high metastasis rate and a disappointing chemotherapy outcome. Thus, improving treatment outcomes by overcoming chemotherapy resistance may be a useful strategy in pancreatic cancer. Various underlying mechanisms involved in the chemoresistance of pancreatic cancer have been investigated. Notably, non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a pivotal role in regulating sensitivity to chemotherapy in pancreatic cancer. In this review, we highlight recent evidence regarding the role of miRNAs and lncRNAs in the chemoresistance of pancreatic cancer, including their expression levels, targets, biological functions and the regulation of chemoresistance, and discuss the potential clinical application of miRNAs and lncRNAs in the treatment of pancreatic cancer.

miR-497 expression, function and clinical application in cancer.

MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression by binding to the 3' untranslated region (3'-UTR) of their target mRNAs. Recent studies show that miR-497 plays an important role in various cancers. Here, we summarize the existing studies of miR-497 as following: (1) miR-497 expression in cancer; (2) regulation mechanisms of miR-497 expression; (3) function of miR-497 in cancer; (4) direct targets of miR-497; (5) Clinical applications of miR-497. Recent analyses verify that miR-497 mainly suppresses tumors; however, it also acts as an oncogene in several cancers. Increasing evidence indicates that miR-497 can serve as a diagnostic and prognostic biomarker and is a promising therapeutic target for future clinical applications.

(1)H NMR-Based Analysis of Serum Metabolites in Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats.

AIMS: To study the changes of the metabolic profile during the pathogenesis in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH). METHODS: Forty male Sprague-Dawley (SD) rats were randomly divided into 5 groups (n = 8, each). PAH rats were induced by a single dose intraperitoneal injection of 60 mg/kg MCT, while 8 rats given intraperitoneal injection of 1 ml normal saline and scarified in the same day (W0) served as control. Mean pulmonary arterial pressure (mPAP) was measured through catherization. The degree of right ventricular hypertrophy and pulmonary hyperplasia were determined at the end of first to fourth weeks; nuclear magnetic resonance (NMR) spectra of sera were then acquired for the analysis of metabolites. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to discriminate different metabolic profiles. RESULTS: The prominent changes of metabolic profiles were seen during these four weeks. Twenty specific metabolites were identified, which were mainly involved in lipid metabolism, glycolysis, energy metabolism, ketogenesis, and methionine metabolism. Profiles of correlation between these metabolites in each stage changed markedly, especially in the fourth week. Highly activated methionine and betaine metabolism pathways were selected by the pathway enrichment analysis. CONCLUSIONS: Metabolic dysfunction is involved in the development and progression of PAH.

Adipose-derived stem cells attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling in monocrotaline-induced pulmonary hypertensive rats.

We investigated the effect of adipose-derived stem cells (ADSCs) transplantation effects on structural remodeling and pulmonary artery pressure in monocrotaline (MCT)-induced pulmonary hypertensive rats. In the first experiment, 32 male Sprague-Dawley (SD) rats were randomly divided into four groups (n = 8/group): 3 ADSCs treated groups and normal control (Ctrl). ADSCs were administered through the left jugular vein at 10(5), 10(6) and 10(7) cells, respectively, and a cell density of 10(6)cells/ml was shown to be optimal. The GFP-tagged ADSCs were identified in the lungs and differentiated into endothelial-like cells. In the second experiment, 96 male SD rats were randomly divided into three groups (n = 32/group): Ctrl, MCT-induced pulmonary arterial hypertension (PAH), and PAH treated with ADSCs (ADSCs). Two weeks post-MCT administration, the ADSCs group received 1 × 10(6) ADSCs via the external jugular vein. Compared to PAH rats, mean pulmonary arterial pressure was decreased in rats at 1, 2, and 3 weeks after ADSCs-treatment (18.63 ± 2.15 mmHg versus 24.53 ± 2.90 mmHg; 23.07 ± 2.84 mmHg versus 33.18 ± 2.30 mmHg; 22.98 ± 2.34 mmHg versus 36.38 ± 3.28 mmHg, p < 0.05). Meanwhile, the right heart hypertrophy index (36.2 1 ± 4.27% versus 41.01 ± 1.29%; 39.47 ± 4.02% versus 48.75 ± 2 .13%; 41.02 ± 0.9% versus 50.52 ± 1.49%, p < 0.05, respectively), ratio of wall/lumen thickness, as well as the wall/lumen area were significantly reduced in PAH rats at these time points following ADSCs-treatment, as compared with untreated PAH rats. In summary, ADSCs may colonize the pulmonary arteries, attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling.

Silencing heat shock protein 27 (HSP27) inhibits the proliferation and migration of vascular smooth muscle cells in vitro.

The objective of this study was to examine the role of heat shock protein 27 (HSP27) in proliferation and migration of vascular smooth muscle cells (VSMCs). Three complementary DNA sequences targeting rat HSP27 gene were designed, synthesized, and subcloned into lentiviral vector. The interfering efficiency was detected by reverse transcriptase-polymerase chain reaction and Western blot. Methyl thiazolyl tetrazolium bromide assay was used for examining cell proliferation. F-actin polymerization was detected by FITC-Phalloidin staining using confocal microscopy. Modified Boyden chamber technique was used to assess VSMCs migration. The recombinant lentivirus containing RNAi targeting HSP27 gene significantly inhibited expression of HSP27 at both mRNA and protein levels. The interfering efficiencies of pNL-HSP27-EGFP-1, pNL-HSP27-EGFP-2, and pNL-HSP27-EGFP-3 were 71 %, 77 %, and 43 %, respectively. Reorganization of actin stimulated by PDGF-BB was markedly blocked by pretreatment with pNL-HSP27-EGFP-2. Proliferation and migration rates of VSMCs induced by PDGF-BB were inhibited by 30.8 % and 45.6 %, respectively, by pNL-HSP27-EGFP-2 (all P < 0.01). To conclude, these data indicate that HSP27 may regulate the proliferation, actin reorganization, and the migration of VSMCs. RNAi targeting at HSP27 may be a potential approach for inhibition of cell migration involved in pathogenesis of proliferative vascular diseases.