Rupatadine inhibits colorectal cancer cell proliferation through the PIP5K1A/Akt/CDK2 pathway.

BACKGROUND: Phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (PIP5K1A) acts upstream of the Akt regulatory pathway and is abnormally expressed in many types of malignancies. However, the role and mechanism of PIP5K1A in colorectal cancer (CRC) have not yet been reported. In this study, we aimed to determine the association between PIP5K1A and progression of CRC and assess the efficacy and mechanism by which rupatadine targets PIP5K1A. METHODS: Firstly, expression and function of PIP5K1A in CRC were investigated by human colon cancer tissue chip analysis and cell proliferation assay. Next, rupatadine was screened by computational screening and cytotoxicity assay and interactions between PIP5K1A and rupatadine assessed by kinase activity detection assay and bio-layer interferometry analysis. Next, rupatadine's anti-tumor effect was evaluated by in vivo and in vitro pharmacodynamic assays. Finally, rupatadine's anti-tumor mechanism was explored by quantitative real-time reverse-transcription polymerase chain reaction, western blot, and immunofluorescence. RESULTS: We found that PIP5K1A exerts tumor-promoting effects as a proto-oncogene in CRC and aberrant PIP5K1A expression correlates with CRC malignancy. We also found that rupatadine down-regulates cyclin-dependent kinase 2 and cyclin D1 protein expression by inhibiting the PIP5K1A/Akt/GSK-3ß pathway, induces cell cycle arrest, and inhibits CRC cell proliferation in vitro and in vivo. CONCLUSIONS: PIP5K1A is a potential drug target for treating CRC. Rupatadine, which targets PIP5K1A, could serve as a new option for treating CRC, its therapeutic mechanism being related to regulation of the Akt/GSK-3ß signaling pathway.

CCLOOW: Chinese children's lexicon of oral words.

In this article, we introduce the Chinese Children's Lexicon of Oral Words (CCLOOW), the first lexical database based on animated movies and TV series for 3-to-9-year-old Chinese children. The database computes from 2.7 million character tokens and 1.8 million word tokens. It contains 3920 unique character and 22,229 word types. CCLOOW reports frequency and contextual diversity metrics of the characters and words, as well as length and syntactic categories of the words. CCLOOW frequency and contextual diversity measures correlated well with other Chinese lexical databases, particularly well with that computed from children's books. The predictive validity of CCLOOW measures were confirmed with Grade 2 children's naming and lexical decision experiments. Further, we found that CCLOOW frequencies could explain a considerable proportion in adults' written word recognition, indicating that early language experience might have lasting impacts on the mature lexicon. CCLOOW provides validated frequency and contextual diversity estimates that complements current children's lexical database based on written language samples. It is freely accessible online at https://www.learn2read.cn/ccloow .

Unraveling lexical semantics in the brain: Comparing internal, external, and hybrid language models.

To explain how the human brain represents and organizes meaning, many theoretical and computational language models have been proposed over the years, varying in their underlying computational principles and in the language samples based on which they are built. However, how well they capture the neural encoding of lexical semantics remains elusive. We used representational similarity analysis (RSA) to evaluate to what extent three models of different types explained neural responses elicited by word stimuli: an External corpus-based word2vec model, an Internal free word association model, and a Hybrid ConceptNet model. Semantic networks were constructed using word relations computed in the three models and experimental stimuli were selected through a community detection procedure. The similarity patterns between language models and neural responses were compared at the community, exemplar, and word node levels to probe the potential hierarchical semantic structure. We found that semantic relations computed with the Internal model provided the closest approximation to the patterns of neural activation, whereas the External model did not capture neural responses as well. Compared with the exemplar and the node levels, community-level RSA demonstrated the broadest involvement of brain regions, engaging areas critical for semantic processing, including the angular gyrus, superior frontal gyrus and a large portion of the anterior temporal lobe. The findings highlight the multidimensional semantic organization in the brain which is better captured by Internal models sensitive to multiple modalities such as word association compared with External models trained on text corpora.

Role of TFEB in regulation of the podocyte actin cytoskeleton.

Podocyte injury is linked to the pathogenesis and progression of renal disease. The Transcription Factor EB (TFEB), a master regulator of the autophagy and lysosomal pathways, has been found to exert cell- and tissue-specific biological function. To explore TFEB function and underlying mechanisms in podocytes, a total of 4645 differentially expressed genes (DEGs) were detected in TFEB-knockdown mouse podocytes by transcriptome sequencing. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis showed that, apart from the enrichment in autophagy and lysosomal pathways, DEGs were enriched in cytoskeleton structure (Actin Cytoskeleton, Focal Adhesion, and Adherens Junction), as well as cytoskeleton regulatory molecular signaling (Hippo and Rho GTPase Signaling). In vitro, TFEB knockdown resulted in podocyte cytoskeletal rearrangement, which was disorganized with cortical distribution of actin filaments. Further, TFEB knockdown decreased mRNA and protein levels of Synaptopodin and led to the rearrangement of Synaptopodin. Inhibition of TFEB decreased mRNA levels for proteins involved in actin cytoskeleton dynamics. Moreover, apoptosis was increased by TFEB knockdown in podocyte. In summary, this study initiated a comprehensive analysis of the role of TFEB in podocyte function and the potential underlying mechanisms, and identified a novel role for TFEB in regulation of the podocyte actin cytoskeleton.

Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats.

AIM: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. METHODS: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. RESULTS: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. CONCLUSION: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.

Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and it usually occurs following chronic liver disease. Although some progress has been made in the treatment of HCC, the prognosis of patients with advanced HCC is not optimistic, mainly because of the inevitable development of drug resistance. Therefore, multi-target kinase inhibitors for the treatment of HCC, such as sorafenib, lenvatinib, cabozantinib, and regorafenib, produce small clinical benefits for patients with HCC. It is necessary to study the mechanism of kinase inhibitor resistance and explore possible solutions to overcome this resistance to improve clinical benefits. In this study, we reviewed the mechanisms of resistance to multi-target kinase inhibitors in HCC and discussed strategies that can be used to improve treatment outcomes.

Growth associated protein 43 deficiency promotes podocyte injury by activating the calmodulin/calcineurin pathway under hyperglycemia.

Podocyte injury is a crucial factor in the pathogenesis of diabetic kidney disease (DKD), and finding potential therapeutic interventions that can mitigate podocyte injury holds significant clinical relevance. This study was to elucidate the role of growth associated protein-43(Gap43) in podocyte injury of high glucose (HG). We confirmed the expression of Gap43 in human glomerulus and found that Gap43 expression was downregulated in podocytes of patients with DKD and HG-treated podocytes in vitro. Gap43 knockdown in podocytes promoted podocyte apoptosis, increased migration ability and decreased nephrin expression, while overexpression of Gap43 markedly suppressed HG-induced injury. Moreover, the increased expression and activity of calcineurin (CaN) were also abrogated by overexpression Gap43 in HG. Pretreatment with a typical CaN inhibitor FK506 in Gap43 knockdown podocytes restored the injury. Mechanistically, co-immunoprecipitation experiments suggested that Gap43 could bind to calmodulin (CaM). Pull-down assay further demonstrated that Gap43 and CaM directly interacts with each other via amino acids 30-52 of Gap43 and amino acids 133-197 of CaM. In addition, we also identified Pax5 as potential transcription inhibitor factor mediating Gap43 expression. In conclusion, the study indicated that the Gap43/CaM-CaN pathway may be exploited as a promising therapeutic target for protecting against podocyte injury in high glucose.

Maternal and neonatal blood vitamin D status and neurodevelopment at 24 months of age: a prospective birth cohort study.

BACKGROUND: This study aimed to explore the relationship of 25-hydroxyvitamin D [25(OH)D] in three trimesters and at birth with neurodevelopment at 24 months of age. METHODS: From 2013 to 2016, pregnant women from the Shanghai Birth Cohort in China were recruited for the study. Altogether, 649 mother-infant pairs were included. Serum 25(OH)D was measured with mass spectrometry in three trimesters, and cord blood was divided into deficiency (< 20 and < 12 ng/mL, respectively), insufficiency (20-30 and 12-20 ng/mL, respectively), and sufficiency (≥ 30 and ≥ 20 ng/mL, respectively). Bayley-III scale was used to assess cognitive, language, motor, social-emotional, and adaptive behavior development at 24 months of age. The Bayley-III scores were grouped into quartiles, and scores within the lowest quartile were defined as suboptimal development. RESULTS: After adjusting for confounding factors, cord blood 25(OH)D in the sufficient group was positively correlated with cognitive [ß = 11.43, 95% confidence interval (CI) = 5.65-17.22], language (ß = 6.01, 95% CI = 1.67-10.3), and motor scores (ß = 6.43, 95% CI = 1.73-11.1); cord blood 25(OH)D in the insufficient group was also positively correlated with cognitive scores (ß = 9.42, 95% CI = 3.74-15.11). Additionally, sufficient vitamin D status in the four periods and persistent 25(OH)D ≥ 30 ng/mL throughout pregnancy were associated with a lower risk of suboptimal cognitive development in adjusted models, although the effects were attenuated after applying the false discovery rate adjustment. CONCLUSIONS: Cord blood 25(OH)D ≥ 12 ng/mL has a significant positive association with cognitive, language, and motor development at 24 months of age. Sufficient vitamin D status in pregnancy might be a protective factor for suboptimal neurocognition development at 24 months of age.

Aberrant NAD synthetic flux in podocytes under diabetic conditions and effects of indoleamine 2,3-dioxygenase on promoting de novo NAD synthesis.

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme in the kidney. The first step in de novo NAD synthesis is regulated by indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme. Here, we investigated NAD synthetic flux and NAD levels in podocytes under diabetic conditions. We also studied the effects of IDO overexpression on NAD synthetic flux and high glucose (HG)-induced podocyte injury. NAD synthetases in the de novo, Preiss-Handler and salvage pathways were analyzed using in vivo single-nucleus RNA sequencing datasets (GSE131882) of control and diabetic kidney disease (DKD). The mRNA levels of these NAD synthetases were measured in vitro in HG-treated podocytes. The effects of IDO on NAD synthesis were examined by transducing cultured podocytes with an adenovirus encoding IDO, and apoptosis, podocyte markers and mobility were investigated. Cellular transcriptome analysis revealed that control podocytes had relatively low levels of NAD synthetases. In DKD podocytes, de novo NAD synthetase levels were further downregulated. IDO levels were virtually undetectable and did not increase in DKD. In vitro experiments confirmed aberrant de novo NAD synthetic flux and decreased IDO levels in HG-treated podocytes. Overexpression of IDO promoted NAD de novo synthesis, reduced NAD-bypass metabolic enzyme, increased NAD content and recovered podocyte injury markers under diabetic conditions. Taken together, our findings suggest that the de novo NAD synthetic flux is aberrant in DKD, and IDO promotes de novo NAD synthesis and NAD levels, as well as alleviates injury in HG-treated podocytes.

CCLOWW: A grade-level Chinese children's lexicon of written words.

In this article, we present the Chinese Children's Lexicon of Written Words (CCLOWW), the first grade-level database that provides frequency statistics of simplified Chinese characters and words for children. The database computes from a corpus of 34,671,424 character tokens and 22,427,010 word tokens (including single- and multicharacter words), extracted from 2131 books. It contains 6746 different character types and 153,079 different word types. CCLOWW provides several frequency indices of simplified Chinese for three grade levels (grade 2 and below, grades 3-4, grades 5-6) to profile children's experience with written Chinese in and outside of school. We describe in this article the distributions of frequency and contextual diversity of the characters and words, as well as word length and syntactic categories of the words in the corpus and the subcorpora. We also report results of correlation analyses with other written corpora and of several naming and lexicon decision experiments. The findings suggest that CCLOWW frequency measures correlate well with other corpora. Importantly, they could reliably predict children's and adults' naming and lexical decision performances. They could also explain variance in adults' visual word recognition, in addition to frequency measures computed in an adult corpus, indicating that early print exposure might influence readers' lexical processing later on beyond an age of acquisition effect. CCLOWW will help researchers in language processing and development as well as educators with selecting language materials appropriate for children's developmental stages. The database is freely available online at https://www.learn2read.cn/database/ .

In silico characterization of bla NDM-harboring plasmids in Klebsiella pneumoniae.

Klebsiella pneumoniae is a primary culprit of antibiotic-resistant nosocomial infections worldwide, and infections caused by NDM-producing strains are a major threat due to limited therapeutic options. The majority of bla NDM cases occur on plasmids; therefore, we explored the relationships between plasmids and bla NDM genes in K. pneumoniae by analyzing the variants of bla NDM, replicon types, conjugative transfer regions of 171 bla NDM-harboring plasmids from 4,451 K. pneumoniae plasmids. Of the nine identified bla NDM variants, bla NDM-1 (73.68%) and bla NDM-5 (16.37%) were the most dominant. Over half of the bla NDM-harboring plasmids of K. pneumoniae were classified into IncF plasmids. IncX3 single-replicon plasmids (46-57 kb) carried genes encoding relaxases of the MOBP family, T4CP genes of the VirD4/TraG subfamily, and VirB-like T4SS gene clusters, which were mainly geographically distributed in China. We found 10 bla NDM-harboring IncN plasmids (38.38-63.05 kb) carrying the NW-type origin of transfer (oriT) regions, genes coding for relaxases of MOBF family, genes encoding T4CPs of the TrwB/TraD subfamily, and Trw-like T4SS gene clusters, which were also mainly geographically distributed in China. Moreover, we identified 21 IncC plasmids carrying bla NDM-1 (140.1-329.2 kb), containing the A/C-type oriTs, genes encoding relaxases of MOBH family, genes encoding T4CPs belonging to TrwB/TraD subfamily, and Tra_F-like T4SS gene clusters. The bla NDM-harboring IncC plasmids were widely geographically distributed all over the world, mainly in the United States, China and Viet Nam. These findings enhance our understanding of the diversity of bla NDM-harboring plasmids in K. pneumoniae.

A Novel circRNA hsa_circRNA_002178 as a Diagnostic Marker in Hepatocellular Carcinoma Enhances Cell Proliferation, Invasion, and Tumor Growth by Stabilizing SRSF1 Expression.

Background: Previous research studies have shown that the elevation of circular RNA (circRNA), hsa_circRNA_002178, was associated with the poor prognosis of breast cancer and colorectal cancer, while its molecular mechanisms underlying the effects on hepatocellular carcinoma (HCC) are still elusive. Methods: The microarray dataset GSE97332 was obtained from the Gene Expression Omnibus (GEO) database and calculated by using the GEO2R tool to identify differentially expressed circRNAs. Differentially expressed hsa_circRNA_002178, in 7 HCC tissue samples and paracancerous tissues, as well as in HCC cell lines and normal hepatocytes, was checked by RT-qPCR. Cell proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT)-related proteins were tested in hsa_circRNA_002178-overexpressed or hsa_circRNA_002178-knocked down HCC cells. Subsequently, we identified whether hsa_circRNA_002178 binds to serine- and arginine-rich splicing factor 1 (SRSF1) and then analyzed their function in regulating HCC cell behavior. The effect on HCC cell xenograft tumor growth was observed by the knockdown of hsa_circRNA_002178 in vivo. Results: GEO2R-based analysis displayed that hsa_circRNA_002178 was upregulated in HCC tissues. Overexpression or knockdown of hsa_circRNA_002178 encouraged or impeded HCC cell proliferation, migration, invasion, and EMT program. Mechanically, hsa_circRNA_002178 bound to SRSF1 3'-untranslated region (UTR) and stabilized its expression. SRSF1 weakening eliminated the effects of pcDNA-hsa_circRNA_002178 on cell malignant behavior. Finally, the knockdown of hsa_circRNA_002178 was confirmed to prevent xenograft tumor growth. Conclusions: hsa_circRNA_002178 overexpression encouraged the stability of SRSF1 mRNA expression, and it may serve as an upstream factor of SRSF1 for the diagnosis of HCC.

Analysis of the prevalence, risk factors, and clinical characteristics of osteoporosis in patients with essential hypertension.

BACKGROUND: The present study investigated the prevalence of osteoporosis (OP) among patients with essential hypertension (EH) in the Changchun community and analysed the correlation between EH and OP. METHODS: The study included 425 subjects with EH and 425 age- and sex-matched healthy controls. Bone mineral density (BMD) and serum creatinine (CR) levels were measured, and the subjects' current EH and OP statuses were surveyed to analyse the correlation between EH and OP. RESULTS: The EH group exhibited lower BMD and a higher rate of having OP than the control group, and this difference was statistically significant (p < 0.05). A significant sex difference in the BMD T-score was observed among the subjects (male: - 1.19 ± 1.55, female: - 1.70 ± 1.34). In both the EH group and the control group, the rate of having OP in females was greater than that in males. However, the OP prevalence among subjects with EH varied significantly by age, body weight, fracture history, nocturnal urination frequency, depression and anxiety status, duration of hypertension, and antihypertensive medication use (p < 0.05). Two-way analysis of variance suggested an effect of the interaction between different EH statuses and bone mass conditions on the serum CR values (F = 3.584, p = 0.028, bias η2 = 0.008). CONCLUSIONS: The prevalence of OP and low BMD were significantly higher among subjects with EH than among healthy controls. Additionally, the findings indicate that age, weight, fracture history, nocturnal urination frequency, depression and anxiety, duration of hypertension and antihypertensive drug use may be correlated to having OP in EH subjects, requiring further studies. Moreover, serum CR levels in subjects with different bone mass profiles were strongly influenced by the presence or absence of EH, and the serum CR levels differed significantly with the interaction of these two factors.

Palladium-catalyzed regioselective hydrosulfonylation of allenes with sulfinic acids.

An atom-economic method of preparing allylic sulfones via hydrosulfonylation of allenes with sulfinic acids under Pd(0)-catalysis was reported. This process has a high degree of regio- and stereoselectivity, and provides the target product with a moderate to excellent yield. A wide range of nitrogen- or oxygen-containing linear E-allylic sulfones have been synthesized. With the support of experimental research, a possible mechanism was proposed.

Association of Blood Biochemical Indexes and Antibiotic Exposure With Severe Immune-related Adverse Events in Patients With Advanced Cancers Receiving PD-1 Inhibitors.

Some patients with cancer treated with programmed death 1 (PD-1) inhibitors experience immune-related severe adverse events (ir-SAEs), however, predictors are limited. The objective was to identify clinicopathologic features that may be associated with a higher ir-SAE risk. This was a nested case-control study. After screening a total of 832 PD-1 inhibitor-treated patients, we identified 42 ir-SAE cases. According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, ir-SAEs were defined as grade ≥3 toxic effects associated with immunotherapy. A total of 126 controls were matched. The crude and adjusted risks of ir-SAEs were estimated by odds ratio (ORs) and 95% CIs using multivariate logistic regression models. Baseline neutrophil-to-lymphocyte ratio (NLR) [per SD increment-adjusted (aOR): 1.16], lactate dehydrogenase (LDH) ≥245 U/L (aOR: 2.39), and antibiotic exposure (aOR: 4.39) were associated with a higher risk of ir-SAEs. When NLR was categorized in 3 groups, significantly higher risks of ir-SAEs (aOR: 4.95) were found in participants in group 3 (>6) than in those in group 1 (<3). Furthermore, NLR (per SD increment-adjusted hazard ratio:1.08) were also significantly associated with shorter overall survival (OS). Baseline LDH ≥245 U/L and antibiotic exposure were no significant association with OS. In conclusion, ir-SAEs were associated between baseline NLR, LDH ≥245 U/L and antibiotic exposure. Lower NLR was correlated with longer OS for cancer.

Comprehensive analysis of immune-related prognostic genes in the tumour microenvironment of hepatocellular carcinoma.

BACKGROUND: The mortality rate of hepatocellular carcinoma (HCC) remains high worldwide despite surgery and chemotherapy. Immunotherapy is a promising treatment for the rapidly expanding HCC spectrum. Therefore, it is necessary to further explore the immune-related characteristics of the tumour microenvironment (TME), which plays a vital role in tumour initiation and progression. METHODS: In this research, 866 immune-related differentially expressed genes (DEGs) were identified by integrating the DEGs of samples from The Cancer Genome Atlas (TCGA)-HCC dataset and the immune-related genes from databases (InnateDB; ImmPort). Afterwards, 144 candidate prognostic genes were defined through weighted gene co-expression network analysis (WGCNA). RESULTS: Seven immune-related prognostic DEGs were identified using the L1-penalized least absolute shrinkage and selection operator (LASSO) Cox proportional hazards (PH) model, and the ImmuneRiskScore model was constructed on this basis. The prognostic index of the ImmuneRiskScore model was then validated in the relevant dataset. Patients were divided into high- and low-risk groups according to the ImmuneRiskScore. Differences in the immune cell infiltration of patients with different ImmuneRiskScore values were clarified, and the correlation of immune cell infiltration with immunotherapy biomarkers was further explored. CONCLUSION: The ImmuneRiskScore of HCC could be a prognostic marker and can reflect the immune characteristics of the TME. Furthermore, it provides a potential biomarker for predicting the response to immunotherapy in HCC patients.

High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy.

Mitochondrial dysfunction and impaired Ca2+ handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca2+ release-activated calcium channel protein 1) calcium channel is important for the increase in Ca2+ entry into cardiomyocytes. We aimed to explore the mechanism of Drp1 and Orai1 in cardiomyocyte hypertrophy caused by high glucose (HG). We found that Zucker diabetic fat rats induced by administration of a high-fat diet develop cardiac hypertrophy and impaired cardiac function, accompanied by the activation of mitochondrial dynamics and calcium handling pathway-related proteins. Moreover, HG induces cardiomyocyte hypertrophy, accompanied by abnormal mitochondrial morphology and function, and increased Orai1-mediated Ca2+ influx. Mechanistically, the Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) prevents cardiomyocyte hypertrophy induced by HG by reducing phosphorylation of Drp1 at serine 616 (S616) and increasing phosphorylation at S637. Inhibition of Orai1 with single guide RNA (sgOrai1) or an inhibitor (BTP2) not only suppressed Drp1 activity and calmodulin-binding catalytic subunit A (CnA) and phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) expression but also alleviated mitochondrial dysfunction and cardiomyocyte hypertrophy caused by HG. In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca2+ entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1-Drp1 axis is a novel target for treating DCM.

Evaluation of Endovascular Therapy Combined with Bowel Resection Treatment on Patients with Acute Mesenteric Venous Thrombosis.

BACKGROUND: This retrospective study aims to investigate the effects of the endovascular and surgical strategy for treating patients with acute mesenteric venous thrombosis (AMVT). METHODS: We retrospectively studied 68 patients with AMVT who underwent treatment in Jinling Hospital during the period from January 2009 to December 2014. The mean age was 45 ± 12 years (range 20-72 years). All patients were treated by using the combined treatment that included endovascular treatment, damage control surgery, surgical intensive care, and intestinal rehabilitation treatment. Clinical outcomes and complications were compared during the follow-up period. RESULTS: All the 68 cases received anticoagulant treatment. However, only 24 received the endovascular intervention, 19 received surgical resection, and 25 patients received endovascular treatment combined with bowel resection. The overall mortality rate was 2.94% (2 cases). Bowel resection range significantly decreased (92 ± 14 cm vs. 162 ± 27 cm, t = -2.377, P = 0.022) in the combination therapy group, when compared with the surgery group. During the 1-year follow-up period, 4 cases suffered from short bowel syndrome. CONCLUSIONS: Our study indicates that AMVT can be successfully treated with the early improvement of intestinal blood circulation. Further, our applied combined approach showed a favorable outcome in mesenteric thrombosis patients and reduced the mortality rate by improving the prognosis significantly.

Irisin functions to inhibit malignant growth of human pancreatic cancer cells via downregulation of the PI3K/AKT signaling pathway.

INTRODUCTION: Irisin is a newly identified cytokine that has gained increasing attention because of its potential therapeutic applications in metabolic diseases and human cancers. Recently, accumulating evidence indicates that irisin plays an important role in the development and metastasis of various tumors. The aim of this study was to evaluate the effects and underlying mechanisms of irisin on malignant growth of pancreatic cancer cells. MATERIALS AND METHODS: The anti-proliferative effect of irisin was examined using the CCK-8 assay. Irisin-induced apoptosis was determined by the annexin V-FITC/PI staining assay. The effects of irisin on cell migration and invasion were assessed using the scratch-induced wound healing assay and transwell invasion assay, respectively. The expression and phosphorylation of signaling proteins were detected by Western blot analysis. RESULTS: Our results showed that irisin inhibited cell proliferation and induced apoptosis of pancreatic cancer cells in a dose-dependent manner. In addition, irisin decreased the migration and invasion of pancreatic cancer cells. Finally, Western blot analysis revealed that irisin downregulated the PI3K/AKT signaling pathway. CONCLUSION: Our findings suggest that irisin is a novel therapeutic agent for pancreatic cancer.

Phonetic radicals, not phonological coding systems, support orthographic learning via self-teaching in Chinese.

According to the self-teaching hypothesis (Share, 1995), phonological decoding is fundamental to acquiring orthographic representations of novel written words. However, phonological decoding is not straightforward in non-alphabetic scripts such as Chinese, where words are presented as characters. Here, we present the first study investigating the role of phonological decoding in orthographic learning in Chinese. We examined two possible types of phonological decoding: the use of phonetic radicals, an internal phonological aid, andthe use of Zhuyin, an external phonological coding system. Seventy-three Grade 2 children were taught the pronunciations and meanings of twelve novel compound characters over four days. They were then exposed to the written characters in short stories, and were assessed on their reading accuracy and on their subsequent orthographic learning via orthographic choice and spelling tasks. The novel characters were assigned three different types of pronunciation in relation to its phonetic radical - (1) a pronunciation that is identical to the phonetic radical in isolation; (2) a common alternative pronunciation associated with the phonetic radical when it appears in other characters; and (3) a pronunciation that is unrelated to the phonetic radical. The presence of Zhuyin was also manipulated. The children read the novel characters more accurately when phonological cues from the phonetic radicals were available and in the presence of Zhuyin. However, only the phonetic radicals facilitated orthographic learning. The findings provide the first empirical evidence of orthographic learning via self-teaching in Chinese, and reveal how phonological decoding functions to support learning in non-alphabetic writing systems.