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Aims Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin–ASK1 pathway, not the classical calcineurin–nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis. Methods and results Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages. Conclusion Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.

Chrysanthemum morifolium is a well-known edible medicinal plant in Asia and some other regions. Content of selenium in Se-enriched C. morifolium (SeCM) is significantly higher than that in traditional C. morifolium (non-Se-enriched C. morifolium, TCM). In order to understand health effects of SeCM, its chemical composition, lifespan-prolonging activities, and impacts on antioxidant defense-related gene expressions of model organism D. melanogaster were systematically studied. A total of eight phenols, including luteolin-7-O-glucoside, linarin, luteolin, apigenin, diosmetin, acacetin, 3-caffeoylquinic acid and 4,5-dicaffeoylquinic acid, were identified in SeCM extract. Compared with TCM, SeCM exhibited superior antioxidant properties. Intake of SeCM dramatically reduced malondialdehyde level and increased activities of endogenous antioxidant enzymes in fruit flies. SeCM was able to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase and hydrogen peroxide catalase, and extend lifespans of fruit flies. Comparatively high antioxidant capacities and lifespan-prolonging activities of SeCM might be attributed to its abundant phenols and selenium, which probably ameliorated accumulation of free radicals and susceptibility to oxidative stress. These findings provide clues on further exploitation and utilization of Se-enriched C. morifolium. PRACTICAL APPLICATIONS: Chrysanthemum morifolium has been used for nutraceutical and curative purposes in China for thousands of years. Se-enriched C. morifolium typically contains more selenium than traditional C. morifolium, and is widely consumed in Asia and some other regions. Selenium is an essential micronutrient for humans, and selenium deficiency may result in several diseases such as myocardial infarction. SeCM is one of important selenium supplements. In this study, SeCM was found to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and hydrogen peroxide catalase, and extend lifespans of experimental animals. These results provide supporting information for developing SeCM-based functional foods with distinct health benefits.

Li-Jun Yan,1,* Fei-Ran Zhang,2,* Yu-Ran Zeng,1 Yang Zheng2 1Department of Hemodialysis, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong Province, People’s Republic of China; 2Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang ZhengDepartment of General Surgery, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Jinping District, Shantou City, 515041, Guangdong Province, People’s Republic of ChinaTel +86-754-88905256Fax +86-754-88905320Email stenoname@163.comAim: A transition toward high serum folate concentrations has been noticed following the mandatory folate fortification. To explore this further, we studied the relationship between folate and health outcomes in population with chronic kidney disease (CKD).Methods: We retrospectively explored the relationships between serum folate and risk of all-cause death in this population. We analyzed data of 2142 subjects with CKD who participated in the National Health and Nutrition Examination Survey (NHANES) 1999– 2006. Vital status was followed through December 31, 2006.Results: Cox regression was used to estimate hazard ratios (HRs) of mortality for individuals with serum folate in rest quintiles compared with individuals with the fourth quintile. After an average follow-up of 57.4 months with 157 deaths recorded, a reversed J-shaped association was revealed after conducting multivariable adjustment. The mortality rate in population with lower and higher folate levels were 8.29% and 12.67%, respectively, and the corresponding adjusted HRs were 2.41 (95% confidence interval, CI=1.32– 4.40) and 2.10 (1.20– 3.70). Kaplan–Meier curve showed survival benefits for the fourth quintile of serum folate as compared to the first and fifth quintile.Conclusion: Serum folate concentrations may influence all-cause mortality in a non-linear pattern in the CKD population. It is reasonable to recommend periodic surveillance in the CKD population to maintain the serum folate concentration in an appropriate level.Keywords: serum folate, mortality, chronic kidney disease; CKD, National Health and Nutrition Examination Survey; NHANES, cohort study

Purpose To evaluate the diagnostic value of combining the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) or lymphocyte-monocyte ratio (LMR) with carcinoembryonic antigen (CEA) in patients with colorectal cancer (CRC). Patients and methods The diagnostic performance of inflammatory makers and CEA was evaluated in cohort 1 (664 patients with CRC, 336 patients with colorectal polyps and 664 healthy controls) and validated in cohort 2 (87 patients with CRC and 87 healthy controls) by using receiver operating characteristic curve analysis. Results In cohort 1, the NLR, PLR and CEA levels were significantly higher, while the LMR was markedly lower in patients with CRC than in healthy controls. The PLR and LMR were significantly associated with invasion depth and lymph node metastasis. Moreover, significant differences in the PLR and LMR were observed between patients with stage I/II CRC and healthy or polyp controls and those with stage III/IV CRC. Using the NLR, PLR or LMR with CEA resulted in a significantly larger area under the curve (AUC) than any of them used alone. Combining the PLR and LMR with CEA exhibited the best diagnostic value for CRC (AUC=0.892). The AUCs of this combination were 0.864 and 0.783 for distinguishing stage I/II CRC from healthy and polyp controls, respectively. When we used the same cut-off values to assess the diagnostic ability of these markers in cohort 2, similar results were observed, and the PLR, LMR and CEA combination also showed the highest accuracy (AUC=0.936). Conclusion Combining inflammatory cell ratios with CEA could improve the diagnostic efficacy for CRC patients. The combination of the PLR and LMR with CEA might be a valuable indicator in the early detection and monitoring of CRC patients.

Gastric cancer (GC) is one of the most common and lethal cancers worldwide. The Nudix hydroxylase (NUDT) genes have been reported to play notable roles in tumor progression. However, the role of NUDT10 in GC has not been reported. In this study, we investigated the expression of NUDT10 in GC and its association with clinicopathological characteristics. Quantitative real-time polymerase chain reaction and analyses of The Cancer Genome Atlas and Human Protein Atlas databases were performed to determine NUDT10 mRNA and protein expression. Receiver operating characteristic curve analysis was used to assess the diagnostic value of NUDT10 in patients with GC. We used Cox regression and the Kaplan–Meier method to assess the correlations between clinicopathological factors and survival outcomes of patients with GC. Gene set enrichment analysis (GSEA) was performed to identify the underlying signaling pathways. NUDT10 mRNA and protein expression was significantly lower in GC tissues compared to normal tissues. Interestingly, higher NUDT10 expression was correlated with advanced tumor stage, deeper local invasion, and worse survival outcomes. Patients with higher NUDT10 expression had a significantly worse prognosis than those with lower NUDT10 expression. Multivariate analysis showed that high NUDT10 expression was an independent predictor of survival outcome. Several pathways, including mismatch repair, nucleotide excision repair, extracellular matrix receptor interaction, and cancer signaling, were identified as enriched pathways in GC through GSEA. To our knowledge, this study is the first to characterize NUDT10 expression in GC. Our study demonstrates that NUDT10 is a promising independent biomarker for GC prognosis.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease, and the mechanisms underpinning its pathogenesis have not been completely established. Transmembrane member 16A (TMEM16A), a component of the Ca2+‐activated chloride channel (CaCC), has recently been implicated in metabolic events. Herein, TMEM16A is shown to be responsible for CaCC activation in hepatocytes and is increased in liver tissues of mice and patients with NAFLD. Hepatocyte‐specific ablation of TMEM16A in mice ameliorates high‐fat diet‐induced obesity, hepatic glucose metabolic disorder, steatosis, insulin resistance, and inflammation. In contrast, hepatocyte‐specific TMEM16A transgenic mice exhibit the opposite phenotype. Mechanistically, hepatocyte TMEM16A interacts with vesicle‐associated membrane protein 3 (VAMP3) to induce its degradation, suppressing the formation of the VAMP3/syntaxin 4 and VAMP3/synaptosome‐associated protein 23 complexes. This leads to the impairment of hepatic glucose transporter 2 (GLUT2) translocation and glucose uptake. Notably, VAMP3 overexpression restrains the functions of hepatocyte TMEM16A in blocking GLUT2 translocation and promoting lipid deposition, insulin resistance, and inflammation. In contrast, VAMP3 knockdown reverses the beneficial effects of TMEM16A downregulation. This study demonstrates a role for TMEM16A in NAFLD and suggests that inhibition of hepatic TMEM16A or disruption of TMEM16A/VAMP3 interaction may provide a new potential therapeutic strategy for NAFLD., Transmembrane member 16A (TMEM16A) is an essential component of the hepatocyte calcium‐activated chloride channel and is increased in livers with hepatic steatosis. It interacts with vesicle‐associated membrane protein 3 to disrupt soluble Nethylmaleimide‐sensitive factor attachment protein receptors formation, thereby limiting glucose transporter 2 translocation and hepatic glucose uptake. Liver‐specific deficiency of TMEM16A ameliorates glucose metabolic disorder and nonalcoholic fatty liver disease.

Background Genomic micro-satellites are the genomic regions that consist of short and repetitive DNA motifs. Estimating the length distribution and state of a micro-satellite region is an important computational step in cancer sequencing data pipelines, which is suggested to facilitate the downstream analysis and clinical decision supporting. Although several state-of-the-art approaches have been proposed to identify micro-satellite instability (MSI) events, they are limited in dealing with regions longer than one read length. Moreover, based on our best knowledge, all of these approaches imply a hypothesis that the tumor purity of the sequenced samples is sufficiently high, which is inconsistent with the reality, leading the inferred length distribution to dilute the data signal and introducing the false positive errors. Results In this article, we proposed a computational approach, named ELMSI, which detected MSI events based on the next generation sequencing technology. ELMSI can estimate the specific length distributions and states of micro-satellite regions from a mixed tumor sample paired with a control one. It first estimated the purity of the tumor sample based on the read counts of the filtered SNVs loci. Then, the algorithm identified the length distributions and the states of short micro-satellites by adding the Maximum Likelihood Estimation (MLE) step to the existing algorithm. After that, ELMSI continued to infer the length distributions of long micro-satellites by incorporating a simplified Expectation Maximization (EM) algorithm with central limit theorem, and then used statistical tests to output the states of these micro-satellites. Based on our experimental results, ELMSI was able to handle micro-satellites with lengths ranging from shorter than one read length to 10kbps. Conclusions To verify the reliability of our algorithm, we first compared the ability of classifying the shorter micro-satellites from the mixed samples with the existing algorithm MSIsensor. Meanwhile, we varied the number of micro-satellite regions, the read length and the sequencing coverage to separately test the performance of ELMSI on estimating the longer ones from the mixed samples. ELMSI performed well on mixed samples, and thus ELMSI was of great value for improving the recognition effect of micro-satellite regions and supporting clinical decision supporting. The source codes have been uploaded and maintained at https://github.com/YixuanWang1120/ELMSI for academic use only.

Chloride (Cl(−)) homeostasis is of great significance in cardiovascular system. Serum Cl(−) level is inversely associated with the mortality of patients with heart failure. Considering the importance of angiogenesis in the progress of heart failure, this study aims to investigate whether and how reduced intracellular Cl(−) concentration ([Cl(−)](i)) affects angiogenesis. Human umbilical endothelial cells (HUVECs) were treated with normal Cl(−) medium or low Cl(−) medium. We showed that reduction of [Cl(−)](i) (from 33.2 to 16.18 mM) inhibited HUVEC proliferation, migration, cytoskeleton reorganization, tube formation, and subsequently suppressed angiogenesis under basal condition, and VEGF stimulation or hypoxia treatment. Moreover, VEGF-induced NADPH-mediated reactive oxygen species (ROS) generation and VEGFR2 axis activation were markedly attenuated in low Cl(−) medium. We revealed that lowering [Cl(−)](i) inhibited the expression of the membrane-bound catalytic subunits of NADPH, i.e., p22phox and Nox2, and blunted the translocation of cytosolic regulatory subunits p47phox and p67phox, thereby restricting NADPH oxidase complex formation and activation. Furthermore, reduced [Cl(−)](i) enhanced ROS-associated protein tyrosine phosphatase 1B (PTP1B) activity and increased the interaction of VEGFR2 and PTP1B. Pharmacological inhibition of PTP1B reversed the effect of lowering [Cl(−)](i) on VEGFR2 phosphorylation and angiogenesis. In mouse hind limb ischemia model, blockade of Cl(−) efflux using Cl(−) channel inhibitors DIDS or DCPIB (10 mg/kg, i.m., every other day for 2 weeks) significantly enhanced blood flow recovery and new capillaries formation. In conclusion, decrease of [Cl(−)](i) suppresses angiogenesis via inhibiting oxidase stress-mediated VEGFR2 signaling activation by preventing NADPH oxidase complex formation and promoting VEGFR2/PTP1B association, suggesting that modulation of [Cl(−)](i) may be a novel therapeutic avenue for the treatment of angiogenic dysfunction-associated diseases.

Background The aim of this study was to investigate the differences in oncological outcome and inflammatory biomarkers between right‐sided colon cancer (RCC) and left‐sided colorectal cancer (LCRC). Methods We retrospectively analyzed 339 patients with stage I‐III colorectal cancer, including 125 RCC patients and 214 LCRC patients, who underwent radical resection from January 2012 to January 2014. Comparison of neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR) between RCC and LCRC was evaluated using the Mann‐Whitney U test. Overall survival (OS) and disease‐free survival (DFS) were analyzed using Kaplan‐Meier analysis and compared using the log‐rank test. Univariate and multivariate Cox regression analyses were used to identify the prognostic value of inflammatory markers. Results Patients with RCC had higher NLR (P = .002) and PLR (P

Rationale: Transmembrane member 16A (TMEM16A) is a component of calcium-activated chloride channels that regulate vascular smooth muscle cell (SMC) proliferation and remodeling. Autophagy, a highly conserved cellular catabolic process in eukaryotes, exerts important physiological functions in vascular SMCs. In the current study, we investigated the relationship between TMEM16A and autophagy during vascular remodeling. Methods: We generated a transgenic mouse that overexpresses TMEM16A specifically in vascular SMCs to verify the role of TMEM16A in vascular remodeling. Techniques employed included immunofluorescence, electron microscopy, co-immunoprecipitation, and Western blotting. Results: Autophagy was activated in aortas from angiotensin II (AngII)-induced hypertensive mice with decreased TMEM16A expression. The numbers of light chain 3B (LC3B)-positive puncta in aortas correlated with the medial cross-sectional aorta areas and TMEM16A expression during hypertension. SMC-specific TMEM16A overexpression markedly inhibited AngII-induced autophagy in mouse aortas. Moreover, in mouse aortic SMCs (MASMCs), AngII-induced autophagosome formation and autophagic flux were blocked by TMEM16A upregulation and were promoted by TMEM16A knockdown. The effect of TMEM16A on autophagy was independent of the mTOR pathway, but was associated with reduced kinase activity of the vacuolar protein sorting 34 (VPS34) enzyme. Overexpression of VPS34 attenuated the effect of TMEM16A overexpression on MASMC proliferation, while the effect of TMEM16A downregulation was abrogated by a VPS34 inhibitor. Further, co-immunoprecipitation assays revealed that TMEM16A interacts with p62. TMEM16A overexpression inhibited AngII-induced p62-Bcl-2 binding and enhanced Bcl-2-Beclin-1 interactions, leading to suppression of Beclin-1/VPS34 complex formation. However, TMEM16A downregulation showed the opposite effects. Conclusion: TMEM16A regulates the four-way interaction between p62, Bcl-2, Beclin-1, and VPS34, and coordinately prevents vascular autophagy and remodeling.

The development of nephrotoxicity largely limits the clinical use of chemotherapy. MiRNAs are able to target various genes and involved in the regulation of diverse cellular processes, including cell apoptosis and death. Our study showed that miR-181a expression was significantly increased after 5-fluorouracil (5-FU) treatment in renal mesangial cells and kidney tissue, which was associated with decreased baculoviral inhibition of apoptosis protein repeat-containing 6 (BIRC6) expression and increased apoptotic rate. Enforced miR-181a expression enhanced 5-FU-induced p53-dependent mitochondrial apoptosis, including declined Bcl-2/Bax ratio, loss of mitochondrial membrane potential, cytochrome c release, and caspase-9 and caspase-3 activation. However, inhibition of miR-181a was associated with reduced p53-mediated mitochondrial apoptosis induced by 5-FU. Moreover, miR-181a increased BIRC6 downstream gene p53 protein expression and transcriptional activity by reducing ubiquitin-mediated protein degradation. We found that miR-181a directly targeted 3′-UTR of BIRC6 mRNA and negatively regulated BIRC6 expression. In vivo study, knockdown of miR-181a with adeno-associated virus harboring miR-181a-tough decoy attenuated 5-FU-induced renal cell apoptosis, inflammation and kidney injury. In conclusion, these results demonstrate that miR-181a increases p53 protein expression and transcriptional activity by targeting BIRC6 and promotes 5-FU-induced apoptosis in mesangial cells. Inhibition of miR-181a ameliorates 5-FU-induced nephrotoxicity, suggesting that miR-181a may be a novel therapeutic target for nephrotoxicity treatment during chemotherapy.

Orai1-dependent Ca2+ entry plays an essential role in inflammatory response through regulating T cell and macrophage activation and neutrophil infiltration. However, whether Orai1 Ca2+ entry contributes to endothelial activation, one of the early steps of vascular inflammation, remains elusive. In the present study, we observed that knockdown of Orai1 reduced, whereas overexpression of Orai1 potentiated, TNFα-induced expression of adhesion molecules such as ICAM-1 and VCAM-1 in HUVECs, and subsequently blocked adhesion of monocyte to HUVECs. In vivo, Orai1 downregulation attenuated TNFα-induced ICAM-1 and VCAM-1 expression in mouse aorta and the levels of pro-inflammatory cytokines in the serum. In addition, Orai1 knockdown also dramatically decreased the expression of pro-inflammatory cytokines and neutrophil infiltration in the lung after TNFα treatment, and thus protected lung tissue injury. Notably, among all isoforms of nuclear factor of activated T cells (NFATs), TNFα only triggered NFATc4 nuclear accumulation in HUVECs. Knockdown of Orai1 or inhibition of calcineurin prevented TNFα-induced NFATc4 nuclear translocation and reduced ICAM-1 and VCAM-1 expression in HUVECs. Overexpression of NFATc4 further enhanced ICAM-1 and VCAM-1 expression induced by TNFα. Our study demonstrates that Orai1-Ca2+-calcineurin-NFATc4 signaling is an essential inflammatory pathway required for TNFα-induced endothelial cell activation and vascular inflammation. Therefore, Orai1 may be a potential therapeutic target for treatment of inflammatory diseases.

Numerical simulation of cooling roller in planar flow melt spinning process was accomplished using CFD software, Get cooling water flow characteristics and the cooling roller wall temperature and pressure distribution with cooling roller rotation speed range 0-50r/s, The results show that: heat transfer coefficient h and Nusselt number between the cooling water and the inner wall surface of a copper roller creases with the increase of the cooling roller rotate speed, but the increase rate is relatively small; Effect of cooling roller rotate speed on inner wall pressure is large, cooling roller inner wall pressure increases with the rotation speed increase. This study provided a theoretical reference of amorphous cooling roller design and optimization.

MicroRNAs have emerged as important post-transcriptional regulators of gene expression and are involved in diverse diseases and cellular process. Decreased expression of miR-181a has been observed in the patients with coronary artery disease, but its function and mechanism in atherogenesis is not clear. This study was designed to determine the roles of miR-181a-5p, as well as its passenger strand, miR-181a-3p, in vascular inflammation and atherogenesis. We found that the levels of both miR-181a-5p and miR-181a-3p are decreased in the aorta plaque and plasma of apoE−/− mice in response to hyperlipidemia and in the plasma of patients with coronary artery disease. Rescue of miR-181a-5p and miR-181a-3p significantly retards atherosclerotic plaque formation in apoE−/− mice. MiR-181a-5p and miR-181a-3p have no effect on lipid metabolism but decrease proinflammatory gene expression and the infiltration of macrophage, leukocyte and T cell into the lesions. In addition, gain-of-function and loss-of-function experiments show that miR-181a-5p and miR-181a-3p inhibit adhesion molecule expression in HUVECs and monocytes-endothelial cell interaction. MiR-181a-5p and miR-181a-3p cooperatively receded endothelium inflammation compared with single miRNA strand. Mechanistically, miR-181a-5p and miR-181a-3p prevent endothelial cell activation through blockade of NF-κB signaling pathway by targeting TAB2 and NEMO, respectively. In conclusion, these findings suggest that miR-181a-5p and miR-181a-3p are both antiatherogenic miRNAs. MiR-181a-5p and miR-181a-3p mimetics retard atherosclerosis progression through blocking NF-κB activation and vascular inflammation by targeting TAB2 and NEMO, respectively. Therefore, restoration of miR-181a-5p and miR-181a-3p may represent a novel therapeutic approach to manage atherosclerosis.

Objective— To determine the role of orai1 store–operated Ca 2+ entry in foam cell formation and atherogenesis. Approach and Results— Acute administration of oxidized low-density lipoprotein (oxLDL) activates an orai1-dependent Ca 2+ entry in macrophages. Chelation of intracellular Ca 2+ , inhibition of orai1 store–operated Ca 2+ entry, or knockdown of orai1 dramatically inhibited oxLDL-induced upregulation of scavenger receptor A, uptake of modified LDL, and foam cell formation. Orai1-dependent Ca 2+ entry induces scavenger receptor A expression and foam cell formation through activation of calcineurin but not calmodulin kinase II. Activation of nuclear factor of activated T cells is not involved in calcineurin signaling to foam cell formation. However, oxLDL dephosohorylates and activates apoptosis signal–regulating kinase 1 in macrophages. Orai1 knockdown prevents oxLDL-induced apoptosis signal–regulating kinase 1 activation. Knockdown of apoptosis signal–regulating kinase 1, or inhibition of its downstream effectors, JNK and p38 mitogen-activated protein kinase, reduces scavenger receptor A expression and foam cell formation. Notably, orai1 expression is increased in atherosclerotic plaques of apolipoprotein E −/− mice fed with high-cholesterol diet. Knockdown of orai1 with adenovirus harboring orai1 siRNA or inhibition of orai1 Ca 2+ entry with SKF96365 for 4 weeks dramatically inhibits atherosclerotic plaque development in high-cholesterol diet feeding apolipoprotein E −/− mice. In addition, inhibition of orai1 Ca 2+ entry prevents macrophage apoptosis in atherosclerotic plaque. Moreover, the expression of inflammatory genes in atherosclerotic lesions and the infiltration of myeloid cells into the aortic sinus plaques are decreased after blocking orai1 signaling. Conclusions— Orai1-dependent Ca 2+ entry promotes atherogenesis possibly by promoting foam cell formation and vascular inflammation, rendering orai1 Ca 2+ channel a potential therapeutic target against atherosclerosis.

Tension-free hernioplasty under local anesthetic infiltration is a reasonable choice for end-stage renal disease patients with hernia.The purpose of the study was to investigate the feasibility of cryotherapy after hernioplasty surgery to relieve pain and scrotal edema.This was a prospective, randomized, and controlled trial held in a large integrated health care facility in South China. One hundred sixty-nine male patients on hemodialysis and scheduled for hernioplasty were enrolled between March 2013 and February 2017. The participants were divided into an intervention group and a control group. In the intervention group, ice packs were applied after surgery. Demographic information, vital signs, pain score, opioid consumption, wound inflammation, scrotal edema, and patient satisfaction were compared between the two groups. The primary outcome was pain score.Cryotherapy-treated patients required less opioid consumption (5.95 vs. 15.29 mg; P 0.05), reported lower pain scores from 30 minutes to 48 hours after operation (P 0.05), less wound inflammation (11.90 vs. 32.94%; P 0.05), lower incidence of scrotal edema in the first and second days (P 0.05), and higher patient satisfaction (8.95 vs. 6.50 cm; P 0.05), with stable vital signs throughout the monitoring period (P 0.05).Owing to its favorable cost, convenience, and low frequency of adverse effects, cryotherapy is useful for end-stage renal disease populations after hernioplasty to relieve pain and scrotal edema.

Orai1-dependent Ca

Arteriovenous grafting offers an alternative for patients whose vessels are unsuitable for arteriovenous fistula. However, as a result of subcutaneous tunnel dissection, postoperative pain and edema of the operated limb present early after surgery. As a traditional therapeutic approach, cryotherapy has the ability to suppress postoperative pain and edema.The purpose of the study was to investigate the feasibility of cryotherapy after arteriovenous graft surgery to decrease perioperative medication usage.This study was a randomized controlled trial.A large integrated health care facility in South China.A total of 85 hemodialysis patients who received arteriovenous graft surgery from March 2011 to February 2017 were enrolled.The participants were divided into an intervention group and a control group according to the postoperative management. Ice packs were applied covering the operative forearm for 120 minutes after wound closure in the intervention group. General information, pain score, analgesic consumption, wound inflammation, forearm edema, and participant satisfaction were compared between the two groups.Cryotherapy-treated patients required less analgesia (26.19% vs. 48.84%, p .05), reported lower pain score from 30 minutes to 48 hours postoperative (p .05), less wound inflammation (11.90% vs. 25.58%, p .05), and higher participant satisfaction (8.92 ± 0.57 vs. 6.52 ± 0.63, p .05), whereas the incidence of forearm edema was equivalent (p .05). No adverse events were reported in either group.Cryotherapy is a preferable intervention for patients after arteriovenous graft implantation as a result of its favorable cost, convenience, and fewer side effects.

Evidence supports an important role of Ca2+ release-activated Ca2+ channel protein 1 (Orai1)-mediated Ca2+ entry in the development of renal fibrosis, a common pathologic feature of CKDs that lead to ESRD, but the molecular mechanisms remain unclear. We determined the role of Orai1 calcium channel in renal fibrosis induced by high-fat diet and by unilateral ureteral obstruction. Mouse kidneys with fibrosis had higher levels of Orai1 protein expression than did kidneys without fibrosis. In vivo knockdown of Orai1 with adenovirus harboring Orai1-short hairpin RNA or inhibition of Orai1 with SKF96365 dramatically prevented renal fibrosis and significantly decreased protein expression of fibronectin, α‑smooth muscle actin, and TGF‑β1 in the kidney cortex of ApoE-/- mice on a high-fat diet and in the obstructed kidneys of mice with unilateral ureteral obstruction. Compared with kidney biopsy specimens of patients with glomerular minimal change disease, those of patients with fibrotic nephropathy had higher expression levels of Orai1. In cultured human proximal tubule epithelial cells (HK2), knockdown of Orai1 Ca2+ channel with adenovirus-Orai1-short hairpin RNA markedly inhibited TGF-β1-induced intracellular Ca2+ influx and phosphorylation of smad2/3. Knockdown or blockade of the Orai1 Ca2+ channel in HK2 cells also prevented epithelial-to-mesenchymal transition induced by TGF‑β1. In conclusion, blockade of the Orai1 Ca2+ channel prevented progression of renal fibrosis in mice, likely by suppressing smad2/3 phosphorylation and TGF-β1-induced epithelial-to-mesenchymal transition. These results render the Orai1 Ca2+ channel a potential therapeutic target against renal fibrosis.

Solasodine 11 is a steroidal alkaloid with various biological activities. Herein, 8 novel solasodine derivatives were synthesized and their effect on prostate cancer cell proliferation was assessed in vitro. Significant improvement in antiproliferative activity was achieved among some of the synthetic analogs. In particular, 19 exhibited the most potent inhibitory effect against the proliferation of PC-3 cell line (IC50 = 3.91 μmol/L).

To examine the association between pregnancy-induced hypertension (PIH) and small-for-gestational-age babies (SGA) in a Chinese population.Subjects were women who delivered a singleton baby (gestational weeks: equal to or greater than 28, and less than 42) in four cities or counties in Jiangsu and Zhejiang provinces, China, during the period of 1995 - 2000. A total number of 93 743 women were included. Incidence of SGA was calculated and compared between women with or without PIH and between groups with different severities of PIH. Multiple logistic regression was used to address the relationship between PIH and SGA while controlling for maternal age, occupation, education, parity, BMI, anemia, premature rupture of membranes and fetal sex. The association between PIH and SGA was also examined according to preterm or term delivery.The incidence of SGA in women with PIH (6.0%) was higher than women without (4.5%), and the incidence increased with severities of PIH. The adjusted relative risk rates (95% CI) of SGA in women with mild,moderate and severe PIH were 1.17 (1.01-1.34), 1.69 (1.33-2.14), and 3.50 (2.57-4.77), respectively, when confounders were controlled for. The risk ratios of SGA in women with PIH among women who delivered a preterm baby were higher than those among women who delivered a term baby.There seemed a statistical association between PIH and SGA and women with PIH having higher incidence of SGA than those without PIH.

To investigate the association between third trimester hemoglobin (Hb) concentrations and the risk of low birth weight and preterm delivery in a Chinese population.Subjects were women who delivered in four cities/counties in Jiangsu and Zhejiang provinces, China, during the period of 1995 - 2000. Incidence of low birth weight and preterm delivery was calculated and compared among groups of women with different levels of Hb during the third trimester. Multiple logistic regression was used to address relationships between Hb levels and the risk of preterm delivery and low birth weight while controlling for potential confounding factors.The overall prevalence of anemia during third trimester of pregnancy was 48.2% , mainly consisting of mild and moderate anemia. Mild and moderate anemia did not increase the risk of preterm delivery and low birth weight statistically. The lowest incidence of preterm delivery and low birth weight was found among pregnant women with Hb levels at 90-99 g/L. The risk for preterm delivery and low birth weight increased with either increasing or decreasing hemoglobin concentrations. However,there was no remarkable elevation of the risk when Hb was in the range of 70-119 g/L. Women with severe anemia (Hb70 g/L) had 80% higher risk (95% CI:1.0-3.3) of preterm delivery and a 4.0-fold higher risk (95 % CI :2. 1-7.5) of low birth weight compared with women with an Hb value of 90-99 g/L. In addition, women with a high Hb concentration (Hb130 g/L) had 20% higher risk (95 % CI: 1..0-1.4) of preterm delivery and 50 % higher risk (95 % CI: 1.2-1.9) of low birth weight.A U-shape relationship was found between Hb concentration and the risk of preterm delivery and low birth weight. Severe anemia and high hemoglobin concentration were both associated with increased risk of preterm deliveries and low birth weight.

To identify the differentially expressed genes associated with hypersplenism in patients with portal hypertension.The total RNA were extracted from the macrophages isolated from normal spleen and the spleen of patients with portal hypertension and reversely transcribed to cDNA with the incorporation of fluorescent (cy3 and cy5)-labeled dCTP to prepare the hybridization probes. After hybridization of Biostar-H140s chip containing 14,112 spots of cDNAs with the prepared probes, the gene chip was scanned for fluorescence intensity to screen the differently expressed genes. Three gene chips were used for hybridization and only the genes with differential expression in all the three chips were considered to associate with hypersplenism in patients with portal hypertension.Totaling 896, 1330 and 898 genes were identified to be differentially expressed by the three chips, respectively, and 121 genes (0.86%) showed differential expression in all the three chips, including 21 up-regulated known genes and 73 down-regulated known genes. The differently expressed genes were functionally related with ion channels and transport proteins, cyclins, cytoskeleton, cell receptors, cell signal transduction, metabolism, immunity, and so forth. These genes might be involved in hypersplenism in the condition of portal hypertension.cDNA microarray-based screening of differentially expressed genes in the macrophages in the spleen may provide new insights into the pathogenesis of hypersplenism in patients with portal hypertension.

To explore the relationship between multi-trace elements levels in hair and human neural tube defects as well as other risk factors.Using 88 paired cases and controls, an 1:1 matched case control study was carried out. The study subjects were collected from the China-U. S. Collaborative Project on Neural Tube Defects Prevention and Birth Defects Surveillance System. Risk factors were obtained by field investigation with standardized questionnaires and hair trace elements levels were determined by AAS and ICP-MS methods. Microwave digestion was used to digest hair samples. The detected elements would include three groups, namely nutritional elements: Cr, Mn, Cu, Zn, Co, Mo; toxic elements: Pb, As, Cd, Hg; and Lanthanons: Y, La, Pr, Nd. Cox Proportional Hazard Regression Model was used to perform risk factors analysis.Pregnancy fever appeared to be a risk factor of neural tube defects (OR = 6.525, P = 0.034) while hair zinc level (OR = 0.541 microg/100 g, P = 0.02) and times of prenatal physical examination (OR = 0.634, P0.001) served as two protective factors appeared in the last model.Zinc deficiency might serve as a risk factor for human neural tube defects, suggesting that the avoidance of pregnancy infection together with more periodical prenatal physical examination might reduce the incidence of neural tube defects.