The indicative effects of apolipoproteins on organic erectile dysfunction: bridging Mendelian randomization and case-control study.

The existing research on the association between apolipoproteins (Apos) and erectile dysfunction (ED) primarily relies on observational studies and does not distinguish between organic and psychogenic causes when diagnosing ED. It is difficult to believe that Apos play a role in psychogenic ED. To address these issues, our study explored the causal relationship between lipoproteins and ED using Mendelian randomization (MR) analysis and differentiate between organic and psychogenic ED through the use of nocturnal penile tumescence and rigidity (NPTR) monitoring. Multivariate MR analysis revealed significant causal associations between high-density lipoprotein (HDL), Apo A1, and Apo B/A1 with ED (OR and 95% CI were 0.33 (0.14-0.78), 3.58 (1.52-8.43), and 0.30 (0.13-0.66)). we conducted statistical and analytical analyses on the data of 212 patients using multivariate analyses and receiver operating characteristic (ROC) curves. Patients with organic ED had significantly lower levels of HDL, Apo A1 and Apo A1/B, whereas patients with organic ED had considerably higher levels of Apo B and low-density lipoprotein (LDL). The diagnostic value of Apos in predicting the risk of organic ED was evaluated using ROC curves. The results indicated that Apo A1 and Apo A1/B demonstrated good predictive value. HDL, Apo A1, and Apo A1/B have been identified as risk factors for ED in our study. Furthermore, our research highlights the significance of Apo A1 and Apo A1/Apo B in the development of organic ED and suggests their potential use as indicators to assess the risks associated with organic ED.

Theoretical framework for mixed-potential-driven catalysis.

Mixed-potential-driven catalysis is expected to be a distinctive heterogeneous catalytic reaction that produces products different from those produced by thermal catalytic reactions without the application of external energy. Electrochemically, the mechanism is similar to that of corrosion. However, a theory that incorporates catalytic activity as a parameter has not been established. Herein, we report the theoretical framework of mixed-potential-driven catalysis, including exchange currents, as a parameter of catalytic activity. The mixed potential and partitioning of the overpotential were determined from the exchange current by applying the Butler-Volmer equation at a steady state far from equilibrium. Mixed-potential-driven catalysis is expected to open new areas not only in the concept of catalyst development but also in the field of energetics of biological enzymatic reactions.

Astragaloside IV protects cardiomyocytes from hypoxic injury by regulating endoplasmic reticulum stress via eIF2α/CHOP signaling pathway.

Endoplasmic reticulum stress (ER stress) is suggested to promote cardiomyocyte apoptosis and ultimately lead to ischemic injury. Inhibition of ER stress-induced apoptosis may be a therapeutic strategy for MI injury. Astragaloside-IV (AST) from Astragalus membranaceus (Fisch) Bge, was reported to have cardioprotective properties. In this study, we investigated the protective effect of AST on cardiomyocytes against hypoxia injury by regulating ER stress and inhibiting apoptosis. H9c2 cardiomyocytes were divided into three groups, normal group, hypoxia group and AST group. Cell viability was determined by CCK-8 assay. Intracellular reactive oxygen species (ROS) production was detected by DCFH-DA (2,7- dichloro-dihydrofluorescein diacetate) florescent staining. The study showed that AST treatment could significantly increase the cell viability of H9c2 cells exposed to hypoxia. Furthermore, AST could restrain cell apoptosis and decrease the production of ROS. Compared with normal group, the protein levels of Bax, caspase-3, caspase-9, GRP78, p-eIF2α, and CHOP were enhanced in the hypoxia group, whereas the protein level of Bcl-2 was dramatically reduced. Compared with hypoxia group, AST markedly inhibited the phosphorylation of eIF2α and the expression of caspase-3, caspase-9 and CHOP, and promoted the protein expression of Bcl-2. Thus, AST can inhibit the ER stress-mediated apoptosis, partly through the eIF2α/CHOP pathway suppression to inhibit ER stress.

Artifact removal for unpaired thorax CBCT images using a feature fusion residual network and contextual loss.

BACKGROUND AND OBJECTIVE: Cone-beam computed tomography (CBCT) has become a more and more active cutting-edge topic in the international computed tomography (CT) research due to its advantages of fast scanning speed, high ray utilization rate and high precision. However, scatter artifacts affect the imaging performance of CBCT, which hinders its application seriously. Therefore, our study aimed to propose a novel algorithm for scatter artifacts suppression in thorax CBCT based on a feature fusion residual network (FFRN), where the contextual loss was introduced to adapt the unpaired datasets better. METHODS: In the method we proposed, a FFRN with contextual loss was used to reduce CBCT artifacts in the region of chest. Unlike L1 or L2 loss, the contextual loss function makes input images which are not aligned strictly in space available, so we performed it on our unpaired datasets. The algorithm aims to reduce artifacts via studying the mapping between CBCT and CT images, where the CBCT images were set as the beginning while planning CT images as the end. RESULTS: The proposed method effectively removes artifacts in thorax CBCT, including shadow artifacts and cup artifacts which can be collectively referred to as uneven grayscale artifacts, in the CBCT image, and perform well in preserving details and maintaining the original shape. In addition, the average PSNR number of our proposed method achieved 27.7, which was higher than the methods this paper referred which indicated the significance of our method. CONCLUSIONS: What is revealed by the results is that our method provides a highly effective, rapid, and robust solution for the removal of scatter artifacts in thorax CBCT images. Moreover, as is shown in Table 1, our method has demonstrated better artifact reduction capability than other methods.

Pan-cancer analysis of the prognostic and immunological role of PAQR4.

Progestin and adipoQ receptor family member 4 (PAQR4) is a protein-coding gene. Recent studies have shown that PAQR4 is related to the development of multiple cancers. However, there is no systematic pan-cancer analysis of this gene. In this study, the expression of PAQR4, correlations with clinical prognosis, immune situation, and its potential molecular functions and mechanisms in pan-cancer were explored by bioinformatics analysis. The Cancer Genome Atlas was applied to investigate the relations between PAQR4 and clinical features, prognostic effects, and tumor immune microenvironment. R software was used to perform statistical analysis and figure creation. The expression of PAQR4 in BLCA and KIRC was validated by qRT-PCR and immunohistochemistry, and its function was explored by cellular experiments. Bioinformatics analysis revealed that PAQR4 was up-regulated in multiple cancers and related to poor prognosis. The high expression of PAQR4 was closely associated with high tumor stage, immune cell infiltration, tumor mutation burden, and microsatellite instability in different cancer types. In addition, the high expression of PAQR4 also indicated involvement in the immune regulatory pathways. The involvement of PAQR4 in the immune regulation of different tumors was confirmed by GSEA enrichment analysis. Moreover, PAQR4 was highly expressed in bladder cancer and renal clear cell carcinoma tissues and cell lines. Cell proliferation, migration, and invasion of bladder cancer and renal clear cell carcinoma cell lines were significantly decreased after the knockdown of PAQR4. This study elucidated the role of PAQR4 in carcinogenesis as well as tumor immunity. PAQR4 may serve as a potential prognostic biomarker in a variety of cancers.

CKAP2L, a crucial target of miR-326, promotes prostate cancer progression.

BACKGROUND: The overexpression of aberrant cell cycle signaling pathway associated protein has been implicated in multiple malignancies and the identification of all-important one among is the crux of the precise targeted therapy. CKAP2L (Cytoskeleton Associated Protein 2 Like) plays a newish role in cancer progression through activation of the process of cell cycle and mitosis. In this study, we aim to delineate the prominent dysregulated expression of CKAP2L and comprehensively reveal its deregulation in prostate cancer.  METHOD: CKAP2L expression was examined in the normal and tumor tissues of prostate cancer patients with RT-QPCR and Western blot. IHC showed the different expression in normal prostate tissue, tissue of BPH, low Gleason Score and high Gleason Score prostate cancer patients. Transwell, colony formation, MTT and flow cytometry were performed to detected the changes in cellular function in vitro. The xenograft model was conducted for the changes in vivo. Dual luciferase and RIP proved the binding relation between CKAP2L and miR-326. RESULTS: In multiple datasets, CKAP2L was found upregulated and positively associated with Gleason grade and poor clinical outcomes of patients. shRNA mediated silence of CKAP2L suppressed cell proliferation, impaired monolayer formation, inhibited cell invasion. CKAP2L was confirmed to be the direct target of miR-326, which had a carcinostatic effect by binding the 3'untranslated regions (3'UTRs) of CKAP2L mRNA. The deletion of CKAP2L resulted in reduced expression of genes involved in the mitotic cell cycle such as multiple cyclin-dependent kinases and cyclins, but also several genes encoding proteins involved in chromosome segregation and spindle assembly. CONCLUSION: Taken together, CKAP2L plays a carcinogenic role in prostate cancer by regulates the expression of cycle-associated proteins.

Silencing ACTG1 Expression Induces Prostate Cancer Epithelial Mesenchymal Transition Through MAPK/ERK Signaling Pathway.

Purpose: Metastatic prostate cancer (PCa) has become a major obstacle in the treatment of PCa. The study's purpose is to find biomarkers of tumor metastasis by proteomics and enzyme-linked immunosorbent assay (ELISA), and to design related experiments to study its role in the progress and metastasis of PCa. Method: We analyzed serum from primary PCa stage and metastatic stage of 12 patients to find metastatic PCa serum protein biomarkers using isobaric tags for relative and absolute quantitation (iTRAQ). An effective diagnostic model based on validated biomarkers using logistic regression was established. In vivo and in vitro biological behavior experiments (wound healing, CCK8, and Transwell tests) were carried out after obtaining the biomarkers. Related mechanism has been studied, which may be associated with metastatic PCa. Result: Actin gamma 1 (ACTG1) is a potential biomarker in the metastasis of PCa. Bioinformatics and related experiments show that ACTG1 is high-expressed in PCa tissues and cells. In vivo and in vitro experiments illustrated that the ability of proliferation, migration, and invasion of PCa cells was significantly inhibited after the knockdown of ACTG1 expression. Surprisingly, ERK protein expression was downregulated after ACTG1 knockdown. At the same time, the expression of epithelial-mesenchymal transition-related markers in PCa cells decrease after treated with ERK1/2 inhibitor, which indicating that ACTG1 may affect the metastatic ability of PCa cells through MAPK/ERK signaling pathway. Conclusion: ACTG1 is a marker of metastasis PCa. It mediates cell proliferation and may regulate the metastasis of PCa through MAPK/ERK signaling pathway, which provides a useful theoretical basis for exploring the treatment of PCa.

Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation.

Chemotherapeutic agents, which contain the Michael acceptor, are potent anticancer molecules by promoting intracellular reactive oxygen species (ROS) generation. In this study, we synthesized a panel of PL (piperlongumine) analogs with chlorine attaching at C2 and an electron-withdrawing/electron-donating group attaching to the aromatic ring. The results displayed that the strong electrophilicity group at the C2-C3 double bond of PL analogs plays an important role in the cytotoxicity whereas the electric effect of substituents, which attached to the aromatic ring, partly contributed to the anticancer activity. Moreover, the protein containing sulfydryl or seleno, such as TrxR, could be irreversibly inhibited by the C2-C3 double bond of PL analogs, and boost intracellular ROS generation. Then, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death. In conclusion, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR and ROS accumulation.

Macrophages enhance lipopolysaccharide induced apoptosis via Ang1 and NF-κB pathways in human umbilical vein endothelial cells.

Lipopolysaccharide (LPS) could induce apoptosis and dysfunction of endothelial cells. We aimed to reveal the effects of macrophages on cell proliferation and apoptosis in LPS induced human umbilical vein endothelial cells (HUVECs). THP-1 derived macrophages and HUVECs were co-cultured in the presence of LPS. Cell viability was measured by Cell Counting Kit-8 and apoptosis was analyzed by flow cytometry. Expression of Ang1, the NF-κB component p65 was evaluated by western blot and quantitative PCR. Small interfering RNAs (siRNAs) were used to knockdown the expression of proinflammatory cytokines and p65 in HUVECs. Plasmid transfection-mediated overexpression of Ang1 was employed to see its effects on cell proliferation and apoptosis in HUVECs. Macrophages enhanced LPS-induced proliferation impairments and apoptosis in HUVECs, which could be attenuated by siRNA-mediated knockdown of cytokines TNF-α, IL-1ß, IL-6 and IL-12p70 in macrophages. The dysfunction of HUVECs was tightly associated with reduced Ang1 expression and increased phosphorylated p65 (p-65). Overexpression of Ang1 in HUVECs significantly decreased p-p65, suggesting negatively regulation of p-p65 by Ang1. Overexpression of Ang1, adding recombinant Ang1 or silencing of p65 substantially attenuated the dysfunction of HUVECs in terms of cell proliferation and apoptosis. In conclusions, THP-1-derived macrophages enhance LPS induced dysfunction of HUVECs via Ang1 and NF-κB pathways, suggesting new therapeutic targets for sepsis.

Value of plasma brain natriuretic peptide levels for predicting postoperative atrial fibrillation: a systemic review and meta-analysis.

BACKGROUND: Blood natriuretic peptide (NP) levels have been reported to be useful for predicting postoperative atrial fibrillation (AF). We aimed to quantitatively synthesize the current evidence of the accuracy of using NP levels in predicting postoperative AF. METHODS AND RESULTS: Medline, Embase, and reference lists were searched. Studies were included if either brain natriuretic peptide (BNP) or N-terminal pro-b type natriuretic peptide (NT-proBNP) had been evaluated perioperatively to predict postoperative AF. Data were analyzed to obtain summary accuracy estimates. Data from 1,844 patients in 10 studies were analyzed. Summary estimates for the sensitivity and specificity of using NP levels for predicting postoperative AF were 75 % [95 % confidence interval (CI) 67-79 %] and 80 % (95 % CI 62-91 %), respectively. The overall diagnostic odds ratio was 3.28 (95 % CI 2.23-4.84). Subgroup analysis showed that elevated NP levels in the perioperative period were a strong independent predictor of postoperative AF. NT-proBNP appeared to have better predictive value than BNP, as did postoperative assessment over preoperative assessment. BNP had a better correlation with postoperative AF in patients undergoing thoracic surgery than in patients undergoing cardiac surgery. CONCLUSIONS: Perioperative assessment of the natriuretic peptide level in patients undergoing major cardiothoracic surgery could be a valuable diagnostic aid for identifying patients at high risk of developing postoperative AF, and for providing critical clinical information to guide prophylactic antiarrhythmic therapy in the perioperative period.

[Microcirculation characters in the elderly septic patients].

OBJECTIVE: To explore the changes of sublingual microcirculation in elderly patients with severe sepsis/septic shock. METHODS: Twenty-three patients with sepsis, 10 patients without sepsis and 10 healthy elderly patients were enrolled. Sublingual microcirculation was evaluated by sidestream darkfield (SDF) imaging. And the 28-day mortality rates of all septic patients were recorded. RESULTS: Compared with the healthy group, all elderly patients had significant sublingual microcirculation dysfunctions. Compared with the severe septic and nonseptic patients, perfused vessel density (PDV) , proportion of perfused vessels (PPV) and microvascular flow index (MFI) of septic shocks were significantly lower. Compared with the severe septic patients, PDV, PPV and MFI instead of lactate and MAP of septic shocks were significantly lower from Day 1 to Day 3. The values of PDV, PPV, MFI and lactate but not MAP of the surviving septic patients were significantly higher than those of the deceased ones. CONCLUSIONS: The elderly patients with septic shock have severe sublingual microcirculatory alterations. And these abnormalities are more marked in septic shock patients. Nonsurvivors showed more severe alterations than survivors. Microcirculatory alterations may be measured to guide the therapy.

[An evaluation of stroke volume variation as a predictor of fluid responsiveness in mechanically ventilated elderly patients with severe sepsis].

OBJECTIVE: To evaluate stroke volume variation (SVV) as a predictor of fluid responsiveness in mechanically ventilated (MV) elderly patients with severe sepsis. METHODS: A prospective observation of 31 fluid challenges during fluid resuscitation for treatment of hemodynamic instability in 17 elderly MV patients with severe sepsis was conducted. SVV was measured by pulse indicator continuous cardiac output (PiCCO) system. Fluid responsiveness was defined as the changes in cardiac index (CI) increase after fluid loading (DeltaCI) > or =10%. The changes in hemodynamic parameters and lung water index were observed at the onset of and after fluid therapy. The correlation between DeltaCI and SVV or central venous pressure (CVP) were analyzed. RESULTS: SVV was decreased significantly after fluid loading [(6.6+/-2.1)% vs.(12.1+/-3.7)%, P<0.01], whereas CVP increased significantly [(12.5+/-3.6) mm Hg vs. (8.9+/-4.1) mm Hg, 1 mm Hg=0.133 kPa, P<0.01]. DeltaCI in response to fluid loading were positively correlated to initial values of SVV (r=0.447, P=0.012), but there was no relationship between CVP and DeltaCI (r=-0.082, P=0.674). The areas under the receiver operating characteristic curve (ROC curve) for SVV was 0.672 [95% confidence interval (95%CI) 0.463-0.885] and CVP was 0.336 (95%CI 0.133-0.539), respectively. A SVV value of 11.5% had the sensitivity of 71% and specificity of 67% for prediction of fluid responsiveness. CONCLUSION: Functional hemodynamic parameter SVV can predict fluid responsiveness in elderly MV patients with severe sepsis during fluid resuscitation, it may serve as a useful index for guiding fluid therapy in elderly patients with severe sepsis.

[A novel missense mutation, K124N, in the troponin T gene of Chinese populations with hypertrophic cardiomyopathy].

OBJECTIVE: To study the cardiac troponin T (TNNT2) gene mutation in Chinese patients with hypertrophic cardiomyopathy (HCM) and to analyze the correlation between the genotype and phenotype. METHODS: Specimens of peripheral blood were collected from 71 unrelated Chinese probands with HCM, aged 40 +/- 18. The genome DNA was extracted. Single-strand conformation polymorphism gel analysis of the polymerase chain reaction-amplified products was conducted to search for mutations in the exons 8, 9, 10, 11, and 16 of the TNNT2 gene. Relevant clinical data were collected. One hundred normal persons, aged 44 +/- 14, were used as controls. RESULTS: A missense mutation, K124N, in the exon 9 of the TNNT2 gene was identified in a 41-year-old female patient with HCM and failed to be detected in the 100 normal controls, which suggested the disease-causing mutation. The patient began to have the symptoms of chest distress and palpitation since the age of 38, presented moderate hypertrophy of the intraventricular septum, and did not have a family history of sudden cardiac death. CONCLUSION: A novel missense mutation of troponin T gene has been identified. Mutation in tail part of cardiac troponin T, essential for it's binding function, causes the disease of HCM. Correlative analysis confirms the genetic heterogeneity of the disease.