Neuroprotective effect of hyperoside in MPP+/MPTP -induced dopaminergic neurodegeneration.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the pathological loss of nigrostriatal dopaminergic neurons, which causes an insufficient release of dopamine (DA) and then induces motor and nonmotor symptoms. Hyperoside (HYP) is a lignan component with anti-inflammatory, antioxidant, and neuroprotective effects. In this study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) were used to induce dopaminergic neurodegeneration. The results showed that HYP (100 µg/mL) reduced MPTP-mediated cytotoxicity of SH-SY5Y cells in vitro, and HYP [25 mg/(kg d)] alleviated MPTP-induced motor symptoms in vivo. HYP treatment reduced the contents of nitric oxide (NO), H2O2, and malondialdehyde (MDA), as well as the mitochondrial damage of dopaminergic neurons, both in vitro and in vivo. Meanwhile, HYP treatment elevated the levels of neurotrophic factors such as glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and recombinant cerebral dopamine neurotrophic factor in vivo, but not in vitro. Finally, Akt signaling was activated after the administration of HYP in MPP+/MPTP-induced dopaminergic neurodegeneration. However, the blockage of the Akt pathway with Akt inhibitor did not abolish the neuroprotective effect of HYP on DA neurons. These results showed that HYP protected the dopaminergic neurons from the MPP+- and MPTP-induced injuries, which did not rely on the Akt pathway.

Association of single nucleotide polymorphisms in the nuclear respiratory factor-2 beta subunit-encoding the GABPB1 gene within the occupational environment.

GABPB1, known as nuclear respiratory factor 2 (Nrf2), activates the mitochondrial genes that are responsible for antioxidant action and detoxification. Two single nucleotide polymorphisms (SNPs) of GABPB1, such as rs7181866 and rs8031031, were reported to be associated with the prevention of the increasing cancer risk caused by environmental deterioration. Between March 1 and May 1, 2018, human peripheral blood mononuclear cells (PBMCs) from a cohort of 300 volunteers working in adverse occupational environments were genotyped for the two SNPs in the present study. The SNP rs7181866 was found to be significantly greater in the male group than in the female group. Frequencies of SNP rs7181866 and bi-allele SNPs (rs7181866 + rs8031031) were significantly different between the <35-year-old group and the ≥35-year-old group. Further, multinomial logistic regression analysis of the occupational environments revealed the highest predictive frequency of SNPs for four environmental factors, of which chemical factors accounted for 15.33% rs7181866, physical factors accounted for 34.79% rs7181866 + rs8031031, physical + chemical factors accounted for 39.5% rs8031031, and unknown factors accounted for 26.5% rs7181866 + rs8031031. In conclusion, the G allele of rs7181866 was found to be significantly more susceptible than the rs8031031 allele under adverse occupational environmental factors, and physical factors such as noise, which appear to play vital roles in causing SNP mutations.

Gut microbes enlarged the protective effect of transplanted regulatory B cells on rejection of cardiac allografts.

BACKGROUND: Regulatory B cells (Bregs) play an important role in maintaining immune homeostasis and have the potential to induce tolerance. Previous work has found that Breg cells are involved in heart transplantation tolerance. However, the effect of Breg on the transplantation tolerance and the underlying mechanisms remain to be clarified. METHODS: Using a within-species heart transplantation model, we aimed to investigate the role of CD19+CD5+CD1dhigh Bregs isolated from transplanted mice in preventing transplant rejection in vivo. We also explored the effects of CD40 and tumor necrosis factor receptor-associated factor 6 (TRAF6) ubiquitin ligase on Breg-mediated prolongation of survival in heart transplant (HT) mice, and the regulatory effects of downstream Cdk4 and Cdk6 proteins on dendritic cells (DCs), which clarified the function and molecular mechanism of Breg cells in HT mice. RESULTS: Our data suggest that adoptive transfer of the transplanted Bregs served as an effective tolerance-inducing mechanism in HT mice and was involved in the CD40-TRAF6 signaling pathway in DCs. Moreover, DCs collected from the Breg treated HT mice also prolonged the survival of HT mice. Furthermore, DC-specific knockout of TRAF6 diminished Breg-mediated prolongation of survival in HT mice. Interestingly, gut microbes from donors increased the survival of cardiac allografts both in both the absence and presence of Bregs but were not implicated in CD40-TRAF6 signaling. CONCLUSIONS: These findings reveal a role of Breg cells in the induction of transplantation tolerance through the blockade of the CD40-TRAF6 signaling pathway, which might be used in the treatment of HT in the clinic.

Overweight is associated with better one-year survival in elderly patients after cardiac surgery: a retrospective analysis of the MIMIC-III database.

BACKGROUND: The relationship of body mass index (BMI) to short- and long-term outcomes after cardiac surgery remains controversial, and the dose-response relationship between BMI and mortality in patients receiving cardiac surgery is unclear. Furthermore, the influence of age, concomitant disease, and types of surgery on the prognostic role of BMI has yet to be determined. METHODS: A retrospective cohort study with 6,473 adult patients receiving cardiac surgery was conducted using the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC-III) database. Multivariate Cox proportional hazard analysis and multivariate logistic regression analysis were used to assess the association of BMI with 1-year and in-hospital mortality. Restricted cubic regression splines were used to evaluate the effect of BMI as a continuous variable and to determine appropriate cut points. Subgroup analyses were performed based on age, hypertension and types of surgery. RESULTS: The baseline characteristics of patients differed between BMI categories. On multivariable analysis, overweight patients (BMI 25-30 kg/m2) had a lower 1-year mortality [hazard ratio (HR) =0.660, 95% confidence interval (CI): 0.516-0.843, P=0.001] when compared with normal weight patients (BMI 18.5-25 kg/m2). For patients with BMI <30 kg/m2, each 1 kg/m2 BMI increase was independently associated with a significant decrease in the 1-year mortality risk (HR =0.936, 95% CI: 0.899-0.975, P=0.002), while in patients with BMI ≥30 kg/m2, an increase in BMI did not increase the 1-year mortality risk (HR =1.032, 95% CI: 0.998-1.067, P=0.064). Subgroup analyses suggested the protective effect of overweight on post-cardiac surgery survival was confined to patients with advanced age (>60 years), hypertension and those undergoing isolated coronary artery bypass grafting (CABG). CONCLUSIONS: Overweight was associated with better 1-year survival in patients after cardiac surgery when compared to normal weight. The protective effect of overweight on post-cardiac surgery survival was confined to elderly patients (>60 years).

Identification of key genes in calcific aortic valve disease by integrated bioinformatics analysis.

Calcific aortic valve disease (CAVD) is highly prevalent in our aging world and has no effective pharmaceutical treatment. Intense efforts have been made but the underlying molecular mechanisms of CAVD are still unclear.This study was designed to identify the critical genes and pathways in CAVD by bioinformatics analysis. Microarray datasets of GSE12644, GSE51472, and GSE83453 were obtained from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and functional and pathway enrichment analysis was performed. Subsequently, the protein-protein interaction network (PPI) was constructed with Search Tool for the Retrieval of Interacting Genes and was visualized with Cytoscape to identify the most significant module. Hub genes were identified by Cytoscape plugin cytoHubba.A total of 179 DEGs, including 101 upregulated genes and 78 downregulated genes, were identified. The enriched functions and pathways of the DEGs include inflammatory and immune response, chemotaxis, extracellular matrix (ECM) organization, complement and coagulation cascades, ECM receptor interaction, and focal adhesion. The most significant module in the PPI network was analyzed and genes among it were mainly enriched in chemotaxis, locomotory behavior, immune response, chemokine signaling pathway, and extracellular space. In addition, DEGs, with degrees ≥ 10 and the top 10 highest Maximal Chique Centrality (MCC) score, were identified as hub genes. CCR1, MMP9, VCAM1, and ITGAX, which were of the highest degree or MCC score, were manually reviewed.The DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the pathogenesis of CAVD and might serve as candidate therapeutic targets for CAVD.

Preoperative uric acid predicts in-hospital death in patients with acute type a aortic dissection.

BACKGROUND: The present study aimed to evaluate the value of admission serum uric acid (UA) level in predicting in-hospital risk of death in patients with acute type A aortic dissection (AAAD). METHODS: From January 2016 to June 2019, 186 consecutive patients with AAAD who underwent thoracic aortic surgery were retrospectively studied. Serum UA levels were measured on admission. Forward conditional logistic regression was performed to identify independent risk factors for in-hospital death. Receiver operating characteristic (ROC) analysis was performed to assess the most clinical useful level of serum UA for predicting postoperative in-hospital mortality. RESULTS: Increased level of serum UA was found in non-survivors compared with those survived (446 ± 123 vs 371 ± 111 umol/L, p < 0.001). Age (OR = 1.063, 95% CI 1.016-1.112, p = 0.009), UA (OR = 1.006, 95% CI 1.002-1.010, p = 0.002), D-dimer (OR = 1.025, 95% CI 1.005-1.013, p = 0.012), operation time (OR = 1.009, 95% CI 1.005-1.013, p < 0.001) and extent of aortic replacement (OR = 0.412, 95% CI 0.220-0.768, p = 0.005) were identified as independent risk factors of in-hospital mortality in AAAD patients. The best cut-off value of admission serum UA in predicting in-hospital mortality was determined to be 415 umol/L. Subgroup analysis showed that in the subgroup of total arch replacement, UA was significantly associated with in-hospital death (OR = 1.010, 95% CI 1.005-1.015, p < 0.001), while in patients underwent ascending aorta replacement or hemiarch replacement, the relationship was no longer significant (OR = 1.001, 95% CI 0.996-1.006, p = 0.611). CONCLUSIONS: Elevated serum UA level on admission is an independent predictor of in-hospital mortality in patients with AAAD.

The effect of ifosfamide, epirubicin, and recombinant human endostatin therapy on a cardiac angiosarcoma: A case report.

RATIONALE: Cardiac angiosarcoma is a rare malignant tumor, for which only surgery has been proven to be effective to date. Currently there are no reports as to whether a postoperative regimen of ifosfamide, epirubicin, and recombinant human endostatin is effective. PATIENT CONCERN: The patient presented to us with chest pain and dyspnea. DIAGNOSIS: Enhanced computerized tomography (CT) and positron emission tomography-computerized tomography (PET-CT) suggested pericarditis and an atrial perforation, but malignancy was suspected, so the patient underwent an operation to resect the tumor and repair. Pathology of the tumor reseccted at operation showed the tumor to be an angiosarcoma. INTERVENTION: After the surgery, the patient was stared on a paclitaxel chemotherapy regimen (135 mg/m once every 3 weeks). However, 2 cycles later, pulmonary and hepatic metastases were found. Chemotherapy was then changed to ifosfamide, epirubicin (ifosfamide 2000 mg/m days 1-3, epirubicin 70 mg/m days 1-2) and recombinant human endostatin (7.5 mg/m days 1-14) in 3 weekly cycles. OUTCOME: Three cycles later, follow-up showed that chemotherapy had delayed progression of the pulmonary metastases, but that the hepatic node was still growing. The patient has now survived 8 months post surgery and is still on follow-up. LESSONS: This case shows us that operation on late stage cardiac angiosarcomas can alleviate a patient's symptoms; postoperative paclitaxel monotherapy was insufficient and ifosfamide and epirubicin plus recombinant human endostatin has a limited effect on late stage cardiac angiosarcoma. Studies with a larger sample size are needed for verification of these findings.

Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.

α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.

Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives.

Subtype-selective α1-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α1-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α1B-AR (pA2 7.13) with a poor selectivity for α1A and α1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α1D subtype (pA2 7.06) and excellent selectivity for α1D over α1B (α1D/α1B ratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α1 receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α1D-selective antagonists.

X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists.

Indole-arylpiperazine derivatives have exhibited good selectivity for the α1A-adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H···π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α1A-adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α1A antagonists with high selectivity.

Novel naftopidil-related derivatives and their biological effects as alpha1-adrenoceptors antagonists and antiproliferative agents.

Eleven novel naftopidil-related compounds that contain amide and indole groups were designed and synthesized. The biological effects of these compounds on three α1-adrenoceptor subtypes and cancerous human prostate cell lines (PC-3, DU-145, and LNCaP) were determined. Compounds 2, 3, 5, 11, and 12 exhibited an α1-adrenoceptor antagonistic activity, whereas compounds 9, 10, and 12 displayed moderate antiproliferative activities. Compound 3 exhibited a significant α(1D/1A) blocking activity in isolated rat tissues (97.7- and 64.6-fold selective for α(1D) and α(1A) compared with α(1B)) but not a relevant cytotoxic activity. Compound 12 demonstrated a potent and selective α(1D/1A) antagonistic activity (47.9- and 19.1-fold for α(1D) and α(1A) compared with α1B) and a potent antiproliferative activity in PC-3 cells (IC50 = 15.70 µM). Further testing confirmed that compound 12 inhibited the growth of PC-3 cells by inducing apoptosis and G0/G1 cell cycle arrest, which was mediated by α1-adrenoceptor. Therefore, compound 12 is a potential multipotent agent that can act as an effective α1-adrenoceptor subtype antagonist for treating benign prostatic hyperplasia and a preventive medication against human prostate cancer.

Exogenous interleukin-10 attenuates hyperoxia-induced acute lung injury in mice.

NEW FINDINGS: What is the central question of this study? It is not known whether treatment with interleukin-10 (IL-10) attenuates hyperoxia-induced acute lung injury in mice. What is the main finding and its importance? Our results showed that exogenous IL-10 treatment alleviated hyperoxia-induced acute lung injury in mice, possibly by regulating neutrophil recruitment and the subsequent generation of cytokines, nitric oxide and matrix metalloproteinases. Lung injury caused by breathing air enriched with oxygen continues to be a major problem in clinical medicine. Here, we investigated the therapeutic role of interleukin-10 (IL-10) in hyperoxia-induced acute lung injury in mice. In the first experiment, mice were exposed to room air or 95% O2 and treated with IL-10 simultaneously. In the second experiment, wild-type mice and IL-10(-/-) mice were exposed to room air or 95% O2 . Exogenous IL-10 treatment attenuated hyperoxia-induced acute lung injury, evidenced by a reduced ratio of lung weight to body weight, ratio of lung wet weight to dry weight, cell numbers and protein content in bronchoalveolar lavage fluid and cell death. Interleukin-10 treatment markedly prolonged the survival of mice during oxygen exposure. Interleukin-10 treatment reduced the activity of myeloperoxidase and mRNA levels of interleukin-6, tumour necrosis factor-α and macrophage inflammatory protein 2, suppressed nuclear factor-κB activation and decreased inducible nitric oxide synthnase expression and nitric oxide formation in lungs of mice exposed to hyperoxia. Interleukin-10 treatment suppressed activities of matrix metalloproteinase 2 and matrix metalloproteinase 9 and reduced lung permeability in mice during oxygen exposure. Furthermore, absence of IL-10 aggravated hyperoxia-induced acute lung injury and reduced the duration of survival of mice during oxygen exposure, which was attenuated by treatment with IL-10. In conclusion, our results show that exogenous IL-10 treatment alleviates hyperoxia-induced acute lung injury in mice, possibly by regulating neutrophil recruitment and the subsequent generation of cytokines, nitric oxide and matrix metalloproteinases. This suggests that IL-10 treatment may be a promising therapeutic strategy to reduce lung injury in patients exposed to hyperoxia.