Promotion of improved intestinal barrier health by soybean-derived bioactive peptides in Chinese mitten crab (Eriocheir sinensis) fed a low fishmeal diet.

To alleviate the growth inhibition, and intestinal damage of Chinese mitten crab (Eriocheir sinensis) induced by low fishmeal diets (LF), an 8-week feeding trial was conducted to evaluate the addition of dietary soybean-derived bioactive peptides (SBP) in LF diets on the regulation of growth, digestion and intestinal health. The crabs were fed isonitrogenous and isoenergetic conventional diet and LF diets (10 % fishmeal replaced by soybean meal, LF) supplemented with 0, 1 %, 2 %, 4 % and 6 % SBP, respectively. The results showed that LF diet inhibited growth while inclusion of SBP quadratically remitted the growth inhibition induced by LF. For digestive function, increasing addition level of SBP quadratically improved the α-amylase and trypsin activities. For antioxidant function, LF group significantly increased the malondialdehyde content, while SBP linearly decreased the malondialdehyde level and cubically increased the anti-superoxide anion activity and total antioxidant capacity level. For intestinal health, the peritrophic membrane (PM) almost completely separated from the inner wall of the intestinal lumen, the epithelial cells reduced, the muscularis became thinner and the apoptotic signals increased in LF group; with SBP addition, the intestinal morphology was improved, with the PM adhering to the inner wall of the intestinal lumen, an increase in the number of epithelial cells and an increase in the thickness of the muscularis. Additionally, there was a decrease in apoptotic signals. Dietary SBP also increased the expression of PT and Crustin1 quadratically and decreased the expression of ALF1 linearly, ALF3 and ILF2 quadratically.

Effect of off-label targeted drugs on long-term survival in chronic thromboembolic pulmonary hypertension: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Off-label pulmonary arterial hypertension (PAH)-targeted drugs are commonly prescribed for non-operated chronic thromboembolic pulmonary hypertension (CTEPH), but their effect on the long-term prognosis of CTEPH remains unknown. This study investigated the effect of off-label PAH-targeted drugs on the long-term survival of CTEPH patients. METHODS: CTEPH patients were enrolled from a prospective multicentre national registry. Except for licensed riociguat and treprostinil, other PAH-targeted drugs were off-label. In the original and propensity score-matched (PSM) samples, five-year survival was compared in two groups: (a) patients not receiving off-label PAH-targeted drugs (control) versus (b) patients receiving off-label PAH-targeted drugs (treatment). The latter group was investigated for the effect of started off-label PAH-targeted drugs at baselines (initial) or during follow-up (subsequent). RESULTS: Of 347 enrolled patients, 212 were treated with off-label PAH-targeted drugs initially (n = 173) or subsequently (n = 39), and 135 were untreated. The 1-, 2-, 3- and 5-year survival of the treatment group was significantly higher than that of the control group (97.1% vs. 89.4%, 92.3% vs. 82.1%, 83.2% vs. 75.1% and 71.1% vs. 55.3%, respectively, log-rank test, p = 0.005). Initial treatment was correlated with better 5-year survival after excluding patients with subsequent treatment to reduce the immortal-time bias (hazard ratio: 0.611; 95% CI: 0.397-0.940; p = 0.025). In PSM samples, patients given initial treatment showed significantly better 5-year survival than untreated patients (68.9% vs. 49.3%, log-rank test, p = 0.008). CONCLUSION: Off-label targeted drugs contributed to improved long-term survival in CTEPH patients receiving pharmacotherapies.

Functions of lysine 2-hydroxyisobutyrylation and future perspectives on plants.

Lysine 2-hydroxyisobutyrylation (Khib) is a novel protein post-translational modifications (PTMs) observed in both eukaryotes and prokaryotes. Recent studies suggested that this novel PTM has the potential to regulate different proteins in various pathways. Khib is regulated by lysine acyltransferases and deacylases. This novel PTM reveals interesting connections between modifications and protein physiological functions, including gene transcription, glycolysis and cell growth, enzymic activity, sperm motility, and aging. Here, we review the discovery and the current understanding of this PTM. Then, we outline the networks of complexity of interactions among PTMs in plants, and raise possible directions of this novel PTM for future investigations in plants.

Prenatal Exposure to General Anesthesia Drug Esketamine Impaired Neurobehavior in Offspring.

Prenatal exposure to anesthetics has raised increasing attention about the neuronal development in offspring. Animal models are usually used for investigation. As a new drug, esketamine is the s-isoform of ketamine and is twice as potent as the racemic ketamine with less reported adverse effects. Esketamine is currently being used and become more favorable in clinical anesthesia work, including surgeries during pregnancy, yet the effect on the offspring is unknown. The present study aimed to elucidate the effects of gestational administration of esketamine on neuronal development in offspring, using a rat model. Gestational day 14.5 pregnant rats received intravenous injections of esketamine. The postnatal day 0 (P0) hippocampus was digested and cultured in vitro to display the neuronal growth morphology. On Day 4 the in vitro experiments revealed a shorter axon length and fewer dendrite branches in the esketamine group. The results from the EdU- imaging kit showed decreased proliferative capacity in the subventricular zone (SVZ) and dentate gyrus (DG) in both P0 and P30 offspring brains in the esketamine group. Moreover, neurogenesis, neuron maturity and spine density were impaired, resulting in attenuated long-term potentiation (LTP). Compromised hippocampal function accounted for the deficits in neuronal cognition, memory and emotion. The evidence obtained suggests that the neurobehavioral deficit due to prenatal exposure to esketamine may be related to the decrease phosphorylation of CREB and abnormalities in N-methyl-D-aspartic acid receptor subunits. Taken together, these results demonstrate the negative effect of prenatal esketamine exposure on neuronal development in offspring rats. G14.5 esketamine administration influenced the neurobehavior of the offspring in adolescence. Poorer neuronal growth and reduced brain proliferative capacity in late gestation and juvenile pups resulted in impaired P30 neuronal plasticity and synaptic spines as well as abnormalities in NMDAR subunits. Attenuated LTP reflected compromised hippocampal function, as confirmed by behavioral tests of cognition, memory and emotions. This figure was completed on the website of Figdraw.

A Cephalosporin-Tripodalamine Conjugate Inhibits Metallo-ß-Lactamase with High Efficacy and Low Toxicity.

The wide spread of metallo-ß-lactamase (MBL)-expressing bacteria has greatly threatened human health, and there is an urgent need for inhibitors against MBLs. Herein, we present a cephalosporin-tripodalamine conjugate (DPASC) as a potent MBL inhibitor with a block-release design. The cephalosporin tag blocks the ligand binding site to reduce toxicity and is cleaved by MBLs to release active ligands to inhibit MBLs in situ. The screening of MBL-expressing pathogenic strains with 16 µg/mL DPASC showed a decrease of the minimum inhibitory concentration of meropenem (MEM) by 16 to 512-fold, and its toxicity was minimal to human HepG2 cells, with an IC50 exceeding 512 µg/mL. An in vivo infection model with Galleria mellonella larvae showed an increased 3-day survival rate of 87% with the coadministration of DPASC and MEM, compared to 50% with MEM alone and no toxicity at a dose of 256 mg/kg of DPASC. Our findings with DPASC demonstrate that it is an effective MBL inhibitor and that the block-release strategy could be useful for the development of new MBL inhibitors.

Effects of dietary carbohydrate/lipid ratios on non-specific immune responses, antioxidant capacity, hepatopancreas and intestines histology, and expression of TLR-MAPK/NF-κB signaling pathway-related genes of Procambarus clarkii.

To investigate the effects of dietary carbohydrate/lipid (CHO: L) ratios on non-specific immune responses, antioxidant capacity, and expression of TLR-MAPK/NF-κB signaling pathway-related genes of red swamp crayfish (Procambarus clarkii). Four isonitrogenous and isoenergetic diets containing different CHO: L ratios were formulated. The results showed that the group with a CHO: L ratio of 5.94 had better growth performance (P < 0.05). The highest T-AOC, CAT, and SOD activities and the lowest MDA content in hemolymph and hepatopancreas were observed in the group with a CHO: L ratio of 5.94 (P < 0.05). The lowest activities of ALT, AST, ACP, AKP, and ALB in the hemolymph were observed in CHO: L ratio 5.94 group (P < 0.05), while the highest LZM activity, TP, and GLB content were observed in CHO: L 5.94 group (P < 0.05). The highest mRNA expression levels of tlr3, myd88, and mapk3, and the lowest mRNA expression levels of nf-kb α, nf-kb ß, nf-kb p105, and traf6 were observed in the CHO: L of 5.94 group (P < 0.05). The highest mRNA expression levels of immune-related genes were observed in the CHO: L of 5.94 group (P < 0.05). Overall, these results indicated that the optimum dietary CHO: L ratio is vital in promoting growth and enhancing antioxidants and immunity to maintain red swamp crayfish's intestinal and hepatopancreas health status. In conclusion, the diets with a CHO:L ratio of 5.94 (approximately 36.23% carbohydrate and 6.10% lipid) is optimal for juvenile red swamp crayfish's physiological condition and health status.

Characteristics, goal-oriented treatments and survival of pulmonary arterial hypertension in China: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Nationally representative reports on the characteristics and long-term survival of pulmonary arterial hypertension (PAH) from developing countries are scarce. The applicability of the current main risk stratifications and the longitudinal changes in goal-oriented treatments have yet to be elucidated in real-world settings. Therefore, we aimed to provide insights into the characteristics, goal-oriented treatments and survival of PAH in China and to explore the applicability of the main risk stratifications in our independent cohort. METHODS: PAH patients were consecutively enrolled from a national prospective multicentre registry. Data on baseline, follow-up re-evaluation and therapeutic changes were collected. RESULTS: A total of 2031 patients were enrolled, with congenital heart disease (CHD)-PAH (45.2%) being the most common aetiology. The mean age was 35 ± 12 years, and 76.2% were females. At baseline, approximately 20% of the patients with intermediate or high risk received combination treatment. At follow-up, approximately half of the re-evaluated patients did not achieve low-risk profiles, and even among patients who received combination therapy at baseline, 4% of them still worsened. The rate of combination therapy increased significantly from 6.7% before 2015 to 35.5% thereafter. The main risk assessment tools demonstrated good performance for predicting survival both at baseline and at follow-up. CONCLUSION: Chinese PAH patients show both similar and distinct features compared to other countries. Current main risk stratifications can significantly discriminate patients at different risk levels. There were still many patients not achieving low-risk profiles at follow-up, indicating more aggressive treatment should be implemented to optimize the goal-oriented treatment strategy.

NCAPG Promotes Pulmonary Artery Smooth Muscle Cell Proliferation as a Promising Therapeutic Target of Idiopathic Pulmonary Hypertension: Bioinformatics Analysis and Experiment Verification.

Idiopathic pulmonary arterial hypertension (IPAH) is a disease with complex etiology. Currently, IPAH treatment is limited, and patients' prognosis is poor. This study aimed to explore new therapeutic targets in IPAH through bioinformatics. Two data sets (GSE113439 and GSE130391) meeting the requirements were obtained from the Gene Expression Omnibus (GEO) database. Then, differentially expressed genes (DEGs) were identified and analyzed by NetworkAnalyst platform. By enriching Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), we examined the function of DEGs. A protein-protein interaction (PPI) network was constructed to identify central genes using the CytoNCA plug-in. Finally, four central genes, ASPM, CENPE, NCAPG, and TOP2A, were screened out. We selected NCAPG for protein-level verification. We established an animal model of PAH and found that the expression of NCAPG was significantly increased in the lung tissue of PAH rats. In vitro experiments showed that the expression of NCAPG was significantly increased in proliferative pulmonary arterial smooth muscle cells (PASMCs). When NCAPG of PASMCs was knocked down, the cell proliferation was inhibited, which suggested that NCAPG was related to the proliferation of PASMCs. Therefore, these results may provide new therapeutic targets for IPAH.

Characteristics and long-term survival of patients with chronic thromboembolic pulmonary hypertension in China.

BACKGROUND AND OBJECTIVE: The purpose of this study was to report the characteristics and long-term survival of patients with CTEPH treated in three distinct ways: PEA, BPA and medical therapy. METHODS: Patients diagnosed with CTEPH were included in the registry that was set up in 18 centres from August 2009 to July 2018. The characteristics and survival of patients with CTEPH receiving the different treatments were reported. Prognostic factors were evaluated by Cox regression model. RESULTS: A total of 593 patients with CTEPH were included. Eighty-one patients were treated with PEA, 61 with BPA and 451 with drugs. The estimated survival rates at 1, 3, 5 and 8 years were, respectively, 95.2%, 84.6%, 73.4% and 66.6% in all patients; 92.6%, 89.6%, 87.5% and 80.2% in surgical patients; and 95.4%, 88.3%, 71.0% and 64.1% in medically treated patients. The estimated survival rates at 1, 3, 5 and 7 years in patients treated with BPA were 96.7%, 88.1%, 70.0% and 70.0%, respectively. For all patients, PEA was an independent predictor of survival. Other independent risk factors were CHD, cardiac index, PVR, big endothelin-1, APE and 6MWD. CONCLUSION: This is the first multicentre prospective registry reporting baseline characteristics and estimated survival of patients with CTEPH in China. The long-term survival rates are similar to those of patients in the international and Spanish registries. PEA is an independent predictor of survival.

Risk prediction in medically treated chronic thromboembolic pulmonary hypertension.

BACKGROUND: At present, there is no generally accepted comprehensive prognostic risk prediction model for medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients. METHODS: Consecutive medically treated CTEPH patients were enrolled in a national multicenter prospective registry study from August 2009 to July 2018. A multivariable Cox proportional hazards model was utilized to derive the prognostic model, and a simplified risk score was created thereafter. Model performance was evaluated in terms of discrimination and calibration, and compared to the Swedish/COMPERA risk stratification method. Internal and external validation were conducted to validate the model performance. RESULTS: A total of 432 patients were enrolled. During a median follow-up time of 38.73 months (IQR: 20.79, 66.10), 94 patients (21.8%) died. The 1-, 3-, and 5-year survival estimates were 95.5%, 83.7%, and 70.9%, respectively. The final model included the following variables: the Swedish/COMPERA risk stratum (low-, intermediate- or high-risk stratum), pulmonary vascular resistance (PVR, ≤ or > 1600 dyn·s/cm5), total bilirubin (TBIL, ≤ or > 38 µmol/L) and chronic kidney disease (CKD, no or yes). Compared with the Swedish/COMPERA risk stratification method alone, both the derived model [C-index: 0.715; net reclassification improvement (NRI): 0.300; integrated discriminatory index (IDI): 0.095] and the risk score (C-index: 0.713; NRI: 0.300; IDI: 0.093) showed improved discriminatory power. The performance was validated in a validation cohort of 84 patients (C-index = 0.707 for the model and 0.721 for the risk score). CONCLUSIONS: A novel risk stratification strategy can serve as a useful tool for determining prognosis and guide management for medically treated CTEPH patients. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01417338).

Effects of hesperidin on the growth performance, antioxidant capacity, immune responses and disease resistance of red swamp crayfish (Procambarus clarkii).

We evaluated the effects of hesperidin on the nonspecific immunity, antioxidant capacity and growth performance of red swamp crayfish (Procambarus clarkii). A total of 900 healthy crayfish were randomly divided into six groups: the control group (fed the basal diet) and the HES25, HES50, HES75, HES100 and HES150 groups, which were fed the basal diet supplemented with 25, 50, 75, 100 and 150 mg kg-1 hesperidin, respectively. The feeding experiment lasted 8 weeks. The results indicated that compared with the control group, the crayfish groups supplemented with 50-150 mg kg-1 hesperidin had a decreased feed conversion ratio (FCR) and increased final body weight (FBW), specific growth rate (SGR) and weight gain (WG) (P < 0.05). The protein carbonyl content (PCC), reactive oxygen species (ROS) level and malondialdehyde (MDA) level in the hepatopancreas and hemocytes were significantly lower, while the total antioxidant capacity (T-AOC), glutathione peroxidase (GPx) activity, and superoxide dismutase (SOD) activity were significantly higher in the crayfish groups supplemented with 50-150 mg kg-1 hesperidin than in the control group. Supplementation with 50-150 mg kg-1 hesperidin significantly increased the activities of acid phosphatase (ACP), alkaline phosphatase (AKP), lysozyme (LZM), and phenoloxidase (PO) compared with the control group (P < 0.05); upregulated the mRNA expression of cyclophilin A (CypA), extracellular copper-zinc superoxide dismutase (ecCuZnSOD), GPxs, crustin, astacidin, Toll3 and heat shock protein 70 (HSP70) (P < 0.05); and decreased crayfish mortality following white spot syndrome virus (WSSV) infection. These findings indicate that dietary hesperidin supplementation at an optimum dose of 50-150 mg kg-1 may effectively improve nonspecific immunity, antioxidant capacity and growth performance in crayfish.

The feeding of dietary Codonopsis pilosula polysaccharide enhances the immune responses, the expression of immune-related genes and the growth performance of red swamp crayfish (Procambarus clarkii).

Polysaccharides have many functions in aquatic animals and are widely used as immunopotentiators. However, despite the emergence of serious diseases, few studies have explored the effects of Codonopsis pilosula polysaccharide (CPP) on crustaceans. We studied the effects of CPP on the growth performance, nonspecific immunity, antioxidant activity and disease resistance of red swamp crayfish (Procambarus clarkii). Healthy crayfish (5.80 ± 0.1 g) were fed diets supplemented with 0% (control), 0.05%, 0.1%, 0.15%, 0.20%, and 0.30% CPP for 8 weeks. At the end of the 8-week feeding trial, the optimal final body weight (FBW), weight gain (WG), specific growth rate (SGR), and feed conversion ratio (FCR) were observed in the crayfish fed the diets with 0.15% and 0.20% CPP, followed by those fed the diet with 0.30% CPP and then those fed the diet with 0.10% CPP, whereas the values of these parameters were obtained with the control crayfish (P < 0.05). The crayfish fed the diets with 0.15% and 0.20% CPP exhibited a significantly higher total hemocyte count (THC) and significantly increased phenoloxidase (PO), lysozyme (LZM), hemocyte (Hc), acid phosphatase (ACP) and alkaline phosphatase (AKP) compared with those belonging to the other groups (P < 0.05). The crayfish fed the diets with 0.15% and 0.2% CPP exhibited significantly higher total superoxide dismutase (T-SOD) and glutathione peroxidase (GPx) activities, a significantly increased total antioxidant capacity (T-AOC) and a significantly lower malondialdehyde (MDA) content compared with the other groups (P < 0.05), which indicated that antioxidant capacity was significantly induced by the CPP-supplemented diets. Significantly upregulated expression of immune-related genes (anti-lipopolysaccharide factors (alf), peroxiredoxin (prx5), cathepsin B (ctsb), mitochondrial manganese superoxide dismutase (mtMnsod), cyclophilin A (cypa), glutathione peroxidase (gpx), Toll-like receptor 3 (tlr3), and heat shock protein 70 (hsp70)) was detected in the crayfish fed the diets supplemented with 0.15% and 0.20% CPP diet compared with the levels observed in the control crayfish. These results showed that dietary CPP supplementation greatly improved the growth, immunity and antioxidant capacities of crayfish, and according to the observed results, 0.15%-0.2% is the recommended optimal level of CPP dietary supplementation for crayfish.

Deep vein thrombosis due to May-Thurner syndrome: a case report.

BACKGROUND: May-Thurner syndrome (MTS) or Cockett's syndrome is a rare clinical syndrome, which refers to the compression of the left common iliac vein (LCIV) by right common iliac artery and vertebral body. Complications of MTS include deep vein thrombus formation and even life-threatening pulmonary embolism. CASE PRESENTATION: Here, we report the case of a 60-year-old female patient with a complaint of swelling in the left lower limb and pain for 5 days. Computed tomography angiography indicated MTS, and thrombus formation of left external iliac vein and femoral vein. The patient was diagnosed with deep venous thrombosis (DVT) and MTS. The patient underwent ascending venography from the lower extremity to inferior vena cava (IVC) and then to the pulmonary artery with IVC filter implantation, left iliac vein balloon plasty, and stent placement. The patient visited the hospital for the removal of IVC filter, 28 days after the operation. After the interventional therapy, the patient had no in-stent restenosis and had remission during the 2-year follow-up. CONCLUSIONS: This case presents a successful management of MTS in presence of DVT. Although clinicians are rarely aware, the presence of unilateral lower limb swelling and thrombosis may be the manifestations of MTS.

Pulmonary Interventional Therapy for Acute Massive and Submassive Pulmonary Embolism in Cases Where Thrombolysis Is Contraindicated.

BACKGROUND: In this study, we sought to analyze the clinical outcomes of pharmacomechanical therapy for massive and submassive acute pulmonary embolism (APE). METHODS: We conducted a retrospective investigation of 97 patients who received pharmacomechanical therapy at out center between January 2013 and June 2018 for acute massive and submassive PE because thrombolysis was contraindicated. RESULTS: Of the 97 patients, 46 (47%) were men, and the mean age of the patients was 56 ± 14 years (median, 58 years; range, 21-84 years). Fifty patients had massive PE, whereas the remaining had submassive PE. Analysis of the site of embolus revealed that 67 (69%) had bilateral emboli in the pulmonary arteries (PAs); 5 (5%) only in the left PA, and 25 (26%) only in the right PA. Seventy-nine (81%) of the 97 patients underwent intraoperative placement of the inferior vena caval filters, whereas 3 (3%) required use of a noninvasive ventilator. Two (2%) patients died within 30 days of the interventional therapy because of severe right ventricular failure. The amount of blood loss was nonsignificant. CONCLUSIONS: Our results indicate that an optimal pharmacomechanical therapy protocol could yield favorable outcomes for rapid clot debulking in cases of massive and submassive APE where thrombolysis is contraindicated. Pending further randomized trials, pharmacomechanical therapy shows promise as an alternative treatment method in cases of acute massive or submassive PE, with minimal risk of major bleeding.

Diminished 25-OH vitamin D3 levels and vitamin D receptor variants are associated with susceptibility to type 2 diabetes with coronary artery diseases.

BACKGROUND: Role of plasma vitamin D and genetic variants of its receptor (VDR) in susceptibility to different diseases has been documented. Various studies in different populations have been highlighted strong associations with diabetes and cardiovascular diseases. Vitamin D deficiency has been linked with the development of type 2 diabetes (T2D) and the onset of coronary artery diseases (CAD). However, the role of vitamin D in predisposition to CAD in patients with T2D is ill-defined. MATERIALS AND METHODS: We enrolled 674 Chinese T2D patients, and based on clinical phenotype, patients were further categorized into patients with (n = 138) or without coronary artery disease (n = 536). Five hundred twenty-one healthy subjects from similar geographical areas, free from diabetic or coronary disorders, were enrolled as controls. Serum levels of 25-OH vitamin D were quantified by ELISA. Common VDR (FokI, TaqI, BsmI, and ApaI) polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Patients with T2D displayed lower levels of 25-OH vitamin D compared with healthy controls. Furthermore, T2D patients with CAD clinical phenotype had the lowest levels of vitamin D. Prevalence of FokI and TaqI mutants was significantly higher in diabetic patients when compared to controls. Interestingly, Tt genotype was more frequent in the artery disease group in comparison with T2D patients without heart involvement. Combined analysis of VDR polymorphisms and serum levels of vitamin D revealed a significant role in predisposition to T2D with or without CAD. CONCLUSIONS: Lower vitamin D levels and variants of VDR polymorphisms (FokI and TaqI) are associated with susceptibility to T2D and clinical manifestation.

Beraprost Upregulates KV Channel Expression and Function via EP4 Receptor in Pulmonary Artery Smooth Muscle Cells Obtained from Rats with Hypoxia-Induced Pulmonary Hypertension.

The reduced expression and function of voltage-dependent potassium (KV) channels have been involved in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH), leading to pulmonary vasoconstriction and vascular remodeling, while the upregulation of KV channels is of therapeutic significance for pulmonary hypertension. Beraprost sodium (BPS) has been shown to be effective in patients with pulmonary hypertension. However, the effect of BPS on O2-sensitive KV channels in pulmonary artery smooth muscle cells (PASMCs) remains unclear. In the present study, the effect of BPS on rats with HPH was observed, and the influence of BPS on the expression and function of O2-sensitive KV channels in PASMCs was investigated. The results revealed that BPS reduced mean pulmonary artery pressure, suppressed right ventricular hypertrophy, and attenuated the remodeling of pulmonary arteries in rats exposed to discontinuous hypoxia for 4 weeks (8 h/day). This was accompanied with the significantly upregulated expression of KV channel α-subunits (KV1.2, KV1.5 and KV2.1) and O2-sensitive voltage-gated K+ (KV) channel current (IK(V)) in small pulmonary arteries in HPH model rats, as well as in hypoxia-induced PASMCs. Furthermore, in vitrostudies have revealed that the upregulation of BPS on O2-sensitive KV channels was significantly inhibited after treatment with prostaglandin E2 receptor subtype EP4 antagonist GW627368X. Taken together, these results suggest that BPS attenuates the development of HPH through the upregulation of O2-sensitive KV channels, which was probably via the EP4 receptor-related pathway.

Fluorodibenzocyclooctynes: A Trackable Click Reagent with Enhanced Reactivity.

Bioorthogonal reactions have widespread applications in biological systems, and development of new bioorthogonal reactions has been of great interest over the past two decades. In this work, the design and synthesis of a family of fluorinated dibenzocyclooctynes (FDIBOs) are reported. The electron-deficient nature of fluorine atoms significantly accelerated the reaction of cyclooctynes in 1,3-dipolar cycloadditions, with either benzyl azide or ethyl diazoacetate, compared to conventional dibenzocyclooctyne (DIBO). In addition, FDIBOs showed unique trackable properties owing to the high NMR sensitivity of the naturally abundant 19 F isotope. Biological molecules, including a monosaccharide, a peptide, and a protein, were tested with FDIBOs, and these reactions could be easily monitored by 19 F NMR spectroscopy to evaluate the progress of the conjugation reactions. In addition, labeling of live cells was also demonstrated with metabolically modified bacteria to expand the possible applications of FDIBOs.

N-Acetylcysteine potentiates the haemodynamic-improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the p38 MAPK pathway.

The current study aimed to investigate the effects of sildenafil and N-acetylcysteine (NAC) on the haemodynamics in a rabbit model of acute pulmonary thromboembolism (APT). We developed an APT model using healthy male China big-ear rabbits (2.7 ± 0.4 kg). The rabbits were divided into five groups subjected to various interventions. We recorded the haemodynamic parameters and assessed the oxidative stress and lipid peroxidation response in the groups. Additionally, we detected apoptosis-associated molecules, FoxO1, Bad and Bcl-2, in the lung tissue. Gelatine zymography was used to detect matrix metalloproteinase (MMP) activity in bronchoalveolar lavage (BLA). Pulmonary artery endothelial cells were isolated, and their apoptosis rates and MMP activity were assayed. N-acetylcysteine potentiated the haemodynamic-improving effect of sildenafil and significantly inhibited the oxidative stress response. N-acetylcysteine combined with sildenafil decreased MMP-2 and MMP-9 activity and NO consumption and inhibited apoptosis of pulmonary arterial endothelial cells. Moreover, NAC combined with sildenafil inhibited the expression of MCP-1 and p-p38 MAPK. Thus, NAC potentiates the haemodynamic-improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the MCP-1 and p38 MAPK signalling pathway. This study may provide a promising treatment method for APT.

Regulation of mitochondrial biosynthesis and function by dietary carbohydrate levels and lipid sources in juvenile blunt snout bream Megalobrama amblycephala.

This study aimed to investigate the effects of dietary non-protein energy adjustments on the mitochondrial biosynthesis and function of juvenile Megalobrama amblycephala. Fish (average weight: 37.98 ±â€¯0.07 g) were fed eight diets containing two dietary carbohydrate levels (30% and 43%) and four lipid sources (fish oil, soybean oil, palm oil and the mixed oil) for 11 weeks. Liver mitochondrial respiratory chain complex V activity and ATP (adenosine triphosphate) content both increased significantly with increasing dietary carbohydrate levels, whereas the opposite was true for the AMP (adenosine 5'-monophosphate)/ATP ratio, hepatic transcripts of AMP-activated protein kinase α1 (AMPKα1), AMPKα2, peroxisome proliferators γ-activated receptor coativator-1α (PGC-1α), NADH dehydrogenase 1 and cytochrome c oxidase 1 (COX1) as well as the activities of Na+-K+-ATPase, succinate dehydrogenase (SDH), citrate synthase (CS) and mitochondrial respiratory chain complex I, III and IV. Additionally, hepatic ATP content, the transcripts of AMPKα, COX1 and ATP6 and the activities of Na+-K+-ATPase, SDH, CS and mitochondrial respiratory chain complex III were all significantly affected by lipid sources. Furthermore, an interaction between dietary carbohydrate levels and lipid sources was also observed in the activities of liver mitochondrial Na+-K+-ATPase and respiratory chain complex III as well as the transcripts of ATP6 and PGC-1α. Overall, these findings suggested that dietary carbohydrate levels and lipid sources remarkably affected the mitochondrial biosynthesis and function of M. amblycephala. A diet containing 30% carbohydrate and FO could boost its mitochondrial biosynthesis, while that of 30% carbohydrate and SO could enhance the mitochondrial function.

Low-dose Sinapic Acid Abates the Pyroptosis of Macrophages by Downregulation of lncRNA-MALAT1 in Rats With Diabetic Atherosclerosis.

Pyroptosis is a type of programmed cell death, which has been associated with multiple inflammatory diseases including diabetic atherosclerosis (DA). This study aims to explore the role of sinapic acid (SA) in the pyroptosis of macrophages in DA. Our results from the in vivo experiments showed that low-dose (≤50 mg/kg) chronic SA administration suppressed serum endothelin 1 (ET-1) and interleukin-1ß (IL-1ß) contents, pyroptotic death of bone marrow-derived macrophages, and the expression of pyroptotic proteins ASC, NRLP3, and caspase-1. Besides, lncRNA-metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was robustly upregulated in the macrophages of rats with DA and could be lowered by low-dose SA administration. Gene overexpression and knockdown experiments showed that MALAT1 had a modestly positive effect on the pyroptosis of normal macrophages. Moreover, in macrophages incubated with high-glucose and Ox-LDL, 1-µM SA treatment displayed a suppressive effect on the cell pyroptosis similar to that of MALAT1 knockdown. Transfection of the pcDNA-MALAT1 expression vector counteracted the decrease in MALAT1 expression and macrophage pyroptosis caused by SA. In conclusion, low-dose SA can abate the pyroptosis of macrophages by downregulation of lncRNA-MALAT1 in rats with DA.