Spinal cord stimulation for postural abnormalities in Parkinson's disease: 1-year prospective pilot study.

BACKGROUND: Postural abnormalities (PA) are common in the advanced stages of Parkinson's disease (PD), but effective therapies are lacking. A few studies suggested that spinal cord stimulation (SCS) could be a potential therapy whereas its effect is still uncertain. We aimed to investigate whether SCS had potential for benefiting PD patients with PA. METHODS: T8-12 SCS was operated on six PD patients with PA and all patients were followed for one year. Evaluations were made before and after SCS. Moreover, three patients were tested separately with SCS on-state and off-state to confirm the efficacy of SCS. RESULTS: Improvements in lateral trunk flexion degree, anterior thoracolumbar flexion degree and motor function were found after SCS. The improvements diminished while SCS was turned off. CONCLUSIONS: Lower thoracic SCS may be effective for improving PA in PD patients, but further studies are needed to confirm this conclusion. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024326, Registered on 6th July 2019; https://www.chictr.org.cn/showproj.aspx?proj=40835 .

Ion-Conductive Metallo-Covalent Organic Frameworks Constructed with Tridentate Ligand and Zn Nodes.

Metallo-covalent organic frameworks (metallo-COFs) are organometallic scaffolds in which covalently bonded organic frameworks are interwoven with metal-coordinated pendant groups. Unlike the rigid ligands traditionally used for metal coordination, the utilization of "soft" ligands allows for configurable topology and pore structure in metallo-COFs, particularly when the ligands are generated in situ during dynamic synthesis. In this study, we present the rational synthesis of metallo-COFs based on pyridine-2,6-diimine (pdi), wherein the incorporation of Zn2+ ions and in situ-generated tridentate ligands (pdi) yields metallo-COFs with a square-like lattice. In the absence of Zn2+ ions, a topological isomer COF with a Kagome lattice is instead produced. Thus, the presence or absence of Zn2+ ions allows us to switch between two distinct morphologies corresponding to metallo-COF or COF. In comparison to Brønsted acid-catalyzed COF, which necessitates postmetallization for loading metal ions, the metal-templated COF synthesis method yields COFs with improved crystallinity and approximately 1:1 [Zn2+]/ligand composition. Building upon the metal-templated COF synthesis approach, we successfully synthesized pdiCOF-Zn-2 and pdiCOF-Zn-3, which possess square-like and honeycomb lattices, respectively. The enhanced crystallinity and near 1:1 [Zn2+]/ligand composition of pdiCOF-Zn-3 (honeycomb) facilitate its application as ion transport channels.

Possible predictors of phenoconversion in isolated REM sleep behaviour disorder: a systematic review and meta-analysis.

BACKGROUND: A number of promising biomarkers for predicting imminent α-synucleinopathies have been suggested in isolated rapid eye movement sleep behaviour disorder (iRBD). However, existing evidence is conflicting without quantitative evaluation. METHODS: PubMed, Web of Science and ClinicalTrials.gov were searched through June 2021 to identify possible predictors of phenoconversion from iRBD to Parkinson's disease (PD). The pooled HRs and standardised mean differences (SMDs) with 95% CIs were calculated using fixed-effects or random-effects model. RESULTS: A total of 123 studies were included in the meta-analysis. Significant motor dysfunction (HR 1.83, 95% CI 1.33 to 2.51, I2=86.8%, p<0.001), constipation (HR 1.52, 95% CI 1.26 to 1.84, I2=8.3%, p=0.365), orthostatic hypotension (HR 1.93, 95% CI 1.05 to 3.53, I2=54.9%, p=0.084), hyposmia (HR 2.78, 95% CI 1.83 to 4.23, I2=23.9%, p=0.255), mild cognitive impairment (HR 2.27, 95% CI 1.58 to 3.27, I2=0%, p=0.681) and abnormal colour vision (SMD -0.34, 95% CI -0.63 to -0.05, I2=45.6%, p=0.087) correlated with susceptibility to PD. The process can also be traced by putaminal dopamine transporter imaging (HR 2.60, 95% CI 1.94 to 3.48, I2=0%, p=0.781) and tonic electromyographic activity (HR 1.50, 95% CI 1.04 to 2.15, I2=70%, p=0.018). CONCLUSIONS: The predictive value of each biomarker was initially highlighted with comprehensive evaluation. Combining specific predictors with high sensitivity is promising for detecting phenoconversion in the prodromal stage. Large-scale and multicentre studies are pivotal to extend our findings.

Cdc42 Promotes Axonogenesis of Primary Hippocampal Neurons by Inhibiting Glycogen Synthase Kinase-3ß.

BACKGROUND: Progressive axon degeneration is a common pathological feature of neurodegenerative diseases. Cdc42 is a member of the Rho GTPase family that participates in axonogenesis. GSK-3ß is a serine/threonine kinase highly implicated in neuronal development and neurodegeneration. This study aimed to examine whether cdc42 promotes axonogenesis by regulating GSK-3ß activity. METHODS: Hippocampal neurons were isolated from neonatal Sprague-Dawley rats and transfected with designated plasmid vectors to alter the activities of cdc42 and GSK-3ß. LiCl treatment was used to inhibit the GSK-3ß activity in primary neurons. GSK-3ß activity was determined by an enzyme activity assay kit. Immunofluorescence staining was used to detect axons stained with anti-Tau-1 antibody and dendrites stained with anti-MAP2 antibody. RESULTS: Transfection with an active cdc42 mutant (cdc42F28L) decreased the activity of GSK-3ß and induced axonogenesis in primary rat hippocampal neurons, while transfection with a negative cdc42 mutant (cdc42N17) resulted an opposite effect. Moreover, transfection with plasmid vectors carrying wild-type GSK-3ß or a constitutively active GSK3ß mutant (GSK-3ß S9A) increased the activity of GSK-3ß and attenuated axonogenesis of primary hippocampal neurons with excessive cdc42 activity, whereas inhibition of GSK-3ß by LiCl abolished the inhibitory effect of the negative cdc42 mutant on axonogenesis. CONCLUSIONS: This study suggests that cdc42 induces axonogenesis of primary rat hippocampal neurons via inhibiting GSK-3ß activity. These findings support further investigation into the mechanisms of cdc42/GSK-3ß-mediated axonogenesis.

Divergent Chemistry Paths for 3D and 1D Metallo-Covalent Organic Frameworks (COFs).

The marriage of dynamic covalent chemistry (DCC) and coordination chemistry is a powerful tool for assembling complex architectures from simple building units. Recently, the synthesis of woven covalent organic frameworks (COFs) with topologically fascinating structures has been achieved using this approach. However, the scope is highly limited and there is a need to discover new pathways that can assemble covalently linked organic threads into crystalline frameworks. Herein, we have identified branching pathways leading to the assembly of three-dimensional (3D) woven COFs or one-dimensional (1D) metallo-COFs (mCOFs), where the mechanism is underpinned by the absence or presence of ligand exchange.

Candidate biomarkers of EV-microRNA in detecting REM sleep behavior disorder and Parkinson's disease.

Parkinson's disease (PD) lacks reliable, non-invasive biomarker tests for early intervention and management. Thus, a minimally invasive test for the early detection and monitoring of PD and REM sleep behavior disorder (iRBD) is a highly unmet need for developing drugs and planning patient care. Extracellular vehicles (EVs) are found in a wide variety of biofluids, including plasma. EV-mediated functional transfer of microRNAs (miRNAs) may be viable candidates as biomarkers for PD and iRBD. Next-generation sequencing (NGS) of EV-derived small RNAs was performed in 60 normal controls, 56 iRBD patients and 53 PD patients to profile small non-coding RNAs (sncRNAs). Moreover, prospective follow-up was performed for these 56 iRBD patients for an average of 3.3 years. Full-scale miRNA profiles of plasma EVs were evaluated by machine-learning methods. After optimizing the library construction method for low RNA inputs (named EVsmall-seq), we built a machine learning algorithm that identified diagnostic miRNA signatures for distinguishing iRBD patients (AUC 0.969) and PD patients (AUC 0.916) from healthy individuals; and PD patients (AUC 0.929) from iRBD patients. We illustrated all the possible expression patterns across healthy-iRBD-PD hierarchy. We also showed 20 examples of miRNAs with consistently increasing or decreasing expression levels from controls to iRBD to PD. In addition, four miRNAs were found to be correlated with iRBD conversion. Distinct characteristics of the miRNA profiles among normal, iRBD and PD samples were discovered, which provides a panel of promising biomarkers for the identification of PD patients and those in the prodromal stage iRBD.

Cropland carbon stocks driven by soil characteristics, rainfall and elevation.

Soil organic carbon (SOC) can influence atmospheric CO2 concentration and then the extent to which the climate emergency is mitigated globally. It follows the elucidation of the driving factors of cropland SOC stocks, which is fundamental to reducing soil carbon loss and promoting soil carbon sequestration. Here, we examined the influence of 16 environmental variables on SOC stocks and sequestration based on three machine learning soil mapping methods, i.e. multiple linear regression (MLR), random forest (RF) and extreme gradient boosting (XGBOOST), with 2875 observed soil samples from cropland topsoil across Hunan Province, China in 2010. We employed a structural equation model (SEM) to extricate the driving mechanisms of environmental variables on SOC stocks at the regional scale. Our results show that XGBOOST had the most reliable performance in predicting SOC stocks, explaining 66 % of the total SOC stock variation. Croplands with high SOC stocks were distributed in low-altitude and water-sufficient areas. The partial dependence of SOC on precipitation showed a trend of increasing and then slowly decreasing. In addition, the grid-based SEM results clearly presented the direct and indirect routes of environmental variables' impacts on cropland SOC stocks. Soil properties regulated by elevation, were the most influential natural factor on SOC stocks. Precipitation and elevation drove SOC stocks through direct and indirect effects respectively. Our SEM combined with machine learning approach can provide an effective explanation of the driving mechanism for SOC accumulation. We expect our proposed modelling approach can be applied to other regions and offer new insights, as a reference for mitigating cropland soil carbon loss under climate emergency conditions.

Fluorinated Covalent Organic Framework-Based Nanofluidic Interface for Robust Lithium-Sulfur Batteries.

To realize the practical application of lithium-sulfur (Li-S) batteries, there is a need to inhibit uncontrolled Li deposition by facilitating Li-ion migration, and suppress the irreversible consumption of cathodes by preventing polysulfide shuttling. However, a permselective artifical membrane or interlayer which features fast ion transport but low polysulfide crossover is elusive. Here, we report the design and synthesis of a fluorinated covalent organic framework (4F-COF)-based membrane with a high permselectivity and increased battery lifespan. Combining density functional theory calculation, molecular dynamic simulation, and in situ Raman analysis, we demonstrate that fluorinated COF eliminates polysulfides shutting and dendritic lithium formation. Consequently, Li symmetrical cells demonstrate Li plating/stripping behaviors for 2000 h under 1 mA cm-2. More importantly, Li-S batteries based on the 4F-COF/PP separator achieve cycling retention of 82.3% over 1000 cycles at 2 C, rate performance of 568.0 mA h g-1 at 10 C, and an areal capacity of 7.60 mA h cm-2 with a high sulfur loading (∼9 mg cm-2). This work demonstrates that functionalizing nanochannels in COFs can impart permselectivity for energy storage applications.

Computational investigation of a 3D-printed skin substitute with orthotropy in mechanical property.

As a promising treatment for third-degree burns, grafting with bioengineering skin substitutes shows a capability to overcome the deficiency of donor skin. Similar mechanical properties with human skin are required for employed skin substitutes to avoid secondary damage to patients. Given the representativeness of orthotropy in mechanical properties, there is a need for developing orthotropic skin substitutes. This paper presents computational investigation as well as structural design for the fabrication of orthotropic skin substitutes. A finite element method (FEM) based mechanics simulation model for analyzing the stress field in the skin substitute was developed, by which the stress distribution in mimetic structures of the epidermis and dermis can be acquired. Moreover, the equation of Young's modulus was deduced based on the simulation result, which expressed the mechanical property of designed skin substitutes. Furthermore, several structures of skin substitutes were proposed and their calculated Young's modulus ranged from 21.87 kPa to 213.32 kPa, which was similar to the human skin. Ultimately, uniaxial tensile tests were performed for three types of 3D-printed orthotropic skin substitutes, which validates the feasibility to regulate Young's modulus by regulating the structure of fabricated skin substitutes.

Investigation on the Temperature Distribution Uniformity of an Extrusion-Based 3D Print Head and Its Temperature Control Strategy.

Extrusion-based 3D printing for thermoplastic polymers manifests potential for the fabrication of biocompatible and biodegradable scaffolds. However, the uncontrollable shape of printed filaments usually negatively impacts on the printing processes. Non-uniform temperature in the print head is a primary cause of inaccuracy in the diameter of filaments formed during the process of extruding thermoplastic polymers. Therefore, the temperature distribution inside the print head must be controlled accurately. This study developed a novel print head configuration with two groups of controllable heat sources for extrusion-based printing of thermoplastic polymers. Subsequently, a numerical thermal analysis based on the finite element method (FEM) was conducted to investigate the temperature field in the print head during the heating process. Moreover, a temperature control strategy is proposed under which the temperature distribution of the print head can be regulated. The temperature uniformity can be improved with the proposed temperature control strategy. Lastly, groups of printing trials were implemented, and the printed filaments showed excellent uniformity of diameter when temperature distribution uniformity was controlled in the print head.

A modified method for Billroth-II gastrojejunostomy after laparoscopy-assisted distal gastrectomy.

Background: There are many types of gastrojejunostomy reconstruction after laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer, each of which has merits and demerits. This study introduced a novel method (called pant-shaped anastomosis) involving the construction of a side-to-side anastomosis between the afferent loop and efferent loop at the site of gastrojejunal anastomosis using a linear stapler. The results of applying pant-shaped anastomosis to LADG were also analyzed. Methods: The clinical data of 96 patients who underwent LADG with pant-shaped anastomosis between June 2018 and June 2020 at The First Affiliated Hospital of Wannan Medical College (Wuhu City, China) were analyzed retrospectively. Results: All procedures were successfully completed without conversion to open laparotomy. An average pant-shaped anastomosis took 22 min to construct and had a mean incision length of 5.3 cm. The mean time to postoperative first flatus was 3.5 days. The mean time to intake of an oral semiliquid diet was 5.5 days. The average postoperative hospital stay was 8.2 days. No patient developed extraluminal bleeding, intraluminal bleeding, anastomosis leakage, afferent obstruction, internal herniation or pancreatitis. The proportion of patients who experienced significant reflux was 10.1% (Visick III-IV). In total, 62.6% of patients exhibited endoscopic reflux gastritis of grade 1 or less. Conclusions: Pant-shaped anastomosis is a safe and simple procedure. It is a feasible option to reduce afferent obstruction after LADG in patients with distal gastric cancer.

Efficacy of idebenone in the Treatment of iRBD into Synucleinopathies (EITRS): rationale, design, and methodology of a randomized, double-blind, multi-center clinical study.

Background: As the strongest prodromal marker of α-synuclein-specific neurodegeneration, idiopathic REM sleep behavior disorder (iRBD) is becoming a focus of interest in disease-modifying therapy. Idebenone has been widely portrayed as a potent antioxidant targeting mitochondrial dysfunction. Previous study has identified the effect of idebenone on Parkinson's disease with promising outcomes by regulating mitophagy. A novel indication of idebenone should be highlighted in iRBD population. Methods: The EITRS study is a randomized, double-blind, multi-center clinical study assessing the efficacy and safety of idebenone in the treatment of iRBD into synucleinopathies. One hundred forty-two patients (aged 40-75 years old) with clinically diagnosed iRBD are planned to be recruited with 80% statistical power and randomly assigned to idebenone (30 mg each time, three times a day) or matching placebo orally for 5 years. The assessment of rating scales, blood testing and neuroimaging examinations will be conducted at baseline, the 1st, 3rd and 5th year of follow-up. The primary efficacy endpoint is the 5-year conversion rate in patients with iRBD. The secondary endpoint is the safety and tolerability of idebenone in the treatment of iRBD. The study has been launched in July 2020. Discussion: This is the first prospective study designed to identify the efficacy and safety of idebenone on the treatment of iRBD into synucleinopathies. The current results are expected to promote the development of evidence-based recommendations for the management of patients with iRBD. Furthermore, we hope to provide insights on a possible disease-modifying approach with robust evidence. Trial Registration: Clinicaltrials.gov, identifier: NCT04534023.

A Modified Anastomosis Technique for Esophagojejunostomy after Laparoscopy-Assisted Total Gastrectomy: A Single Team Preliminary Experience.

RESULTS: There were no significant differences between the cRY group and pRY group regarding age, sex, BMI, neoadjuvant therapy, preoperative comorbidities, history of laparotomy, ASA score, tumor location, pathological stage, total operative time, incision length, blood loss, time-to-first flatus, time-to-first soft diet, and postoperative hospital stays. The proportions of patients who received a 21 mm stapler were higher in the cRY group (7/44) than that in the pRY group (0/68) (P = 0.003). 7 anastomotic complications were reported (6 in the cRY group versus 1 in pRY group; P = 0.028) of which five (83.3%) in the cRY were anastomotic stenosis versus none in the pRY group (P = 0.044). CONCLUSIONS: The application of pant-shaped anastomosis for esophagojejunostomy after LTG is a safe and feasible procedure and has an advantage when the jejunum diameter is small.

Phosphorus/Phosphide-Based Materials for Alkali Metal-Ion Batteries.

Phosphorus- and phosphide-based materials with remarkable physicochemical properties and low costs have attracted significant attention as the anodes of alkali metal (e.g., Li, Na, K, Mg, Ca)-ion batteries (AIBs). However, the low electrical conductivity and large volume expansion of these materials during electrochemical reactions inhibit their practical applications. To solve these problems, various promising solutions have been explored and utilized. In this review, the recent progress in AIBs using phosphorus- and phosphide-based materials is summarized. Thereafter, the in-depth working principles of diverse AIBs are discussed and predicted. Representative works with design concepts, construction approaches, engineering strategies, special functions, and electrochemical results are listed and discussed in detail. Finally, the existing challenges and issues are concluded and analyzed, and future perspectives and research directions are given. This review can provide new guidance for the future design and practical applications of phosphorus- and phosphide-based materials used in AIBs.

Development and Validation of a Prognostic Model for Cognitive Impairment in Parkinson's Disease With REM Sleep Behavior Disorder.

The presentation and progression of Parkinson's disease (PD) are not uniform, but the presence of rapid eye movement sleep behavior disorder (RBD) in PD patients may indicate a worse prognosis than isolated PD. Increasing evidence suggests that patients with comorbid PD and RBD (PD-RBD) are more likely to develop cognitive impairment (CI) than those with isolated PD; however, the predictors of CI in PD-RBD patients are not well understood. This study aimed to develop a prognostic model for predicting mild cognitive impairment (MCI) in PD-RBD patients. The data of PD-RBD patients were extracted from the Parkinson's Progression Markers Initiative study (PPMI), and the sample was randomly divided into a training set (n = 96) and a validation set (n = 24). PD-MCI as defined by the level II Movement Disorder Society (MDS) diagnostic criteria was the outcome of interest. The demographic features, clinical assessments, dopamine transporter (DAT) imaging data, cerebrospinal fluid (CSF) analyses and genetic data of PD patients were considered candidate predictors. We found that performance on the University of Pennsylvania Smell Identification Test (UPSIT), the mean signal and asymmetry index of the putamen on DAT imaging, p-tau/α-syn and p-tau in CSF, and rs55785911 genotype were predictors of PD-MCI in PD-RBD patients. A C-index of 0.81 was obtained with this model, and a C-index of 0.73 was obtained in the validation set. Favorable results of calibrations and decision curve analysis demonstrated the efficacy and feasibility of this model. In conclusion, we developed a prognostic model for predicting MCI in PD-RBD patients; the model displayed good discrimination and calibration and may be a convenient tool for clinical application. Larger samples and external validation sets are needed to validate this model.

Inverted core-shell potential energy landscape of icosahedral clusters in deeply undercooled metallic liquids and glasses and its effect on the glass forming ability of bcc and fcc metals.

Current understanding of the origin of icosahedral clusters or icosahedral short-range ordering in undercooled metallic liquids or glasses is based on Frank's consideration of an isolated icosahedron whose core has lower potential energy than the shell. Using large scale atomistic simulations and statistical analysis of several bcc (body-centered-cubic) and fcc (face-centered-cubic) metals, here we show that the shells of icosahedrons spontaneously formed inside deeply undercooled metallic liquids or glasses in fact have lower (averaged) potential energy than the cores. The shell potential energy deficiency occurs only to the icosahedral clusters but not to the equilibrium-crystal clusters, and, for icosahedral clusters, this deficiency grows with decreasing temperature. Compared with fcc metals, bcc metals exhibit greater potential energy deficiency on the icosahedral shells and produce significantly more icosahedral clusters upon liquid quenching, which explains the higher tendency of bcc metals to be vitrified observed in ultrafast cooling experiments. Inspecting the potential energy deficiency on the icosahedral shells through computation provides a new avenue to the search for amorphous metals (i.e. metallic glasses) with high glass forming ability and processability.

3D surface condensation of large atomic shear strain in nanoscale metallic glasses under low uniaxial stress.

Nanoscale metallic glasses (MGs) are frequently used in experimental and computational studies to probe the deformation mechanisms in amorphous metals. Potential consequences of the significant surface to volume ratio in these extremely small materials, nevertheless, are not well understood. Here, using molecular dynamics simulations and novel selective 3D visualization, we show that significant irreversible atomic shear strain condenses on the 3D surface of these materials under low uniaxial stress, while the interior atoms are bearing much lower, mostly reversible shear strain. This is observed for various sample geometries, dimensions, strain rates and temperatures, and attributable to the correlations of atomic shear strain with atomic potential energy and coordination number. The results reveal the profound influence of the surface on the strain partitioning in nanoscale MGs across the 3D volume, critical to the initiation and continuation of plasticity.

Grape seed proanthocyanidin inhibits monocrotaline-induced pulmonary arterial hypertension via attenuating inflammation: in vivo and in vitro studies.

Inflammation in pulmonary arterioles initiates and maintains pathological processes in pulmonary arterial hypertension (PAH), and inhibition of it attenuates PAH development. Grape seed proanthocyanidin (GSP) is believed to be effective in protecting vascular system via inhibiting inflammation, while its effect on pulmonary circulation remains inconclusive. In this study, we made observations in monocrotaline (MCT)-induced PAH rats and found decreases in mean pulmonary arterial pressure, pulmonary vessel resistance, right ventricular hypertrophy index, percentage of medial wall thickness, percentage of medial wall area, and lung weight of wet and dry tissue ratio after GSP administration in vivo. At the cellular and molecular levels, we also found several effects of GSP on MCT-induced PAH: (a) endothelial nitric oxide synthase expression in lung tissue and plasma NO level were increased; (b) Ca2+ level in pulmonary arterial smooth muscle cell (PASMC) was decreased; (c) transcription of inflammatory factors such as myeloperoxidase, interleukin (IL)-1ß, IL-6 and tumor necrosis factor alpha (TNF-α) was down-regulated in lung tissue; (d) nuclear factor-κB pathway was inhibited as IκBα was less phosphorylated; (e) TNFα-induced PASMC overproliferation could be inhibited. These results indicated a possible mechanism of GSP reversing pulmonary vascular remodeling and vascular contraction by inhibiting inflammation, and it may be useful for preventing PAH development.

[Effects of apple polyphenols on monocrotaline-induced pulmonary vascular remodeling in rats and its mechanism].

OBJECTIVE: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. METHODS: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca2+ in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. RESULTS: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca2 + in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P＜0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca2+ indicators of the apple polyphenol treatment group were decreased significantly (P＜0.05). CONCLUSION: MCT can increase COX-2 expression and intracellular Ca2+ in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.

3-Bromopyruvate reverses hypoxia-induced pulmonary arterial hypertension through inhibiting glycolysis: In vitro and in vivo studies.

BACKGROUND: Pulmonary arterial smooth muscle cell (PASMC) proliferation is vital to pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) pathogenesis, and inhibiting PASMC metabolism could serve as a new possible therapy to reverse the process. 3-Bromopyruvate (3-BrPA) is an effective glycolysis inhibitor with its effect in PAH remains unclear. Our study aims to assess the therapeutic effect of 3-BrPA in PAH rats and investigate the possible mechanism of 3-BrPA in PASMC proliferation and apoptosis. METHODS: 27 healthy SD rats were grouped and treated with hypoxia/normoxia and administration of 3-BrPA/physiological saline. Mean pulmonary artery pressure (mPAP) and cardiac output (CO) were measured and pulmonary vascular resistance (PVR) was calculated. Right ventricular hypertrophy index (RVHI) was calculated to evaluate the right ventricular hypertrophy degree. The percentage of medial wall area (WA%) and medial wall thickness (WT%) were measured by image analysis. PASMCs groups received hypoxia/normoxia treatments and 3-BrPA/physiological saline. PASMC proliferation and migration were respectively detected by CCK-8 and cell wound scratch assay. Hexokinase II (HK-2) expression and lactate level were respectively measured by Western Blotting and lactate test kit to detect glycolysis. RESULTS: mPAP, PVR, PVHI, WA% and WT% in rats increased after the hypoxia treatment, but were lower compared to rats received 3-BrPA in hypoxia environment. HK-2 expression, lactate concentration, OD value and scratch areas in PASMCs increased after the hypoxia treatment, but were decreased after the administration of 3-BrPA. CONCLUSION: 3-BrPA can inhibit PASMC proliferation and migration by inhibiting glycolysis, and is effective in reversing the vascular remodeling in hypoxia-induced PAH rats.