Patients' expectancy scale of acupuncture: Development and clinical performance test.

PURPOSE: This study aims to develop and validate a concise tool for evaluating acupuncture expectancy that is easy to understand and conforms to acupuncture characteristics. MATERIALS AND METHODS: A draft was created using the Delphi consensus method. Reliability, validity, discrimination, and feasibility tests were conducted at the item and scale levels. RESULTS: The scale themes were defined as disease-related, treatment-related, process-related, and outcome-related. After two rounds of Delphi surveys with good experts' reliability (authority coefficients of experts were 0.86 and 0.87 in the two rounds) and agreement (Kendall's concordance coefficient of the participants were 0.33 and 0.15 in the two rounds, P < 0.05), 11 items (the mean score for item importance, full mark ratios, and coefficient of variation of items were ≥3.5, ≥25%, and ≤0.30, respectively) were included in the draft. A total of 145 individuals were recruited to test the draft. Reliability was assessed by Cronbach's α coefficient (0.90), split-half reliability coefficient (0.89), and test-retest reliability (Pearson's coefficient = 0.74, P < 0.05). Content validity was assessed by the content validity index (Item-CVI ≥ 0.78 and Scale-CVI/Ave = 0.92), and a confirmatory factor analysis was performed to assess the construct validity. The discrimination of scale items was evaluated by the critical ratio (CR > 3.00) and the homogeneity test (item-total correlations >0.40). Feasibility was assessed through the acceptance rate (recovery rate = 98.60%, response rate = 100%), completion rate (100%), and completion time (4.99 ± 6.80 min). CONCLUSION: The patients' expectancy scale of acupuncture (PESA) consists of 11 items with four themes, disease-related, treatment-related, process-related, and outcome-related. It has great reliability, validity, discrimination, and feasibility and has the potential to evaluate acupuncture expectancy in clinical trials.

Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice.

The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.

Ubiquitination of the GluA1 Subunit of AMPA Receptors Is Required for Synaptic Plasticity, Memory, and Cognitive Flexibility.

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice.SIGNIFICANCE STATEMENT Subcellular targeting and membrane trafficking determine the precise number of AMPA-type glutamate receptors at synapses, processes that are essential for synaptic plasticity, learning, and memory. Post-translational ubiquitination of the GluA1 subunit marks AMPARs for degradation, but its functional role in vivo remains unknown. Here we demonstrate that the GluA1 ubiquitin-deficient mice exhibit an altered threshold for synaptic plasticity accompanied by deficits in short-term memory and cognitive flexibility. Our findings suggest that activity-dependent ubiquitination of GluA1 fine-tunes the optimal number of synaptic AMPARs required for bidirectional synaptic plasticity and cognition in male mice. Given that increases in amyloid-ß cause excessive ubiquitination of GluA1, inhibiting that GluA1 ubiquitination may have the potential to ameliorate amyloid-ß-induced synaptic depression in Alzheimer's disease.

lncRNA MEG3 Promotes PDK4/GSK-3ß/ß-Catenin Axis in MEFs by Targeting miR-532-5p.

Studies reported the positive and negative osteogenic effects of MEG3 in mesenchymal stem cells (MSCs). This study aims at clarifying the osteogenic potential of MEG3 and the underlying mechanism. Bone morphogenetic protein 9- (BMP9-) transfected MSCs were recruited as an osteogenic model in vitro, and ectopic bone formation were used in vivo to explore the effect of MEG3 on osteogenesis. We found that overexpression of MEG3 facilitated BMP9-induced osteogenic markers, ALP activities, and matrix mineralization. However, knockdown of MEG3 attenuated BMP9-induced osteogenic markers. MEG3 increased the phosphorylation of GSK-3ß and the protein level of ß-catenin. Pyruvate dehydrogenase kinase 4 (PDK4) can also combine with GSK-3ß and increase the latter phosphorylation. Moreover, MEG3 increased the mRNA level of PDK4. The ceRNA analysis showed that MEG3 may regulate the expression of PDK4 via microRNA 532-5p (miR-532-5p). The MEG3-enhanced GSK-3ß/ß-catenin axis can be attenuated by miR-532-5p, and miR-532-5p inhibitor partly rescued endogenous PDK4 and MEG3-mediated expression of PDK4. MEG3 may potentiate PDK4 and GSK-3ß/ß-catenin by inhibiting miR-532-5p.

Risk Factors for Glycemic Control in Hospitalized Patients with Type 2 Diabetes Receiving Continuous Subcutaneous Insulin Infusion Therapy.

INTRODUCTION: Patients with diabetes are confronted with numerous obstacles to achieve adequate glycemic control during hospitalization. The aim of this study was to explore the risk factors associated with glycemic control in hospitalized patients with type 2 diabetes mellitus (T2DM) treated with continuous subcutaneous insulin infusion (CSII). METHODS: This cross-sectional study included 5223 patients hospitalized with T2DM in a tertiary hospital in Xiamen (China) between January 2017 and December 2019. All patients were managed according to established protocols for glycemic monitoring and insulin pump treatment regimens. Demographic information and clinical profiles were collected from electronic health records. Multiple linear regression analysis was used to identify the risk factors associated with glycemic control. RESULTS: Among the 5223 hospitalized patients with T2DM receiving CSII therapy, 55.2% achieved their ideal blood glucose level (3.9-10.0 mmol/L), 44.5% experienced hyperglycemia (> 10.0 mmol/L), and 0.3% experienced hypoglycemia (< 3.9 mmol/L) during their hospitalization. Multivariate analyses showed that among inpatients with T2DM, older age, male gender, higher low-density lipoprotein-cholesterol (LDL-C) level, lower C-peptide (C-P) level, lower body mass index (BMI), longer duration of diabetes, previous insulin prescriptions, nephropathy, and retinopathy were factors more likely to be associated with a blood glucose level in the hyperglycemic range (P < 0.05). We also observed that among hospitalized patients with T2DM, those with lower BMI, lower C-P, lower LDL-C, longer disease duration, and previous insulin prescriptions were more likely to correlate with a higher proportion of hypoglycemia range (all P < 0.05). CONCLUSION: Older age, male gender, lower BMI, lower C-P, higher LDL-C, previous insulin prescriptions, longer duration of diabetes, nephropathy, and retinopathy may be risk factors for a higher proportion of hyperglycemic events in hospitalized patients with T2DM under CSII therapy. Furthermore, lower BMI, lower C-P, lower LDL-C, longer duration of diabetes, and previous insulin prescriptions were found to be important factors for a higher proportion of hypoglycemic events. Evaluating the clinical features, comorbidities, and complications of hospitalized patients is essential to achieve reasonable glycemic control.

Study on the Effect of Early Comprehensive Intervention of Skin Contact Combined with Breastfeeding on Improving Blood Glucose in Early Birth of Newborns with Gestational Diabetes Mellitus.

Objective: To explore the value of early comprehensive intervention of skin contact combined with breastfeeding on improving early blood glucose in newborns with gestational diabetes mellitus (GDM). Methods: A total of 300 newborns from pregnant women with gestational diabetes who were hospitalized in Wuxi People's Hospital from January 2021 to December 2021 were randomly assigned into the observation group (n = 150) and the control group (n = 150). The former group received early comprehensive intervention of skin contact combined with breastfeeding, and the latter group received postnatal naked contact, physical examination after late navel severing, and routine nursing intervention such as early contact and early sucking in 30 min. The peripheral blood microglucose value at 1 and 2 hours after birth, neonatal hospitalization rate, ear temperature of 30 min, 60 min, 90 min, and 120 min after birth, neonatal crying, incidence of postpartum hemorrhage, uterine contraction/wound pain index, lactation before delivery, immediately after delivery, early sucking 15 min, and 2 hours postpartum were observed. Results: Compared to the control group, the values of trace blood glucose at 1 hour and 2 hours after birth in the observation group were higher, and the difference between groups was statistically significant (P < 0.05), the neonatal hospitalization rate in the observation group was lower, and the difference between groups was statistically significant (P < 0.05); the ear temperature of 30 min, 60 min, 90 min and 120 min after birth in the observation group was higher, and the difference between groups was statistically significant (P < 0.05). The crying frequency of newborns in the observation group was lower, and the difference between groups was statistically significant (P < 0.05). The incidence of postpartum hemorrhage in the observation group was lower, and the difference between groups was statistically significant (P < 0.05). The rate of uterine contraction/wound pain index grade 1 in the observation group was higher, and the difference between groups was statistically significant (P < 0.05). The rates of uterine contraction/wound pain index grade 2 and grade 3 in the observation group were lower, and the difference between groups was statistically significant (P < 0.05). The rate of lactation at 2 hours postpartum in the observation group was higher, and the difference between groups was statistically significant (P < 0.05). Conclusion: Early comprehensive intervention of skin contact combined with breastfeeding can significantly increase the early blood glucose of newborns with GDM, effectively promote the occurrence of early hypoglycemia of GDM newborns, avoid a series of serious complications caused by excessive fluctuation of blood sugar, promote the stability of vital signs of newborns, reduce the hospitalization rate of newborns, improve the success rate of breastfeeding, reduce uterine contraction/wound pain, and reduce the incidence of postpartum hemorrhage. My clinical registration number is chictr220059454.

Impact of Azithromycin on Forsythiaside Pharmacokinetics in Rats: A Population Modeling Method.

OBJECTIVE: Lianhuaqingwen and Shuanghuanglian are drug treatment options for Corona Virus Disease 2019 (COVID-19). In China, use of traditional Chinese medicine with Shuanghuanglian or Lianhuaqingwen (for them, forsythiaside is the active antiviral and antibacterial component) in combination with azithromycin is common for the treatment of pediatric pneumonia. It is important to understand the reason why the combination of these compounds is better than a single drug treatment. This study aimed to explore the pharmacokinetic interaction between forsythiaside and azithromycin. METHODS: Twelve male Sprague-Dawley rats were randomly divided into an experimental group (Forsythia suspensa extract and azithromycin) and a control group (a single dose of Forsythia suspensa extract in 5% glucose solution). Plasma samples were collected at scheduled time points, and the high-performance liquid chromatography combined with ultraviolet method was used to determine the plasma forsythiaside concentration. Non-compartmental analysis and population pharmacokinetic methods were used to investigate the forsythiaside pharmacokinetic difference between the experimental and control group. RESULTS: Compared with a single administration, the area under the curve and half-life of forsythiaside increased, and forsythiaside clearance decreased significantly after co-administration with azithromycin. The in vivo behavior of forsythiaside could be described by the one compartment model. The forsythiaside clearance decreased when combined with azithromycin. Visual evaluation and bootstrap results suggested that the final model was precise and stable. CONCLUSION: Co-administration of azithromycin can significantly decrease the forsythiaside clearance and increase drug exposure. A lower dose of azithromycin can obtain sufficient forsythiaside concentration to provide antiviral and antibacterial activity.

Genome-Wide Association Study Suggests the Variant rs7551288*A within the DHCR24 Gene Is Associated with Poor Overall Survival in Melanoma Patients.

Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected (p = 2 × 10-6). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.

Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice.

Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.

Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit.

NMDA receptor (NMDAR)-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. Most synaptic NMDAR currents in the adult forebrain are mediated by GluN2A-containing receptors, which are rapidly inserted into synapses during long-term potentiation (LTP); however, the underlying molecular mechanisms remain poorly understood. In this study, we show that GluN2A is phosphorylated at Ser-1459 by Ca2+/calmodulin-dependent kinase IIα (CaMKIIα) in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the sorting nexin 27 (SNX27)-retromer complex, thereby enhancing the endosomal recycling of NMDARs. Loss of SNX27 or CaMKIIα function blocks the glycine-induced increase in GluN2A-NMDARs on the neuronal membrane. Interestingly, mutations of Ser-1459, including the rare S1459G human epilepsy variant, prolong the decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the duration of channel opening. These findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but they also explain how the S1459G variant dysregulates NMDAR function.

Nanoparticle-Hydrogel Composite Drug Delivery System for Potential Ocular Applications.

Intravitreal injections are clinically established procedures in the treatment of posterior eye diseases, such as wet age-related macular degeneration (wet AMD) which requires monthly intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) protein drugs that can lead to complications due to frequent dosing. In this study, we designed a composite drug delivery system (DDS) consisting of drug-loaded poly (lactide-co-glycolide) (PLGA) nanoparticles and a chemically crosslinked hyaluronan hydrogel to reduce the dosing frequency. The morphology, size, composition, and drug loading efficiency of the prepared nanoparticles were characterized. The properties of the modified hyaluronan polymers used were also examined. The degree of swelling/degradation and controlled release ability of the hyaluronan hydrogel and the composite DDS were identified using bovine serum albumin (BSA) as a model drug. The results show that this system can retain 75% of its wet weight without losing its integrity and release the model drug at the rate of 0.4 µg/day for more than two months under physiological conditions. In addition, the nanoparticulate formulation of the system can further improve bioavailability of the drugs by penetrating deep into the retinal layers. In conclusion, the proposed composite DDS is easily prepared with biocompatible materials and is promising for providing the sustained release of the protein drugs as a better treatment for ocular neovascular diseases like wet AMD.

Simvastatin protects heart function and myocardial energy metabolism in pulmonary arterial hypertension induced right heart failure.

The favorable effect of simvastatin on pulmonary arterial hypertension (PAH) has been well defined despite the unknown etiology of PAH. However, whether simvastatin exerts similar effects on PAH induced right heart failure (RHF) remains to be determined. We aimed to investigate the function of simvastatin in PAH induced RHF. Rats in the RHF and simvastatin groups were injected intraperitoneally with monocrotaline to establish PAH-induced RHF model. The expression of miR-21-5p in rat myocardium was detected and miR-21-5p expression was inhibited using antagomiRNA. The effect of simvastatin on hemodynamic indexes, ventricular remodeling of myocardial tissues, myocardial energy metabolism, and calmodulin was explored. Dual-luciferase reporter system was used to verify the binding relationship between miR-21-5p and Smad7. In addition, the regulatory role of simvastatin in Smad7, TGFBR1 and Smad2/3 was investigated. Simvastatin treatment improved hemodynamic condition, myocardial tissue remodeling, and myocardial energy metabolism, as well as increasing calmodulin expression in rats with PAH-induced RHF. After simvastatin treatment, the expression of miR-21-5p in myocardium of rats was decreased significantly. miR-21-5p targeted Smad7 and inhibited the expression of Smad7. Compared with RHF rats, the expressions of TGFBR1 and Smad2/3 in myocardium of simvastatin-treated rats were decreased significantly. Collectively, we provided evidence that simvastatin can protect ATPase activity and maintain myocardial ATP energy reserve through the miR-21-5p/Smad/TGF-ß axis, thus ameliorating PAH induced RHF.

HSD3B1 variant and androgen-deprivation therapy outcome in prostate cancer.

OBJECTIVE: Rate-limiting enzyme 3b-hydroxysteroid dehydrogenase type 1 (3ßHSD1) encoded by HSD3B1 catalyzes the transition of dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT). The HSD3B1 (1245C) variant renders 3bHSD1 of resistant to ubiquitination and degradation, leading to a large amount of protein accumulation in the cell. Multiple clinical studies have shown that this mutation was correlated with resistance to androgen-deprivation therapy in prostate cancer. However, the results were not consistent depending on different treatment strategy and in some researches, the number of observed cases was relatively small. METHODS: To determine the effects of HSD3B1 (1245C) variant on resistance to androgen-deprivation therapy in prostate cancer, we performed a meta-analysis of the available literature. Electronic database searches identified appropriately designed studies that detected HSD3B1 in prostate cancer. We conducted a systematic search of studies in the following databases: PubMed, and EMBASE published until August 10, 2020 using the following search terms: (HSD3B1 AND ((((prostate cancer) OR prostatic neoplasm) OR prostatic carcinoma) OR prostatic cancer). RESULTS: Eight researches were included in this research. The result validated that the HSD3B1 (1245C) variant allele was associated with a shorter PFS (HR, 1.97; 95% CI, 1.39-2.79; P = 0.0001) (homozygous wild-type group) in men with prostate cancer when treated with ADT, however, a higher PFS (HR, 0.68; 95% CI, 0.48-0.96; P = 0.03) when treated with ADT and CYP17A1 inhibitor. CONCLUSION: The HSD3B1 (1245C) variant is a predictor of ADT plus CYP17A1 inhibitor response in prostate cancer.

PICK1 Controls Activity-Dependent Synaptic Vesicle Cargo Retrieval.

Efficient retrieval of synaptic vesicles (SVs) is crucial to sustain synaptic transmission. Protein interacting with C-kinase 1 (PICK1) is a unique PDZ (postsynaptic density-95/disc-large/zona-occluden-1)- and BAR (Bin-Amphiphysin-Rvs )-domain-containing protein that regulates the trafficking of postsynaptic glutamate receptors. It is also expressed in presynaptic terminals and is associated with the SVs; however, its role in regulating SV recycling remains unknown. Here, we show that PICK1 loss of function selectively slows the kinetics of SV endocytosis in primary hippocampal neurons during high-frequency stimulation. PICK1 knockdown also causes surface stranding and mislocalization of major SV proteins, synaptophysin and vGlut1, along the axon. A functional PDZ domain of PICK1 and its interaction with the core endocytic adaptor protein (AP)-2 are required for the proper targeting and clustering of synaptophysin. Furthermore, PICK1 and its interaction with AP-2 are required for efficient SV endocytosis and sustained glutamate release. Our findings, therefore, identify PICK1 as a key regulator of presynaptic vesicle recycling in central synapses.

Berberine Improves Inflammatory Responses of Diabetes Mellitus in Zucker Diabetic Fatty Rats and Insulin-Resistant HepG2 Cells through the PPM1B Pathway.

Berberine (BBR), a natural compound extracted from a Chinese herb, has been shown to effectively attenuate insulin resistance (IR) and inflammation in the clinic. However, its ameliorative mechanism against IR is not well defined. This study is aimed at investigating the effect of BBR and protein phosphatase, Mg2+/Mn2+-dependent 1B (PPM1B) on IR. Biochemical measurements and liver histopathology were detected using the biochemical analyzer and HE staining in ZDF rats, respectively. Microarray analysis of liver tissues was performed, and differentially expressed gene (DEG) levels were examined by quantitative real-time PCR (qPCR) and Western blot. Additionally, the effect of BBR was also explored in HepG2-IR cells. The glucose oxidase method and the fluorescent glucose analog were used to detect glucose consumption and uptake, respectively. The PKA inhibitor H89, ELISA, qPCR, Western blot, and immunofluorescence staining were employed to estimate the expression levels of related signaling pathways. To evaluate the roles of PPM1B, HepG2-IR cells were stably infected with lentivirus targeting PPM1B. The administration of BBR drastically decreased the body weight, urine volume, blood glucose, blood urea nitrogen (BUN), CHOL, hepatic index levels, and pathologic changes and improved ALB levels in ZDF rats with PPM1B upregulation. Furthermore, BBR effectively improves glucose consumption, uptake, and inflammation in HepG2-IR cells. The knockdown of PPM1B expression aggravated the inflammatory response and glycometabolism disorder in HepG2-IR cells. Mechanistically, a reversal in the expression of cAMP, PKA, PPM1B, PPARγ, LRP1, GLUT4, NF-κB p65, JNK, pIKKß Ser181, IKKß, IRS-1 Ser307, IRS-1, IRS-2 Ser731, IRS-2, PI3K p85, and AKT Ser473 contributes to ameliorate IR in HepG2-IR cells with BBR treatment. Altogether, these results suggest that BBR might regulate IR progression through the regulation of the cAMP, PKA, PPM1B, PPARγ, LRP1, GLUT4, NF-κB p65, JNK, pIKKß Ser181, IKKß, IRS-1 Ser307, IRS-1, IRS-2 Ser731, IRS-2, PI3K p85, and AKT Ser473 expression in the liver.

MSCs attenuate hypoxia induced pulmonary hypertension by activating P53 and NF-kB signaling pathway through TNFα secretion.

Hypoxia could cause vascular smooth muscle hypertrophy, leading to high pulmonary circulation resistance, pulmonary artery (PA) pressure, even pulmonary arterial hypertension (PAH). Recent studies have demonstrated the ability of mesenchymal stem cell (MSC) to ameliorate PAH but the mechanism was controversial. In this study, we revealed that the growth rate of pulmonary artery smooth muscle cells (PASMCs) treated with hypoxia was significantly increased than normal and showed lower expression of potassium channels. However, cells co-cultured with MSC showed decreased proliferation capability and down-regulated expression of ion channel of PAMSCs. The protein array data showed that the changes of PAMSCs was substantially associated with a high level of tumor necrosis factor alpha (TNFα) secretion from MSC. We further demonstrated that TNFα rescued the cell behavior of PAMSCs through activating the expression of P53 and NF-kB and inducing cell cycle arrest by P21/CDK2/CDK4 downregulation. These findings suggested that MSCs could attenuate abnormal function of PAMSCs by TNFα secretion, which was more or less associated with the beneficial effects of MSC on improving PAH.

Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study.

BACKGROUND: This study was planned to investigate the association betweenhuman cytomegalovirus (HCMV) infection and gastrointestinal cancer (GIC) risk, by undertaking a meta-analysis and case-control cross-sectional study. SUMMARY: A cross-sectional study analysis of 160 GIC patients and 100 control subjects indicated significantly higher HCMV prevalence in GIC patients based on the HCMV IgM test. However, a similar analysis based on an IgG test revealed no significant relationship. Further meta-analysis of 11 studies, including 1,044 patients and 991 healthy subjects, displayed HCMV infection as an important risk factor for not only colorectal cancer occurrence and development based on a HCMV DNA test, but also for GIC based on a HCMV IgM test. However, the IgG test again displayed no significant relationship between HCMV infection and GIC occurrence. Key Message: Overall, our study revealed that HCMV infection is associated with an increased GIC risk. However, additional studies are warranted to elucidate the molecular mechanism underlying this association.

Targeted Metabolomics for Plasma Amino Acids and Carnitines in Patients with Metabolic Syndrome Using HPLC-MS/MS.

Metabolic syndrome (MetS) is a health disorder characterized by metabolic abnormalities that predict an increased risk to develop cardiovascular disease (CVD) and type 2 diabetes. Biomarkers can provide an insight into the novel mechanism for MetS and can be potentially used for personalized response to therapies. We exploited a targeted HPLC-MS/MS method to characterize plasma amino acids and carnitine metabolic profile in MetS patients. A training set (40 cases and 40 controls) and validation set (80 MetS patients and 80 healthy controls) were carried out to find the metabolic profiles. We discovered two carnitine metabolites including hydroxydecanoyl carnitine and methylglutarylcarnitine. Our results indicated that the decreased level of hydroxydecanoyl carnitine and methylglutarylcarnitine may be associated with the risk of MetS. These biomarkers may improve the risk prediction and provide a novel tool for monitoring of the progression of disease and response to treatment in MetS patients.

Curcumin inhibits the formation of atherosclerosis in ApoE-/- mice by suppressing cytomegalovirus activity in endothelial cells.

BACKGROUND: Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells. AIMS: This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro. MATERIALS AND METHODS: Cur (0.5, 1, and 2 µM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE-/- mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo. KEY FINDINGS: As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments. SIGNIFICANCE: This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.

MicroRNA-143-5p modulates pulmonary artery smooth muscle cells functions in hypoxic pulmonary hypertension through targeting HIF-1α.

This paper explores the potential mechanism of microRNA-143-5p regulation effects on pulmonary artery smooth muscle cells (PASMCs) functions in hypoxic pulmonary hypertension (HPH) via targeting HIF-1a, which may offer a new idea for HPH therapy. PASMCs were transfected with mimics control/miR-143-5p mimics or inhibitor control/miR-143-5p inhibitor. We used Western blotting and RT-qPCR to detect the protein and mRNA expressions, CCK-8 assay to detect cellular viability, Annexin V-FITC/PI staining and caspase- 3/cleaved caspase-3 protein to evaluate cellular apoptosis, transwell migration experiment for cellular migration measurement and Dual luciferase reporter gene assay to prove the target of miR-143-5p. Cells under hypoxic condition presented the decreased protein and mRNA expressions of α-smooth muscle actin (SM-α-actin), Myocardin, smooth muscle myosin heavy chain (SMMHC), and smooth muscle-22α (SM22α), Calponin1 and Hypoxia-inducible factor-1α(HIF-1α), the increased cell viability and miR-143-5p level; Overexpression of miR-143-5p obviously reduced vascular smooth muscle-specific contraction marker protein levels and cellular apoptosis, increased cellular migration of PASMCs with hypoxia stimulation; Low-expression of miR-143-5p caused the opposite changes, while co-transfected with Si HIF-1 α blocked the beneficial effects of miR-143-5p inhibition on PASMCs under hypoxia. MicroRNA-143-5p can promote the phenotype conversion, proliferation and migration of pulmonary artery smooth muscle cells under hypoxic condition through direct targeting of HIF-1α.