Distinct characteristics of the gut virome in patients with osteoarthritis and gouty arthritis.

BACKGROUND/PURPOSE(S): The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation. METHODS: We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples. RESULTS: Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA. CONCLUSION: Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies.

Effects of ultrasound monitoring of gastric residual volume on feeding complications, caloric intake and prognosis of patients with severe mechanical ventilation.

BACKGROUND: Monitoring of gastric residual is an important approach for assessing gastric emptying in patients with mechanical ventilation. By monitoring gastric contents, the enteral nutrition scheme can be adjusted in time to ensure feeding safety. AIM: To investigate the effects of ultrasound monitoring on the incidence of feeding complications, daily caloric intake and prognosis of patients with severe mechanical ventilation. To analyze the clinical significance of ultrasound monitoring of gastric residual volume (GRV) up to 250 mL to provide a theoretical basis for clinical practice. METHODS: Patients admitted to the department of emergency medicine of the Affiliated Hospital of Nantong University from January 2018 to June 2022 who received invasive mechanical ventilation and continuous enteral nutrition support within 24-48 h after admission were enrolled in this study. Medical records for patients within 7 d of hospitalization were retrospectively analyzed to compare the incidence of feeding complications, daily caloric intake and clinical prognosis between patients with gastric residual ≥ 250 mL and < 250 mL, as monitored by ultrasound on the third day. RESULTS: A total of 513 patients were enrolled in this study. Incidences of abdominal distension, diarrhea, and vomiting in the < 250 mL and ≥ 250 mL groups were: 18.4% vs 21.0%, 23.9% vs 32.3% and 4.0% vs 6.5%, respectively; mortality rates were 20.8% vs 22.65%; mechanical ventilation durations were 18.30 d vs 17.56 d while lengths of stay in the intensive care units (ICU) were 19.87 d vs 19.19 ± 5.19 d. Differences in the above factors between groups were not significant. Gastric residual ≥ 250 mL was not an independent risk factor for death and prolonged ICU stay. However, target feeding time of patients in the ≥ 250 mL group was longer than that of patients in the ≥ 250 mL group, and caloric intake (22.0, 23.6, 24.8, 25.3 kcal/kg/d) for patients in the ≥ 250 mL group from the 4th day to the 7th day of hospitalization was lower than that of patients in the ≥ 250 mL group (23.2, 24.8, 25.7, 25.8 kcal/kg/d). On the 4th day (Z = 4.324, P = 0.013), on the 5th day (Z = 3.376, P = 0.033), while on the 6th day (Z = 3.098, P = 0.04), the differences were statistically significant. CONCLUSION: The use of ultrasound to monitor GRV and undertaking clinical interventions when the monitoring value is ≥ 250 mL has no significant effects on incidences of feeding complications and clinical prognostic outcomes, however, it significantly prolongs the time to reach target feeding, reduces the daily intake of calories during ICU hospitalization, and increases the risk of insufficient nutrition of patients. The accuracy and necessity of monitoring gastric remnants and monitoring frequencies should be investigated further.

Circ_C4orf36 Promotes the Proliferation and Osteogenic Differentiation of BMSCs by Regulating VEGFA.

Fracture healing is a complicated process containing the regulation of cellular process. It has been reported that circRNAs are involved in fracture healing. Our study aims to explore the role and mechanism of circ_C4orf36 in fracture healing. Here, we found that the expressions of Circ_C4orf36 and VEGFA were increased during osteoblast differentiation in MC3T3-E1 cells. Circ_C4orf36 overexpression could accelerate the proliferation and migration, as well as osteoblast differentiation in MC3T3-E1 cells, as well as increased ALP activity and osteogenic markers (Runx2, OCN) via upregulating VEGFA expression. Mechanistically, circ_C4orf36 facilitated the expression of VEGFA by recruiting EIF4A3. Taken together, our results elucidated that circ_C4orf6 promoted the migration, proliferation and osteoblast differentiation in BMSCs by upregulating VEGFA, which indicated that circ_C4orf36 might be a potential target in fracture healing treatment.

Stress-induced myelin damage in the hippocampal formation in a rat model of depression.

BACKGROUND: According to previous studies, myelin damage may be involved in the occurrence of depression. However, to date, no study has quantitatively investigated the changes in myelinated fibers and myelin sheaths in the hippocampal formation (HF) and hippocampal subfields in the context of depression. METHODS: Male Sprague-Dawley (SD) rats (aged 4-5 weeks) were evenly divided into the control group and chronic unpredictable stress (CUS) group. Behavioral tests were performed, and then changes in myelinated fibers and myelin ultrastructure in hippocampal subfields in depression model rats were investigated using modern stereological methods and transmission electron microscopy techniques. RESULTS: After a four-week CUS protocol, CUS rats showed depressive-like and anxiety-like behaviors. The total length and total volume of myelinated fibers were reduced in the CA1 region and DG in the CUS group compared with the control group. The total volumes of myelin sheaths and axons in the CA1 region but not in the DG were significantly lower in the CUS group than in the control group. The decrease in the total length of myelinated nerve fibers in the CA1 region in CUS rats was mainly due to a decrease in the length of myelinated fibers with a myelin sheath thickness of 0.15 µm-0.20 µm. LIMITATIONS: The exact relationship between the degeneration of myelin sheaths and depression-like, anxiety-like behaviors needs to be further investigated. CONCLUSIONS: CUS induces depression- and anxiety-like behaviors, and the demyelination in the CA1 region induced by 4 weeks of CUS might be an important structural basis for these behaviors.

Hsa_circ_0016070/micro-340-5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/ß-Catenin Complex.

Background Hypoxia is considered a major leading cause of pulmonary hypertension (PH). In this study, the roles and molecular mechanism of circ_0016070 in PH were studied. Methods and Results The expression of circ_0016070 in serum samples, human pulmonary artery smooth muscle cells and hypoxia/monocrotaline-treated rats was determined by real-time quantitative polymerase chain reaction. Cell viability, migration, and apoptosis were analyzed by Cell Counting Kit-8, wound healing, flow cytometry, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays, respectively. The molecular interactions were validated using RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase reporter assays. The levels of phenotype switch-related proteins were evaluated by Western blot and immunohistochemistry. The pathological characteristics were assessed using hematoxylin and eosin staining. circ_0016070 was highly expressed in the serum samples, hypoxia-induced pulmonary artery smooth muscle cells and pulmonary arterial tissues of PH rats. Downregulation of circ_0016070 ameliorated the excessive proliferation, migration, vascular remodeling, and phenotypic transformation but enhanced cell apoptosis in the PH rat model. In addition, micro (miR)-340-5p was verified as a direct target of circ_0016070 and negatively regulated TCF4 (transcription factor 4) expression. TCF4 formed a transcriptional complex with ß-catenin to activate TWIST1 (Twist family bHLH transcription factor 1) expression. Functional rescue experiments showed that neither miR-340-5p inhibition nor TWIST1 or TCF4 upregulation significantly impeded the biological roles of circ_0010670 silencing in PH. Conclusions These results uncovered a novel mechanism by which circ_0016070 play as a competing endogenouse RNA of miR-340-5p to aggravate PH progression by promoting TCF4/ß-catenin/TWIST1 complex, which may provide potential therapeutic targets for PH.

Early warning prevention and control strategies to reduce perioperative venous thromboembolism in patients with gastrointestinal cancer.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of unexpected and perioperative in-hospital deaths. It is characterized by high morbidity, high mortality, high misdiagnosis rate, and high missed diagnosis rates. VTE is a common postoperative complication in cancer patients. VTE is preventable, and early identification of risk factors leading to VTE and appropriate early preventive actions can reduce its occurrence and mortality. Presently, there is no uniform standard for the prevention and control of VTE in clinical practice, and hospitals in China lack mature and effective protocols for the assessment, prevention, and treatment of VTE. AIM: To explore whether an early warning program could influence the occurrence of deep vein thrombosis (DVT) postoperatively. METHODS: This is a comparative retrospective cohort study, which enrolled patients who underwent laparotomic or laparoscopic gastrointestinal tumor resection for gastrointestinal cancer between January 2016 and December 2019. Patients were divided into a control group and an early warning group depending on whether or not the early warning program was implemented. A venous thromboembolism prevention and control team was established. The outcomes included the occurrence of DVT, the correct rate of VTE assessment, the coagulation indicators, and the mastery of VTE knowledge by the nurses. RESULTS: A total of 264 patients were included in this study, with 128 patients in the control group and 136 patients in the early warning group. The occurrence rate of DVT in the early warning group was 6.6% (9/136), compared with 14.1% (18/128) in the control group (P < 0.05). The correct rates of VTE risk assessment by the nurses and standard implementation rate of VTE preventive measures were 86.8% vs 65.6% and 80.2% vs 57.8% in early warning and control groups, respectively (all P < 0.001). The independent factors associated with postoperative DVT occurrence were age (OR = 1.083, 95%CI: 1.070-3.265, P = 0.032), Hyperlipidemia (OR = 1.127, 95%CI: 1.139-2.564, P = 0.042), preoperative high VTE risk (OR = 2.131, 95%CI: 1.085-5.178, P = 0.001), time of operation (OR = 2.268, 95%CI: 2.005-5.546, P = 0.026) and not adoption of early warning prevention (OR = 3.747, 95%CI: 1.523-6.956, P = 0.017). CONCLUSION: The early warning strategy was independently associated with the decreasing occurrence of VTE, and it might be suitable for protection from VTE in patients undergoing gastrointestinal cancer surgery.

Effects of 4-month running exercise on the spatial learning ability and white matter volume and microvessels of middle-aged female and male rats.

Age-related degeneration of microvessels is known to occur in white matter, and exercise training can enhance brain function and promote cerebral blood flow. However, the effects of exercise training on microvessels in aged white matter are unknown. Forty-one middle-aged male and female Sprague-Dawley rats were randomly divided into a sedentary group and an exercised group. The rats in the exercised group were made to run on treadmills for 4 months. The spatial learning capacities of all groups were then assessed with the Morris water maze. White matter and its microvessels were investigated using immunohistological techniques and stereological methods. In the exercised group, females but not males, showed improved performance over time in the Morris water maze. In females but not males, the exercised rats showed significantly increased white matter volume compared with that of sedentary rats. The total length of microvessels in the white matter in the exercised group was significantly increased compared with that in the sedentary group in both males and females, but the total volume and total surface area of microvessels in the white matter did not differ significantly between the sedentary and exercised rats. Regular treadmill exercise had protective effects on spatial learning capacity, white matter volume, and the total length of microvessels in the white matter in middle-aged female rats and on the total length of microvessels in the white matter in middle-aged male rats. The results obtained might increase our understanding of the mechanisms by which exercise delays brain aging.

Comparison of Survival Outcomes of Different Treatment Options for cT1-2, N0 Glottic Carcinoma: A Propensity Score-Weighted Analysis.

Background: Treatments for cT1-2, N0 glottic squamous cell carcinoma (GLSCC) include endoscopic resection, open surgery, and radiotherapy. The purpose of this study was to compare the outcomes of three treatment modalities and provide reference data for treatment selection. Methods: In all, 4274 patients with cT1-2, N0 GLSCC underwent these three treatment modalities from 2004 to 2015 were identified from the Surveillance, Epidemiology, and End Results-18 database. Overall survival (OS) and disease-specific survival (DSS) of patients treated with the three modalities were compared. Results: In the entire cohort, there were no significant differences in 5-year OS and 5-year DSS among the three treatment groups. In subgroup analyses based on stage and age, endoscopic resection provided significantly better 5-year survival than radiotherapy for cT1, N0 patients aged <65 years, with an OS rate of 89.0% vs. 82.3% (p = 0.009) and a DSS rate of 95.6% vs. 88.2% (p = 0.021). For 5-year DSS, open surgery also had better outcomes than patients who received radiotherapy (5-year DSS: 98.5% vs. 88.2%, respectively; p = 0.046). Conclusions: To summarize, for cT1, N0 GLSCC patients younger than 65 years, surgical treatment (either endoscopic or open) appears to be superior to the radiotherapy, and endoscopic resection should probably be the first consideration.

The MFF-SIRT1/3 axis, regulated by miR-340-5p, restores mitochondrial homeostasis of hypoxia-induced pulmonary artery smooth muscle cells.

Mitochondrial dynamics and quality control play a central role in the maintenance of the proliferation-apoptosis balance, which is closely related to the progression of pulmonary arterial hypertension (PAH). However, the exact mechanism of this balance remains unknown. Pulmonary artery smooth muscle cells (PASMCs) were cultured in hypoxia condition for constructing a PAH model in vitro. The expression of genes and proteins were determined by qRT-PCR and western bolt assays. Cell proliferation-apoptosis balance were tested by MTT, EdU and TUNEL assays. The mitochondrial functions were assessed by flow cytometry, JC-1, Mito tracker red staining, and corresponding kits. Besides, the molecular interaction was validated by dual-luciferase reporter assay. MFF was overexpressed in hypoxia-treated PAMSCs. Knockdown of MFF significantly repressed the excessive proliferation but enhanced cell apoptosis in hypoxia-treated PAMSCs. Moreover, MFF silencing improved mitochondrial function of hypoxia-treated PAMSCs by increasing ATP production and decreasing ROS release and mitochondrial fission. Mechanistically, MFF was a directly target of miR-340-5p, and could negatively regulate SIRT1/3 expression. Subsequently, functional rescue assays showed that the biological effects of MFF in hypoxia-treated PAMSCs were negatively regulated by miR-340-5p and depended on the regulation on SIRT1/3 pathway. These results provided evidences that miR-340-5p regulated MFF-SIRT1/3 axis to improve mitochondrial homeostasis and proliferation-apoptosis imbalance of hypoxia-treated PAMSCs, which provided a theoretical basis for the prevention and treatment of PAH.

Pan-cancer analysis of GALNTs expression identifies a prognostic of GALNTs feature in low grade glioma.

Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts), a group of isoenzymes that initiate mucin-type O-glycosylation, have been shown to mediate tumor growth and metastasis in various cancer types. However, data on the clinical significance and features of GalNAc-Ts remain scant. Here, we used Oncomine and The Cancer Genome Atlas (TCGA) databases to analyze the transcription and survival effect of GALNTs (N-acetylgalactosaminyltransferase genes) in pan-cancer. The data showed that the GALNTs were aberrantly expressed in various human cancers and significantly associated with patients' clinical outcomes. The expression of 13 GALNTs were correlated with prognosis in brain low grade glioma (LGG) patients. In addition, based on the expression profiles of GALNT family genes in TCGA-LGG dataset, we identified 2 molecular subtypes (cluster1/2) by consensus clustering and analyzed tumor heterogeneity. Our results demonstrated that cluster 2 group was associated with poor prognosis, CD8+ T cells, macrophages and DCs infiltration, up-regulated expression of immune checkpoints, and higher tumor immune dysfunction and exclusion score, indicating that GalNAc-Ts might contribute to tumor immune escape. Furthermore, we employed LASSO regression and time-dependent ROC analysis to construct a GALNTs-related prognostic signature with the TCGA-LGG dataset, and then validated the signature using 2 external cohorts. Taken together, our study successfully developed a novel prognostic biomarker for LGG and provides a basis for personalized immunotherapy in brain cancer.

This study successfully developed a novel prognostic biomarker for LGG and provides a basis for personalized immunotherapy in brain cancer.

Type I IFNs repolarized a CD169+ macrophage population with anti-tumor potentials in hepatocellular carcinoma.

Macrophages constitute a major component in human hepatocellular carcinoma (HCC) and perform various functions to facilitate disease progression. Reprogramming or reconstituting the tumor surveillance phenotypes of macrophages represents an attractive immunotherapeutic strategy in cancer treatments. The current study identified CD169 as a potential target for macrophage repolarization since it signified a population of macrophages positively correlated with an activated immune signature and better prognosis of patients with HCC. In vitro experiments revealed that a low dose of type I interferon (IFN) could effectively reprogram human monocyte-derived macrophages to upregulate CD169 expression, and such induced CD169+ macrophages exhibited significantly enhanced phagocytotic and CD8+ T cell-activating capacities compared to controls. A low dose of IFNα also inhibited hepatoma growth in mice in vivo, presumably through polarizing the CD169+ macrophage population and enhancing CD8+ T cell activities. Notably, IFNα also induced substantial PD-L1 expression on macrophages in vivo, and thus blockade of PD-L1 could further increase the anti-tumor efficacy of IFNα in the treatment of HCC. We propose a low dose of IFNα in combination with a PD-L1 blocking agent as a potential anti-tumor therapeutic strategy via its effects on macrophage polarization.

Long-Term Running Exercise Delays Age-Related Changes in White Matter in Rats.

Running exercise, one of the strategies to protect brain function, has positive effects on neurons and synapses in the cortex and hippocampus. However, white matter, as an important structure of the brain, is often overlooked, and the effects of long-term running exercise on white matter are unknown. Here, 14-month-old male Sprague-Dawley (SD) rats were divided into a middle-aged control group (18-month-old control group), an old control group (28-month-old control group), and a long-term runner group (28-month-old runner group). The rats in the runner group underwent a 14-month running exercise regime. Spatial learning ability was tested using the Morris water maze, and white matter volume, myelinated fiber parameters, total mature oligodendrocyte number, and white matter capillary parameters were investigated using stereological methods. The levels of growth factors related to nerve growth and vascular growth in peripheral blood and the level of neurite outgrowth inhibitor-A (Nogo-A) in white matter were measured using an enzyme-linked immunosorbent assay (ELISA). The present results indicated that long-term running exercise effectively delayed the age-related decline in spatial learning ability and the atrophy of white matter by protecting against age-related changes in myelinated fibers and oligodendrocytes in the white matter. Moreover, long-term running exercise prevented age-related changes in capillaries within white matter, which might be related to the protective effects of long-term exercise on aged white matter.

Identification of key genes in ruptured atherosclerotic plaques by weighted gene correlation network analysis.

The rupture of atherosclerotic plaques is essential for cardiovascular and cerebrovascular events. Identification of the key genes related to plaque rupture is an important approach to predict the status of plaque and to prevent the clinical events. In the present study, we downloaded two expression profiles related to the rupture of atherosclerotic plaques (GSE41571 and GSE120521) from GEO database. 11 samples in GSE41571 were used to identify the differentially expressed genes (DEGs) and to construct the weighted gene correlation network analysis (WGCNA) by R software. The gene oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment tool in DAVID website, and the Protein-protein interactions in STRING website were used to predict the functions and mechanisms of genes. Furthermore, we mapped the hub genes extracted from WGCNA to DEGs, and constructed a sub-network using Cytoscape 3.7.2. The key genes were identified by the molecular complex detection (MCODE) in Cytoscape. Further validation was conducted using dataset GSE120521 and human carotid endarterectomy (CEA) plaques. Results: In our study, 868 DEGs were identified in GSE41571. Six modules with 236 hub genes were identified through WGCNA analysis. Among these six modules, blue and brown modules were of the highest correlations with ruptured plaques (with a correlation of 0.82 and -0.9 respectively). 72 hub genes were identified from blue and brown modules. These 72 genes were the most likely ones being related to cell adhesion, extracellular matrix organization, cell growth, cell migration, leukocyte migration, PI3K-Akt signaling, focal adhesion, and ECM-receptor interaction. Among the 72 hub genes, 45 were mapped to the DEGs (logFC > 1.0, p-value < 0.05). The sub-network of these 45 hub genes and MCODE analysis indicated 3 clusters (13 genes) as key genes. They were LOXL1, FBLN5, FMOD, ELN, EFEMP1 in cluster 1, RILP, HLA-DRA, HLA-DMB, HLA-DMA in cluster 2, and SFRP4, FZD6, DKK3 in cluster 3. Further expression detection indicated EFEMP1, BGN, ELN, FMOD, DKK3, FBLN5, FZD6, HLA-DRA, HLA-DMB, HLA-DMA, and RILP might have potential diagnostic value.

The Association between MUC5B Rs35705950 and Risks of Idiopathic Interstitial Pneumonia, Systemic Sclerosis Interstitial Lung Disease, and Familial Interstitial Pneumonia: A Meta-Analysis.

BACKGROUND: Interstitial lung disease (ILD) is a category of chronic lung diseases with more than 200 subtypes. Idiopathic interstitial pneumonia (IIP), systemic sclerosis (SSc) ILD, and familial interstitial pneumonia (FIP) are three major groups of lung diseases with different causes or with unknown causes. Mucin5B (MUC5B) belongs to the mucin family, which contribute to the lubricating and viscoelastic properties of the whole saliva, normal lung mucus, and cervical mucus. The association between MUC5B rs35705950 and ILDs risks has been widely studied. However, the results were inconclusive and inconsistent. METHODS: In the present meta-analysis, the database PubMed, Embase, Cochrane Central Register of Controlled Trials, CNKI and Chinese Biomedical Literature Database were searched till Aug 20th, 2018. Overall 16 publications with 28 studies, 76345 cases and 18402 controls were included. RESULTS: The results indicated a significant increase of overall IIP risk for TT genotype and T allele of the rs35705950 in all genetic models (TT vs GG, OR=9.11; TT vs GT+TT, OR=5.80; GT+TT vs GG, OR=4.34; T vs G, OR=4.03. P<0.0001). Subgroup analysis by subtypes of IIP revealed higher risks of TT genotype and T allele for IPF and iNSIP (P<0.05). A significant increase of FIP risk was also found for the TT genotype and T allele of the rs35705950 (TT vs GG, OR=17.08; GT+TT vs GG, OR=6.02; T vs G, OR=1.64.P<0.05). CONCLUSION: No significant relations existed between the rs35705950 and SSc-ILD risks. MUC5B rs35705950 might be a predictor for the susceptibility of IIP and FIP.

Exercise improves depressive symptoms by increasing the number of excitatory synapses in the hippocampus of CUS-Induced depression model rats.

Exercise has been considered for the treatment of depression, but the mechanism by which exercise improves depression is still unclear. To clarify the mechanism, rats were randomly divided into the control, chronic unpredictable stress (CUS)/standard and CUS/running groups. The rats in the CUS/running group ran for four weeks. In this study, a sucrose preference test (SPT) was used to evaluate the depression-like symptoms in the rats, and western blot, immunohistochemical and stereological analyses were performed to study the expression of synaptic-related proteins in the hippocampus and the changes in excitatory synapses in each sub-region. The results show that sucrose preference in the CUS/standard group was significantly lower than that in the control group, but in the CUS/running group, sucrose preference was higher than that in the CUS/standard group. Surprisingly, there was no difference in the synaptic-related proteins in the hippocampus among groups. The CUS/standard group exhibited fewer spinophilin+ (Sp+) dendritic spines representing excitatory synapses in CA1, CA3 and dentate gyrus (DG) of the hippocampus than the control group, whereas the CUS/running group exhibited significantly more Sp+ dendritic spines in these regions than the CUS/standard group, indicating that excitatory synapses were reduced in depressed rats and that running exercises could reverse this change. We hypothesize that the changes in the number of excitatory synapses better reflect the changes in depressive symptoms than the level of synaptic proteins and that the effect of exercise on excitatory synapses in the sub-regions of the hippocampus may be an important structural indicator of the improvement of depressive symptoms.

Specific Biomarkers of Prostate Cancer-Associated Ischemic Stroke: A Case-Control Study.

BACKGROUND Ischemic stroke in cancer patients is associated with poor prognosis. However, the specific biomarkers of cancer-associated ischemic stroke (CaIS) have not been well defined. MATERIAL AND METHODS A retrospective study was conducted on PCaIS patients. Clinical data and laboratory and imaging findings were collected. Multivariable logistic regression analysis was used to analyze the independent risk factors for PCaIS. A multiple model combining the independent risk factors of PCaIS was developed using the receiver operating characteristic (ROC) and area under the ROC curve (AUC). RESULTS A total of 83 PCaIS patients and 83 prostate cancer (PCa) patients were included. PCaIS patients had higher levels of D-dimer, neutrophil-to-lymphocyte ratio (NLR), and total prostate-specific antigen (T-PSA). In the multivariate analysis, D-dimer [OR=1.001, 95% CI: 1.00,1.00, P=0.002], NLR [OR=1.12, 95% CI: 1.04,1.22, P=0.005], and T-PSA [OR=6.275, 95% CI: 2.57,15.31, P<0.001] were independent risk factors of PCaIS. Additionally, the AUC of the multiple model of PCaIS was 0.815 (95% CI, 0.750-0.869), with sensitivity of 81.71% and specificity of 70.21%. CONCLUSIONS Elevated levels of D-dimer and T-PSA and increased NLR are independent risk factors of PCaIS. The multiple model of PCaIS can be a specific biomarker and is a reliable predictor of development of PCaIS.

Meta-analysis of the association between MBOAT7 rs641738, TM6SF2 rs58542926 and nonalcoholic fatty liver disease susceptibility.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a kind of liver disease caused by factors other than excessive alcohol use. It is the leading cause of liver injury in developed countries. The membrane-bound O-acyltransferase 7 (MBOAT7) and transmembrane 6 superfamily member 2 (TM6SF2) are associated with lipid metabolism. Studies found a mutation on MBOAT7, rs641738 and another on TM6SF2, rs58542926 were associated with liver diseases, including NAFLD. However, the results were inconclusive and inconsistent. METHODS: In the present meta-analysis, the databases Pubmed, Embase, Chinese National Knowledge Infrastructure, and Chinse Biomedical Literature Database were searched for related studies. The deadline of publications was July 10th, 2018. The data from included studies were extracted by 2 independent investigators. STATA 12.0 software was used in the present meta-analysis. RESULTS: A total of 9 papers with 20 studies, including 5415 cases and 17896 controls were identified for the meta-analysis. The results indicated lower risks of NAFLD for CC genotype of TM6SF2 rs58542926 in homozygous, heterozygous, dominant and recessive models (CC vs. TT: OR = 0.33; CC vs. CT: OR = 0.58; CC vs. CT + TT: OR = 0.64; CC + CT vs. TT: OR = 0.32). These decreased risks of NAFLD also existed in Asians in all genetic models except allelic model, and in Caucasians in the heterozygous model (CC vs. CT, OR = 0.52) and the dominant model (CC + CT vs. TT, OR = 0.50). No association existed between MBOAT7 rs641738 and NAFLD risks in all genetic models (CC vs. TT: OR = 0.91; CC vs. CT: OR = 0.96; CC vs. CT + TT: OR = 0.95; CC + CT vs. TT: OR = 0.91; C vs. T: OR = 0.99). CONCLUSION: CC genotype of TM6SF2 rs58542926 was associated with a significantly lower risk of NAFLD, while MBOAT7 rs641738 was not related to NAFLD risks.

Changes in white matter and the effects of fluoxetine on such changes in the CUS rat model of depression.

OBJECTIVE: To explore the pathogenesis of depression and the possible mechanism of the effects of selective serotonin reuptake inhibitors (SSRIs) on the myelinated fibers and myelin sheaths in the white matter during the antidepressant action of fluoxetine. METHODS: In this study, Sprague Dawley (SD) rats were divided into a Control group, a group treated with CUS and no drugs (CUS/Standard group) and a group treated with CUS and fluoxetine (CUS/FLX group). The CUS/FLX group was treated with fluoxetine at dose of 5 mg/kg for 21 days. The white matter volume, the myelinated fiber parameters and the myelin sheath volume in the white matter were calculated from transmission electron microscope images through unbiased stereological methods. RESULTS: The total volume and total length of myelinated fibers;and mean volume of white matter of the CUS/Standard group were significantly decreased compared to values from the control group (p = 0.025, p = 0.007, p = 0.000), whereas no significant differences in these stereological parameters were found between the CUS/Standard and CUS/FLX groups (p > 0.05). CONCLUSIONS: Fluoxetine successfully treated depression-like behavior but had no effects on the white matter or its component myelinated fibers in the CUS rat model of depression.

Spinal NGF induces anti-intrathecal opioid-initiated cardioprotective effect via regulation of TRPV1 expression.

Evidences from previous studies confirmed that intrathecal morphine preconditioning (ITMP) reduces the cardiac injury of ischemia-reperfusion (IR) via the central nervous system. However, the molecular mechanism is not fully understood. The breath of central nerve growth factor (NGF) during nociceptive transmission has been well documented, and little is known about the significance of NGF in myocardial injury of IR and intrathecal morphine-induced cardioprotection. To address these questions, we over-expressed or silenced NGF in the spinal cord by using intrathecal injection of lentivirus-NGF or shRNA respectively, accompanied by ITMP in the IR rat model. The levels of NGF and tropomyosin receptor kinase A (Trka) as well as transient receptor potential vanilloid 1 (TRPV1) in the T2-6 spinal cord were evaluated. The results showed that cardiac damage indicators induced by IR, including the increased infarct size, arrhythmia score and serum troponin levels were attenuated after ITMP. However, overexpression of spinal NGF significantly reversed these decreases, as well as reduced the expression and phosphorylation of TRPV1 that was elicited by ITMP. Conversely, silencing of spinal NGF enhanced ITMP-induced cardioprotective effects. Phosphorylation and expression of TRPV1 in the spinal cord were significantly decreased after regional NGF silencing. These findings suggested that the cardioprotective effects of ITMP may implement by mediating through spinal NGF expression, wherein it involves the nociceptor TRPV1. NGF may act as a potential therapeutic target in the development of new agents for the treatment of cardiac injury induced by IR.

Silica nanoparticles induce neurodegeneration-like changes in behavior, neuropathology, and affect synapse through MAPK activation.

BACKGROUND: Silica nanoparticles (SiO2-NPs) are naturally enriched and broadly utilized in the manufacturing industry. While previous studies have demonstrated toxicity in neuronal cell lines after SiO2-NPs exposure, the role of SiO2-NPs in neurodegeneration is largely unknown. Here, we evaluated the effects of SiO2-NPs-exposure on behavior, neuropathology, and synapse in young adult mice and primary cortical neuron cultures. RESULTS: Male C57BL/6 N mice (3 months old) were exposed to either vehicle (sterile PBS) or fluorescein isothiocyanate (FITC)-tagged SiO2-NPs (NP) using intranasal instillation. Behavioral tests were performed after 1 and 2 months of exposure. We observed decreased social activity at both time points as well as anxiety and cognitive impairment after 2 months in the NP-exposed mice. NP deposition was primarily detected in the medial prefrontal cortex and the hippocampus. Neurodegeneration-like pathological changes, including reduced Nissl staining, increased tau phosphorylation, and neuroinflammation, were also present in the brains of NP-exposed mice. Furthermore, we observed NP-induced impairment in exocytosis along with decreased synapsin I and increased synaptophysin expression in the synaptosome fractions isolated from the frontal cortex as well as primary neuronal cultures. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were also activated in the frontal cortex of NP-exposed mice. Moreover, inhibition of ERK activation prevented NP-mediated changes in exocytosis in cultured neurons, highlighting a key role in the changes induced by NP exposure. CONCLUSIONS: Intranasal instillation of SiO2-NPs results in mood dysfunction and cognitive impairment in young adult mice and causes neurodegeneration-like pathology and synaptic changes via ERK activation.