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Objective: To investigate the ultrasonographic characteristics of the hemodynamic changes of the contralateral vertebral artery (VA) in patients with different types of subclavian steal syndrome (SSS). Methods: A total of 152 cases of SSS diagnosed by carotid Doppler ultrasonography (CDU) and confirmed by CT angiography (CTA) were enrolled as the study group. The 152 cases of SSS were divided into type I (47 cases of occult steal blood),type II (60 cases of partial steal blood) and type III (45 cases of complete steal blood).Meanwhile,46 cases of cardiovascular and cerebrovascular diseases were excluded from the health examination center as the control group. The diameter and hemodynamic changes of VA in healthy side of patients with different types of steal blood were analyzed and compared with the control group. Results: The hemodynamic parameters of VA on the contralateral side of three types of SSS in the study group were compared with those in the control group, there was no significant difference between type I and the control group (P>0.05), and there was significant difference between type II and type III and the control group (P

Graphical abstract, Introduction Some epidemiological studies have revealed that vitamin D (VD) deficiency is closely linked with the prevalence of obesity, however, the role of VD in energy homeostasis is yet to be investigated, especially in central nervous system. Given that VD negatively regulates renin in adipose tissue, we hypothesized that central VD might play a potential role in energy homeostasis. Objectives The present study aims to investigate the potential role of VD in energy homeostasis in the CNS and elaborate its underlying mechanisms. Methods This study was conducted in Cyp27b1−/− mice, VD-treated and wild-type mice. After the intraventricular injection of renin or its inhibitors, the changes of renin-angiotensin system (RAS) and its down-stream pathway as well as their effects on metabolic rate were examined. Results The RAS activity was enhanced in Cyp27b1−/− mice, exhibiting a increased metabolic rate. Additionally, corticotropin-releasing hormone (CRH), a RAS-mediated protein regulating energy metabolism in the hypothalamus, increased significantly in Cyp27b1−/− mice. While in VD-treated group, the RAS and sympathetic nerve activities were slightly inhibited, hence the reduced metabolic rate. Conclusion Collectively, the present study demonstrates that the VD/vitamin D receptor (VDR) has a significant impact on energy homeostasis through the modulation of RAS activity in the hypothalamus, subsequently altering CRH expression and sympathetic nervous activity.

Ischemic preconditioning induced by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischemic insult. In this study we investigated whether a short-term nonischemic stimulation of hypertrophy renders the heart resistant to subsequent ischemic injury. Male mice were subjected to transient transverse aortic constriction (TAC) for 3 days followed aortic debanding on D4 (T3D4), as well as ligation of the left coronary artery to induce myocardial infarction (MI). The TAC preconditioning mice showed markedly improved contractile function and significantly reduced myocardial fibrotic area and apoptosis following MI. We revealed that TAC preconditioning significantly reduced MI-induced oxidative stress, evidenced by increased NADPH/NADP ratio and GSH/GSSG ratio, as well as decreased mitochondrial ROS production. Furthermore, TAC preconditioning significantly increased the expression and activity of SIRT3 protein following MI. Cardiac-specific overexpression of SIRT3 gene through in vivo AAV-SIRT3 transfection partially mimicked the protective effects of TAC preconditioning, whereas genetic ablation of SIRT3 in mice blocked the protective effects of TAC preconditioning. Moreover, expression of an IDH2 mutant mimicking deacetylation (IDH2 K413R) in cardiomyocytes promoted myocardial IDH2 activation, quenched mitochondrial reactive oxygen species (ROS), and alleviated post-MI injury, whereas expression of an acetylation mimic (IDH2 K413Q) in cardiomyocytes inactivated IDH2, exacerbated mitochondrial ROS overload, and aggravated post-MI injury. In conclusion, this study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Therapeutic strategies targeting IDH2 are promising treatment approaches for cardiac ischemic injury.

Many elderly individuals suffer from Alzheimer's disease (AD), which causes a growing concern. We investigated the mechanism underlying the effects of vitamin D (VD) as a prophylactic treatment. A mouse model of okadaic-acid-induced AD-like pathology was used in vivo and in vitro. Morris water maze and field trials were used to assess cognitive function. The expression levels of VDR, MTHFR, LCMT-1, PP2A, p-TAU (Thr396), and T-TAU and the methylation level of PP2A were measured by Western blotting, and a reversal of the increase in the levels of these proteins in an AD cell model was observed. We used MTHFR-knockdown SH-SY5Y cells to further test the effects of VD, treated these cells with cycloheximide and MG132, and used RT-PCR to explore the mechanism underlying MTHFR targeting. We found that the effects of VD on AD were impaired by MTHFR knockdown through a pretranscriptional mechanism. In addition, VD attenuated AD-induced cognitive impairment and significantly suppressed the expression of TAU. Our findings indicated that VD treatment alleviated TAU accumulation and rescued methylated PP2A by increasing the expression of LCMT-1 and MTHFR.

Graphical abstract, Introduction Intrinsic vitamin D affects the proliferation, apoptosis, invasion, metastasis, and tumorigenesis of lung cancer by regulating tumor signaling pathways. Histidine-rich calcium-binding protein (HRC) maintains Ca2+ homeostasis, which plays crucial roles in the occurrence and development of cancer. Objectives Our study aims to investigate the ability of vitamin D in the regulation of HRC and the role of HRC playing in lung cancer. Methods We investigated the effects of vitamin D on lung cancer and the underlying mechanisms, by measuring HRC and vitamin D receptor (VDR) expression in lung cancer, paracancer, and normal tissues from patients using immunohistochemistry, western blotting, and real time RT-PCR. We transfected H460 lung cancer cells (supplemented or not with vitamin D) with PX458-HRC and pcDNA3.1-HRC plasmids and injected mice with lung cancer cells harboring pcDNA3.1-vector or pcDNA3.1-HRC plasmids. Results Vitamin D inhibited HRC expression and H460 cell migration and proliferation, and promoted apoptosis compared with controls. The expression of HRC and VDR was significantly upregulated and downregulated, respectively, in lung cancer versus paracancer or normal tissues. Cell proliferation and migration were reduced, apoptotic cells were more and tumors were smaller in mice treated with vitamin D/cholecalciferol cholesterol emulsion (CCE) than in vitamin D/CCE+HRC+/+ mice. Conclusion Vitamin D inhibited lung cancer tumor growth, migration, and proliferation by downregulating HRC.

Pharmacological stimulation of adipose tissue remodeling and thermogenesis to increase energy expenditure is expected to be a viable therapeutic strategy for obesity. Berberine has been reported to have pharmacological activity in adipose tissue to anti-obesity, while the mechanism remains unclear. Here, we observed that berberine significantly reduced the body weight and insulin resistance of high-fat diet mice by promoting the distribution of brown adipose tissue and thermogenesis. We have further demonstrated that berberine activated energy metabolic sensing pathway AMPK/SIRT1 axis to increase the level of PPARγ deacetylation, which leads to promoting adipose tissue remodeling and increasing the expression of the thermogenic protein UCP-1. These findings suggest that berberine that enhances the AMPK/SIRT1 pathway can act as a selective PPARγ activator to promote adipose tissue remodeling and thermogenesis. This study proposes a new mechanism for the regulation of berberine in adipose tissue and offers a great prospect for berberine in obesity treatment.

Background Human chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is implicated in the pathogenesis of immune, reproductive systems and various cancers. However, the expression and clinical significance of CMTM4 in lung cancer have not been identified. Methods We performed immunohistochemistry to detect the expression of CMTM4 in 75 paired lung adenocarcinoma and non-tumor lung tissues. The correlation between CMTM4 expression and clinical significance of lung cancer patients was analyzed by Chi-square test. Kaplan-Meier method and Log-Rank test were used to calculate the survival time of lung cancer patients. Results We found that CMTM4 was positively expressed in 34/75 (45.3%) cases of lung adenocarcinoma tissues, while positively expressed in 59/75 (78.6%) cases of non-tumor lung tissues, suggesting a lower expression of CMTM4 in lung adenocarcinoma tissues than non-tumor lung tissues (P

Background Globally, colorectal cancer (CRC) affects more than 1 million people each year. In addition to non-modifiable and other environmental risk factors, Fusobacterium nucleatum infection has been linked to CRC recently. In this study, we explored mechanisms underlying the role of Fusobacterium nucleatum infection in the progression of CRC in a mouse model. Methods C57BL/6 J-Adenomatous polyposis coli (APC) Min/J mice [APC (Min/+)] were treated with Fusobacterium nucleatum (109 cfu/mL, 0.2 mL/time/day, i.g., 12 weeks), saline, or FadA knockout (FadA−/−) Fusobacterium nucleatum. The number, size, and weight of CRC tumors were determined in isolated tumor masses. The human CRC cell lines HCT29 and HT116 were treated with lentiviral vectors overexpressing chk2 or silencing β-catenin. DNA damage was determined by Comet assay and γH2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, β-catenin, and chk2 were determined by Western blot analysis. Results Fusobacterium nucleatum treatment promoted DNA damage in CRC in APC (Min/+) mice. Fusobacterium nucleatum also increased the number of CRC cells that were in the S phase of the cell cycle. FadA−/− reduced tumor number, size, and burden in vivo. FadA−/− also reduced DNA damage, cell proliferation, expression of E-cadherin and chk2, and cells in the S phase. Chk2 overexpression elevated DNA damage and tumor growth in APC (Min/+) mice. Conclusions In conclusion, this study provided evidence that Fusobacterium nucleatum induced DNA damage and cell growth in CRC through FadA-dependent activation of the E-cadherin/β-catenin pathway, leading to up-regulation of chk2.

Microglia-involved neuroinflammation in the central nervous system (CNS) has been shown to aggravate brain damage and is associated with the pathogenesis of various neurodegenerative diseases. Thus, suppression of microglial activity has the potential to be a strategy for the treatment of neurodegenerative diseases. Pinitol, a methylated product of D-chiro-inositol, has been used as a treatment for blood-sugar metabolism and as an anti-tumor agent via its anti-inflammatory effects in cancer. However, whether or not pinitol can inhibit microglia-associated neuroinflammation is still unknown. This study aims to determine the effects of pinitol on inflammatory responses in BV2 microglia induced by LPS. Here, we found that the presence of pinitol ameliorates LPS-induced oxidative stress by reducing the production of ROS. Pinitol suppresses the expression and secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Notably, pinitol prevents the production of NO and PGE2 by inhibiting the expression of iNOS and COX-2. Mechanistically, our findings demonstrate that pinitol inhibits the phosphorylation and degradation of IκBα and subsequent activation of NF-κB. Furthermore, we show that pinitol increases the expression of TREM2 in BV2 microglia, and silencing of TREM2 abolished the anti-inflammatory effects of pinitol. These findings suggest that TREM2 mediates the protective effects of pinitol against LPS in microglia. In summary, our results display that pinitol possesses a robust and beneficial effect against the LPS-induced inflammatory response in microglia.

As a specific inhibitor of serine/threonine protein phosphatases, okadaic acid (OA) has been found to be a tumor promoter. However, whether OA plays a role in metastasis of hepatocellular carcinoma (HCC) has not been well elucidated. In this study, Hep3B and HepG2 cells were treated with different doses of OA and the cell viability was determined by CCK8 test. As a result, Hep3B and HepG2 cells showed no obvious cytotoxicity after OA treatment below 20 or 25 nM for 12 or 24 hours. However, wound healing, invasion, and migration abilities of HCC cells were significantly enhanced in the OA-treated groups than those of the control group (P < .05), measured by cell scratching and BD transwell assays. Moreover, we found that the expression of epithelial-mesenchymal transition (EMT)-related key factors was changed upon OA treatment in a dose-dependent manner. In addition, the activity of protein phosphatase 2A (PP2A) in OA-treated cells was also decreased significantly compared with the control cells (P < .05). Interfering of PP2A subunit A or C caused a similar expression change of EMT-related key factors as the OA treatment in HCC cells. Our results suggest that OA promotes the EMT process of HCC cells by inhibiting the activity of PP2A.

Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China, with high metastasis and poor prognosis. Recently, as the core component of the polycomb repressive complexes 1 (PRC1), chromobox protein homolog 8 (CBX8) is considered as an oncogene and prognostic marker in HCC. Methods A tissue microarray of 166 paired HCC and adjacent non-tumor samples were collected to identify the relationship between CBX8 and epithelial mesenchymal transition (EMT) associated proteins by Spearman correlation analysis. Knock-down of CBX8 in HCC cells was conducted to detect the biologic functions of CBX8 in HCC metastasis. Results We found out that CBX8 was over-expressed in HCC and its expression was closely related to the metastasis of HCC patients. In addition, knock-down of CBX8 was found to inhibit the invasion and migration ability of HCC cells. Moreover, there was a significant relationship between expression of CBX8 and EMT associated proteins both in HCC cells and tumor tissues. Conclusions Our results indicate that CBX8 promotes metastasis of HCC by inducing EMT process.

Although remote ischemic postconditioning (RIPC) was shown to confer cardioprotection against myocardial ischemia/reperfusion (I/R) injury in normal animals, whether RIPC-induced cardioprotection is altered in the presence of hypercholesterolemia, a comorbidity with acute myocardial infarction (AMI) patients has yet to be determined. Normal or 2% cholesterol chow was fed to male C57BL/6J mice for 12 weeks to induce hypercholesterolemia, then normal or hypercholesterolemic murine hearts were exposed to AMI by coronary artery ligation. RIPC was induced by four episodes of 5 min femoral artery occlusion followed by 5 min reperfusion immediately after myocardial reperfusion in mice. Following I/R, RIPC significantly attenuated postischemic infarct size, hindered cardiomyocyte apoptosis, improved cardiac systolic function, decreased phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression, and further increased Akt and GSK-3β phosphorylation in non-hypercholesterolemic, but not in hypercholesterolemic mice. Application of the PTEN inhibitor bisperoxovanadium (BpV) (1.0 mg/kg) reduced postischemic infarct size, attenuated cardiomyocyte apoptosis, and improved cardiac dysfunction in normal, but not in hypercholesterolemic mice. Further, increased dose of BpV (2 mg/kg or 10 mg/kg) failed to rescue the detrimental effects of hypercholesterolemia on I/R in mice following I/R. Especially important, we demonstrated that the combination BpV and RIPC exerted marked cardioprotective effects both in normal and hypercholesterolemic mice with I/R, indicating that PTEN inhibition restores RIPC-elicited myocardial protection in the presence of hypercholesterolemia. Our results demonstrated that hypercholesterolemia attenuated RIPC-induced cardioprotection against I/R injury by alteration of PTEN/Akt/GSK3β signals, and inhibition of PTEN rescued RIPC-induced cardioprotection in the presence of hypercholesterolemia.

Introduction Gestational diabetes mellitus (GDM) is a metabolic disorder during mid- to late-pregnancy characterized by hyperglycemia, insulin resistance and fetal mal-development. Glucose transporter type 2 (GLUT2) and sodium-coupled glucose cotransporters 2 (SGLT2) in the proximal tubules play a critical role in the reabsorption of glucose and have been linked to the occurrence of type 2 diabetes mellitus (T2DM). Our study was designed to investigate the role of GLUT2 and SGLT2 in the pathogenesis of GDM, which is considered a forerunner of T2DM, and investigate the related molecular mechanism. Methods High-fat diet (HFD) was utilized to build a GDM mouse model that closely induces metabolic abnormalities similar to human GDM. Body weight, blood glucose and serum insulin were recorded in the experimental process. Glucose tolerance was determined by the use of an intraperitoneal glucose tolerance test (IPGTT). In addition, levels of GLUT2 and SGLT2 were evaluated to further explore the underlying mechanism of GDM. Results HFD feeding induced abnormal glucose metabolism as manifested by increased levels of blood glucose and insulin and prominent glucose intolerance. Additionally, fetal mice from mother feed on HFD showed higher mean body weight. Furthermore, HFD feeding led to an increase in the number of positive cells of GLUT2 and SGLT2 in the renal proximal tubule and the expressions of renal GLUT2 and SGLT2 mRNA and proteins in mice. However, no obvious change was observed in renal morphology. Conclusion Our study demonstrates a potential involvement of renal GLUT2 and SGLT2 in GDM pathology in an HFD-induced GDM mouse model, which further supports the role of renal GLUT2 and SGLT2 not only in T1DM and T2DM but also in GDM.

Objectives. Hyperhomocysteinemia (HHcy) is an easily neglected disease, which can be hidden in the body for many years without signs or symptoms. We want to explore the causes of HHcy, the correlation of HHcy with micronutrients, lifestyle, dietary habits and HHcy related genes, preventing the occurrence of HHcy.Methods. 800 subjects (M/F, 403/397) were divided into normal Hcy and HHcy group according to the plasma levels of Hcy, compared essential characteristics by questionnaires, genetic polymorphism tested by Realtime PCR and micronutrients detected by mass spectrometry. The statistical analysis methods were Chi - square tests, ANOVA, logistic regression. This trial has been registered with the trial number ChiCTR1900025136. Results. 42.66% of 143 HHcy cases were aged from 10 to 18, with higher levels of zinc (Zn), vitamin A, Uric acid (P < 0.05) and a lower level of 25-OH-D3, VB12, folic acid (Fol) (P < 0.05) compared to the normal group. The multivariate logistic regression significantly predicted HHcy development containing higher level of Zinc (Exp(B) = 1.042; 95% CI, 1.000 - 1.086), higher Uric (Exp(B) = 1.014; 95% CI, 1.008 - 1.019), lower B12 (Exp(B) = 0.993; 95%CI, 0.989 - 0.997), lower Folic acid (Exp(B) = 0.772; 95% CI, 0.657 - 0.907), and polymorphism of MTHFR C677T (Exp(B) = 2.923; 95% CI, 1.399–6.107).Conclusion. Pay more attention to those students who were facing great pressure because they are very likely to be potential HHcy patients with high levels of uric acid and zinc and anxiety.

OBJECTIVE The efficacy and safety of surfactant administration via thin catheter in preterm infants with neonatal respiratory distress syndrome (NRDS) was investigated. METHODS PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify randomized controlled trials (RCTs) that comparing thin catheter technique with intubation for surfactant delivery in preterm infants with NRDS. RESULTS Thirteen RCTs (1931 infants) were included in the meta-analysis. The use of thin catheter technique decreased the incidences of bronchopulmonary dysplasia (BPD), pneumothorax, and hemodynamically significant patent ductus arteriosus (hsPDA) (risk ratio [RR]: 0.59, 95% confidence interval [CI]: 0.46-0.75, p

The transverse aortic constriction (TAC) model surgery is a widely used disease model to study pressure overload–induced cardiac hypertrophy and heart failure in mice. The severity of adverse cardiac remodeling of the TAC model is largely dependent on the degree of constriction around the aorta, and the phenotypes of TAC are also different in different mouse strains. Few studies focus on directly comparing phenotypes of the TAC model with different degrees of constriction around the aorta, and no study compares the difference in C57BL/6N mice. In the present study, C57BL/6N mice aged 10 weeks were subjected to sham, 25G TAC, 26G TAC, and 27G TAC surgery for 4 weeks. We then analyzed the different phenotypes induced by 25G TAC, 26G TAC, and 27G TAC in c57BL/6N mice in terms of pressure gradient, cardiac hypertrophy, cardiac function, heart failure situation, survival condition, and cardiac fibrosis. All C57BL/6N mice subjected to TAC surgery developed significantly hypertrophy. Mice subjected to 27G TAC had severe cardiac dysfunction, severe cardiac fibrosis, and exhibited characteristics of heart failure at 4 weeks post-TAC. Compared with 27G TAC mice, 26G TAC mice showed a much milder response in cardiac dysfunction and cardiac fibrosis compared to 27G TAC, and a very small fraction of the 26G TAC group exhibited characteristics of heart failure. There was no obvious cardiac dysfunction, cardiac fibrosis, and characteristics of heart failure observed in 25G TAC mice. Based on our results, we conclude that the 25G TAC, 26G TAC, and 27G TAC induced distinct phenotypes in C57BL/6N mice.

Energy substrate imbalance is a major cause of cardiac dysfunction. Vitamin D/vitamin D receptor (VD/VDR) deficiency is involved in the pathogenesis of various cardiac diseases; however, the exact underlying mechanism remains unclear. The aim of this study was to investigate whether vitamin D modulates mitochondrial fatty acid oxidase via sirtuin 3 signaling to protect the myocardium. 1-Alpha-hydroxylase-defficient mice exhibited a high metabolic rate and lower myocardial contractility than wild-type mice. Sirtuin 3 upregulation was detected in high-fat diet-fed mice receiving vitamin D3 compared with that in high-fat diet-fed mice. Both sirtuin 3 blockade and knockout inhibited the VD/VDR-induced downregulation of fatty acid oxidase in myocardial mitochondria. VD/VDR suppressed fatty acid metabolism by upregulating sirtuin 3 and lowering mitochondrial fat uptake, thereby improving myocardial function and balancing energy substrates, rather than by altering fat endocytosis and exocytosis.

Background Ischaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short‐term non‐ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury. Methods and Results Transient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia‐reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R‐induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3‐dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral‐mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R‐induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning. Conclusions The present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self‐defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway‐dependent manner., Hypertrophic preconditioning exerted marked protective effects by eliminating mitochondrial‐derived superoxide and suppressing autophagic cell death. SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. ​

Vitamin D plays an important role in maintaining skeletal development and bone homeostasis. Although vitamin D has been extensively researched, the direct effect of 1,25(OH)2D3 on osteoblasts is unclear. To explore the 1,25(OH)2D3 action on murine osteoblasts, we performed tandem mass tag experiments on MC3T3-E1 cells treated with and without 1,25(OH)2D3. Three up-regulated proteins (MRC2, WWTR1 and RASSF2) related to bone metabolism were confirmed in this study. 1,25(OH)2D3 up-regulated the expression of MRC2 through vitamin D receptor. MRC2 affects collagen metabolism in osteoblasts. Combined with bioinformatics and parallel reaction monitoring analysis, we inhibited the expression of MRC2 to explore the relationship between MRC2 and collagens. Then we found MRC2 down-regulated COL5A2 and up-regulated MMP13. This study provides a protein profile of 1,25(OH)2D3-treated murine osteoblasts, reveals a newly discovered signaling axis (1,25(OH)2D3/VDR/MRC2/COL5A2 and MMP13), and explains the effect of 1,25(OH)2D3 on bone metabolism from a new perspective.

Acute lung injury (ALI) is a type of diffuse lung inflammation with a high mortality rate. Studies show that miR-155 plays an important role in inflammation. Here, we investigated the role of miR-155 in lipopolysaccharide (LPS)-induced ALI. The mice with bone marrow transplantation between MiR-155 knockout and wild-type were used as animal models of LPS-induced sepsis. In response to LPS injection, ALI was less severe in miR-155 knockout mice than in wild-type mice, and mainly manifested as reduced pulmonary vascular leakage, pulmonary edema, and neutrophil infiltration. The expression levels of Ang-2 and apoptosis-associated caspases-3 and -9, as well as myosin light chain (MLC) phosphorylation in the lungs were also decreased. A bone marrow transplantation experiment showed that miR-155 expressed in bone marrow-derived lymphocytes rather than lung parenchymal lymphocytes promoted inflammation. Findings suggest that miR-155 expressed in bone marrow-derived lymphocytes promoted LPS-induced ALI through the modulation of the Ang-2-Tie-2 pathway.

Background: The effects of minimally invasive surfactant administration (MISA) in preterm infants with neonatal respiratory distress syndrome (NRDS) are unclear. Methods: We searched randomized controlled trials (RCTs) and compared MISA techniques with intubation for surfactant delivery in preterm infants with NRDS in PubMed, Embase, Cochrane Library, and Web of Science. Results: Thirteen RCTs (1931 infants) were included in the meta-analysis. The use of MISA techniques decrease the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks, pneumothorax, and hemodynamically significant patent ductus arteriosus (hsPDA) (Risk Ratio(RR) : 0.59, 95% confidence interval (CI) : 0.46 to 0.75, p < .0001; RR : 0.60, 95% CI : 0.39 to 0.93, p= .02 and RR : 0.88, 95% CI : 0.78 to 1.00, p= .04, respectively). In addition, infants in the MISA group required less mechanical ventilation within 72 h of life or during hospitalization (RR : 0.60, 95% CI : 0.48 to 0.75, p< .00001 and RR : 0.64, 95% CI : 0.49 to 0.82, p = .0005, respectively) compared with infants in the control group. However, the rate of surfactant reflux was higher in the MISA group than that in the control group (RR : 2.12, 95% CI : 1.37 to 3.29, p = .0008). There were no significant differences in mortality and other outcomes beteween the MISA group and the control group. Conclusions: The administration of surfactant with MISA techniques could lower the requirement for mechanical ventilation, and decrease the incidence of BPD at 36 weeks, pneumothorax, and hsPDA.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China, with high metastasis and poor prognosis. Recently, as the core component of the polycomb repressive complexes 1 (PRC1), chromobox protein homolog 8 (CBX8) is considered as an oncogene and prognostic marker in HCC. A tissue microarray of 166 paired HCC and adjacent non-tumor samples were collected to identify the relationship between CBX8 and epithelial mesenchymal transition (EMT) associated proteins by Spearman correlation analysis. Knock-down of CBX8 in HCC cells was conducted to detect the biologic functions of CBX8 in HCC metastasis. We found out that CBX8 was over-expressed in HCC and its expression was closely related to the metastasis of HCC patients. In addition, knock-down of CBX8 was found to inhibit the invasion and migration ability of HCC cells. Moreover, there was a significant relationship between expression of CBX8 and EMT associated proteins both in HCC cells and tumor tissues. Our results indicate that CBX8 promotes metastasis of HCC by inducing EMT process.

New Ebselen-like derivatives resulted to be very strong in vitro inhibitors of SARS-CoV-2 main protease. We demonstrated that this activity mainly depends on the electrophilicity of the selenium atom that is considerably higher in the N-substituted 1,2- benzoselenazol-3(2H)-ones respect to the corresponding diselenides allowing it to be rapidly attached by free thiols affording sulfur-selenium intermediates that are further subjected to thiol exchange processes. This data paints a very complex scenario that requires us to consider Ebselen and Ebselen-like derivatives as potential electrophilic substrates for the several other free thiols present in the cell beside the target free cysteine. The sulfur selenium intermediates are milder electrophiles that could be theoretically implicated in both the detoxification process as well as in the final enzymatic inhibition. We here demonstrated that the in vitro inhibition activity is not fully reproduced in the prevention of viral replication in the cell-based assay. This indicates that the structure of the substituents introduced in the Ebselen scaffold is a crucial factor to control the reactivity of the selenated molecule in the network of thiol exchanges, as well as for molecular recognition of the targeted enzymatic cysteine. For this reason, an in-depth investigation is strongly desirable to better understand how to increase the activity and the selectivity of Ebselen derivatives overcoming the issues of the apparent PAINS-like role of Ebselen. Furthermore, besides the antiviral activity, thee selected compounds also showed a different ability to reduce the virus-induced cytopathic effect, indicating that other mechanisms could be implicated. One may consider here the well-known cytoprotective antioxidant activity of Ebselen and its derivatives.

Chloroplasts are semi-autonomous organelles, with more than 95% of their proteins encoded by the nuclear genome. The chloroplast-to-nucleus retrograde signals are critical for the nucleus to coordinate its gene expression for optimizing or repairing chloroplast functions in response to changing environments. In chloroplasts, the pentatricopeptide-repeat protein GENOMES UNCOUPLED 1 (GUN1) is a master switch that senses aberrant physiological states, such as the photooxidative stress induced by norflurazon (NF) treatment, and represses the expression of photosynthesis-associated nuclear genes (PhANGs). However, it is largely unknown how the retrograde signal is transmitted beyond GUN1. In this study, a protein GUN1-INTERACTING PROTEIN 1 (GIP1), encoded by At3g53630, was identified to interact with GUN1 by different approaches. We demonstrated that GIP1 has both cytosol and chloroplast localizations, and its abundance in chloroplasts is enhanced by NF treatment with the presence of GUN1. Our results suggest that GIP1 and GUN1 may function antagonistically in the retrograde signaling pathway.

Background Human chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) members are found deregulated in various cancers and play a role in cancer development. Recent studies showed that CMTM7 was down-regulated in liver cancer and functioned as a tumor suppressor. Methods The expression of CMTM7 in hepatocellular carcinoma (HCC) tissues was measured by bioinformatics analysis, Western blot, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). CCK8 and cell colony formation assays were conducted to detect the cell proliferation. Cell invasion and migration ability was assessed by wound healing and Transwell assays. Results We identified a decreased expression of CMTM7 in HCC tissues was closely related to the metastasis and prognosis of HCC patients. To explore the effect of CMTM7 on the biological function of HCC cells, we over-expressed CMTM7 in two HCC cell lines, SK-Hep-1 and Bel-7402 cells. Cell proliferation was reduced significantly after exogenous expression of CMTM7, detected by both CCK8 and colony formation assay. Moreover, the invasion and migration ability of HCC cells were also inhibited by exogenous expression of CMTM7 in wound healing and Transwell assay. Furthermore, there was a significantly positive correlation between CMTM7 and CMTM3 both in HCC cells and tumor tissues. Conclusions Our results suggest that down-regulated CMTM7 promotes metastasis of HCC through inducing the expression of its family member CMTM3.

Background Skeletal development is a complicated process. The status of vitamin D (VD) is closely related to fetal bone development in the embryonic period. Recently, miRNAs have been found to participate in the regulation of skeletal growth and development in several species. However, the mechanisms underlying the interactions among vitamin D, its receptor (VDR), and miRNAs during the process of bone development remain unclear. The aim of this study was to identify miRNAs that are regulated by 1,25(OH)2D3 in murine osteoblasts and to analyze the relationship and the effects of VD/VDR and miRNAs in vitro and in vivo. Methods We performed miRNA sequencing in murine primary osteoblasts and in an osteoblast cell line treated with 1,25(OH)2D3 to identify miRNAs in these cells. After qRT-PCR validation, miR-140-5p was selected for further analysis. We assessed the pathways comprising predicted target genes for several expressed miRNAs, including miR-140-5p, validated predicted target genes in the MAPK pathway by qRT-PCR, and explored the correlation between VD/VDR and miR-140-5p in vitro and in vivo. Results 88 miRNAs in murine primary osteoblasts and 49 miRNAs in osteoblast cell line were found to be differentially expressed. MiR-140-5p was upregulated in these 2 types of murine osteoblasts. The expression of miR-140-5p was promoted by 1,25(OH)2D3 through transcriptional activation by VDR, with targeted inhibition of MAPK signaling in osteoblasts. A positive correlation between vitamin D/VDR and miR-140-5p was observed in VDR-knockout mice and in 165 human serum specimens. These data show for the first time that VDR transcriptionally activates miR-140-5p. Therefore, the VD/VDR/miR-140-5p/MAPK signaling axis plays an important role in transmitting the effects of 1,25(OH)2D3. Conclusion Our results demonstrate a novel regulatory mechanism by which miR-140-5p targets the MAPK pathway by means of VD/VDR in vitro and in vivo. These findings provide a new reference for mechanistic research and therapeutic approaches for vitamin D-related bone diseases.

Ai pian (AP) is a well-known Miao national herb with resuscitative effects. However, pharmacological and clinical applications of AP are limited because its precise molecular mechanism remains unclear. This study was conducted to evaluate the anti-inflammatory activities of the volatile compounds of AP in in vivo animal models and determine the molecular mechanism underlying the anti-inflammatory effects based on network pharmacology and molecular docking. We performed gas chromatography-mass spectrometric analysis of volatile compounds with chemometric methods, including hierarchical clustering analysis and principal component analysis, to identify AP from different origins. Mouse models of xylene-induced ear edema were used to examine the in vivo anti-inflammatory activities of AP with cotton ball-granulation test. The mechanism of AP was determined by network pharmacology analysis and molecular docking. Significant differences in chemical constituents and percentage contents were observed among different habitats. We found that AP exerted potent anti-inflammatory effect, and that multiple targets and pathways were involved in this effect. These results provided a foundation for further comprehensive development and application of AP from Miao national herb.

Calcium binding protein calbindin-D28K (CaBP28K) mediates the relationship between vitamin D and calcium, but its mechanism remains unclear during bone formation. The present study reports that maternal CaBP28K levels were positively correlated with paired umbilical cord CaBP28K levels. In addition, CaBP28K levels were positively correlated with the body length, and head and chest circumferences of neonates, but negatively correlated with maternal 25(OH)D3 levels. CaBP28K was also downregulated in MC3T3-E1 osteoblasts when treated with 1,25(OH)2D or VDR overexpression, but was upregulated in the femur of 1α(OH)ase(-/-) mice. Furthermore, it was found CaBP28K may influence cell differentiation and matrix formation through the regulation of DMP1 and the interaction with MMP13 in osteoblasts. This suggests that CaBP28K could be a candidate for the negative role of 1,25(OH)2D/VDR in regulating bone mass.

There was evidence that 1,25(OH)2D3 regulated aquaporin (AQP) 2 and 4 expression while ameliorating renal fibrosis. This study investigated whether cholecalciferol cholesterol emulsion (CCE), a precursor of 1,25(OH)2D3, has similar effects. The impact of CCE on renal fibrosis and AQP2 and AQP4 expression were studied in a unilateralureteral obstruction (UUO) mouse nephropathy model. CCE reduced both the extent of fibrosis and transforming growth factor (TGF)-β signaling compared with vehicle-treated UUO model controls. AQP2 protein expression was higher and AQP4 expression was lower in UUO-model mice treated with CCE than in vehicle-treated control mice. The results showed that CCE attenuated renal fibrosis by inhibiting TGF-β signaling, and regulated AQP2 and AQP4 expression in this UUO mouse model.

Diabetic cognitive dysfunction has gained widespread attention for its deleterious impact on individuals with diabetes. However, few clinical interventions are available to prevent the disorder. The glucagon-like peptide-1 analog liraglutide exerts neuroprotective effects in several models of neurodegenerative diseases. We investigated the effect of liraglutide pretreatment on diabetes-induced cognitive decline and explored the underlying mechanisms in vivo and in vitro. Liraglutide pretreatment prevented diabetes-induced cognitive impairment as assessed by the Morris Water Maze test, and alleviated neuronal injuries and ultrastructural damage to synapses in the hippocampal CA1 region. Furthermore, liraglutide promoted autophagy as indicated by enhanced expression of the autophagy markers Microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin 1, decreased expression of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. In vitro, liraglutide treatment elevated phosphorylated (p)-AMP-activated protein kinase (AMPK) levels and reduced p-mammalian target of rapamycin (p-mTOR) expression. Additionally, the AMPK inhibitor Compound C exhibited an inhibitory effect on liraglutide-induced increased LC3-II expression and p62 degradation. Liraglutide exhibits neuroprotective effects against diabetes-induced hippocampal neuronal injuries and cognitive impairment by promoting autophagy via the AMPK/mTOR pathway.

Diabetes mellitus is a significant global public health problem depicting a rising prevalence worldwide. As a serious complication of diabetes, diabetes-associated cognitive decline is attracting increasing attention. However, the underlying mechanisms are yet to be fully determined. Both endoplasmic reticulum (ER) stress and autophagy have been reported to modulate neuronal survival and death and be associated with several neurodegenerative diseases. Here, a streptozotocin-induced diabetic mouse model and primary cultured mouse hippocampal neurons were employed to investigate the possible role of ER stress and autophagy in diabetes-induced neuronal apoptosis and cognitive impairments, and further explore the potential molecular mechanisms. ER stress markers GRP78 and CHOP were both enhanced in diabetic mice, as was phosphorylation of PERK, IRE1α, and JNK. In addition, the results indicated an elevated level of autophagy in diabetic mice, as demonstrated by up-regulated expressions of autophagy markers LC3-II, beclin 1 and down-regulated level of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. Meanwhile, we found that these effects could be abolished by ER stress inhibitor 4-phenylbutyrate or JNK inhibitor SP600125 in vitro. Furthermore, neuronal apoptosis of diabetic mice was attenuated by pretreatment with 4-phenylbutyrate, while aggravated by application of inhibitor of autophagy bafilomycin A1 in vitro. These results suggest that ER stress pathway may be involved in diabetes-mediated neurotoxicity and promote the following cognitive impairments. More important, autophagy was induced by diabetes possibly through ER stress-mediated JNK pathway, which may protect neurons against ER stress-associated cell damages.

Pathological cardiac hypertrophy aggravated myocardial infarction and is causally related to autophagy dysfunction and increased oxidative stress. Rapamycin is an inhibitor of serine/threonine kinase mammalian target of rapamycin (mTOR) involved in the regulation of autophagy as well as oxidative/nitrative stress. Here, we demonstrated that rapamycin ameliorates myocardial ischaemia reperfusion injury by rescuing the defective cytoprotective mechanisms in hypertrophic heart. Our results showed that chronic rapamycin treatment markedly reduced the phosphorylated mTOR and ribosomal protein S6 expression, but not Akt in both normal and aortic‐banded mice. Moreover, chronic rapamycin treatment significantly mitigated TAC‐induced autophagy dysfunction demonstrated by prompted Beclin‐1 activation, elevated LC3‐II/LC3‐I ratio and increased autophagosome abundance. Most importantly, we found that MI/R‐induced myocardial injury was markedly reduced by rapamycin treatment manifested by the inhibition of myocardial apoptosis, the reduction of myocardial infarct size and the improvement of cardiac function in hypertrophic heart. Mechanically, rapamycin reduced the MI/R‐induced iNOS/gp91phox protein expression and decreased the generation of NO and superoxide, as well as the cytotoxic peroxynitrite. Moreover, rapamycin significantly mitigated MI/R‐induced endoplasmic reticulum stress and mitochondrial impairment demonstrated by reduced Caspase‐12 activity, inhibited CHOP activation, decreased cytoplasmic Cyto‐C release and preserved intact mitochondria. In addition, inhibition of mTOR also enhanced the phosphorylated ERK and eNOS, and inactivated GSK3β, a pivotal downstream target of Akt and ERK signallings. Taken together, these results suggest that mTOR signalling protects against MI/R injury through autophagy induction and ERK‐mediated antioxidative and anti‐nitrative stress in mice with hypertrophic myocardium.

Background/Aims: Nephropathy related with renin can be alleviated with ACE-inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases. Methods: The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model. Results: The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro. Conclusion: C20 plays importantly reno-protective roles most likely through the relocation of CREB-CBP complex.

Remote ischemic preconditioning (RIPC) is one of the most powerful intrinsic cardioprotective strategies discovered so far and experimental data indicate that comorbidity may interfere with the protection by RIPC. Therefore, we investigate whether RIPC-induced cardioprotection was intact in hypercholesterolemic rat hearts exposed to ischemia reperfusion in vivo. Normal or hypercholesterolemic rat hearts were exposed to 30 min of ischemia and 2 h of reperfusion, with or without RIPC, PI3K inhibitor wortmannin, MEK-ERK1/2 inhibitor PD98059, GSK3β inhibitor SB216763. Infarct size, apoptosis, MG53, PI3K-p85, p-Akt, p-ERK1/2, p-GSK3β, and cleaved Caspase-3 were determined. RIPC reduced infarct size, limited cardiomyocyte apoptosis following IR that was blocked by wortmannin but not PD98059. RIPC triggered unique cardioprotective signaling including MG53, phosphorylation of Akt, and glycogen synthase kinase-3ß (GSK3β) in concert with reduced proapoptotic active caspase-3. In contrast, RIPC failed to reduce myocardial necrosis and apoptosis as well as to increase the phosphorylated Akt and GSK3β in hypercholestorolemic myocardium. Importantly, we found that inhibition of GSK with SB216763 reduced myocardial infarct size in healthy and hypercholesterolemic hearts, but no additional cardioprotective effect was achieved when combined with RIPC. Our results suggest that acute GSK3β inhibition may provide a novel therapeutic strategy for hypercholesterolemic patients during acute myocardial infarction, whereas RIPC is less effective due to signaling events that adversely affect GSK3β.

Curcumin is a natural polyphenol with powerful antioxidant and anti-inflammatory properties. The present study evaluated the protective effect of curcumin on myocardial injury in rats as well as the mechanisms underlying these effects, and examined the expression of nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor-γ (PPAR-γ) and B-cell leukemia/lymphoma-2 (Bcl-2) following myocardial infarction. A rat model of myocardial infarction was successfully established. Hematoxylin and eosin staining showed cellular atrophy and hyperchromatic cytoplasm in the myocardial infarction area. The myocardial cells displayed lysis and breakage of cardiac muscle fibers, karyopyknosis and karyorrhexis associated with infiltration of inflammatory cells and proliferation of fibrous tissue. Curcumin treatment at a dosage of 150 mg/kg/body weight resulted in an increase in surviving cells, fewer apoptotic cells, decreased proliferation of fibrous tissue and reduced infiltration of inflammatory cells, though necrosis was still present compared with the rats without curcumin treatment. The immunohistochemical assay demonstrated that curcumin treatment inhibited the expression of NF-κB, but increased the expression of PPAR-γ. The results of the reverse transcription-polymerase chain reaction indicated that curcumin treatment significantly increased the mRNA expression levels of Bcl-2 (P

Vitamin D receptor (VDR) plays an important role in regulating energy metabolism. Adipose tissue is a vital metabolic organ in energy balance and glucose homeostasis. In this study, we investigated the role of VDR expressed on adipose tissue in the balance of energy metabolism. This study was conducted in VDR-KO mice, VDR-Tg mice and wild-type mice. Energy metabolism was determined based on the energy expenditure, oxygen consumption, respiratory exchange rate, food and water intake, and a cool room test. VDR expression in the tissues of VDR-Tg mice was assessed by western blotting. The levels of total cholesterol, triglycerides, free fatty acids, leptin, and glucose were assessed using the respective kits. Insulin resistance in the whole body was evaluated by an intraperitoneal glucose tolerance test and insulin tolerance test. mRNA associated with energy metabolism expression in adipose and skeletal muscle tissue was examined by RT-PCR. Our results show that overexpression of VDR in adipose tissue induced an increase in body weight, fat mass, and serum lipid levels, and a decline in energy metabolism; these changes were ameliorated by VDR-KO mice. Overexpression of VDR in the adipose tissue of VDR-Tg mice induced a state of insulin resistance, which corresponded with decreased expression of UCP1, UCP2, UCP3, CPT2 and HK in both white adipose tissue and brown adipose tissue; these changes were also reversed by VDR-KO mice. Our study confirms that expression levels of VDR in adipose tissue play pivotal roles in energy balance and glycolipid metabolism by regulating adipose tissue remodeling.

Background: Female overweight/obesity has been reported to be associated with compromised pregnancy outcomes in fresh embryo transfer cycles. It is unclear whether the cumulative live birth rate (CLBR) is adversely affected after all viable embryos are transferred from the first ovarian stimulation cycle. Objectives: To investigate whether the CLBR was compromised in obese women. Method: A total of 9,772 young women underwent their first IVF/ICSI cycles from January 2012 to October 2017. Pregnancy outcomes were compared according to female BMI. Results: Among 1,671 women with polycystic ovary syndrome (PCOS), those with a BMI ≥ 28 kg/m2 had a lower cumulative clinical pregnancy rate (CCPR) and CLBR during the first complete ovarian stimulation cycle. Additionally, the pregnancy loss rate was increased in this group, although the difference was not significant. Among the 8,101 women without PCOS, the CCPR and CLBR of obese patients was also significantly decreased, and this group also showed increased pregnancy loss rates. Moreover, overweight women also had a decreased CLBR. Conclusions: Female obesity adversely affected the CLBR after utilizing the viable embryos from first oocytes retrieval.

Hyperuricemia is a metabolic disease of the kidney that results in decreased uric acid excretion. Here, we aimed to investigate the effects of ginsenosides and anserine on hyperuricemia and the expression of aquaporin (AQP) 1–4, which are indicators of renal excretion. Ginsenosides and anserine were administered separately or together after the establishment of hyperuricemia with adenine in BALB/c mice. Renal function indexes such as serum uric acid, creatinine, and urea nitrogen were measured in each group of mice, and the expression of AQP1–4 in renal tissues was detected. Serum uric acid and urea nitrogen were decreased in the ginsenoside and the anserine +UA groups. Meanwhile, the uric acid excretion and clearance rate were clearly increased in the co-treatment +UA group ([Formula: see text].05). Moreover, ginsenosides or anserine ginsenosides or anserine alone and treatment with both increased the expression of AQP1–4; however, the synergistic effects were more significantly enhanced ([Formula: see text].01). We provide the first reported evidence that ginsenosides and anserine have synergistic effects on uric acid excretion. The improvement in renal function in hyperuricemic mice after treatment with ginsenosides and anserine may result from up-regulation of AQP1–4 expressions.

Glioma is the most common primary brain tumor and is characterized by a poor prognosis. Protein tyrosine phosphatase 1B (PTPN1), as a non‑transmembrane protein tyrosine phosphatase, has been reported to serve a critical role in different diseases, including cancer. However, the role of PTPN1 in the progression of glioma remains unclear. The present study investigated the expression and clinicopathological characteristics of PTPN1 by analyzing the data from The Cancer Genome Atlas and 136 patients with glioma. It was indicated that PTPN1 was overexpressed in glioma tissues and served as a predictor for poor prognosis in patients with glioma. In addition, a series of in vitro experiments were performed to examine the underlying mechanism of PTPN1 overexpression and the clinical prognosis in patients with glioma. Knockdown of PTPN1 by small interfering RNA suppressed proliferation of glioma cells, including SF295 and A172. In addition, cell mobility was also inhibited by PTPN1 knockdown, downregulating the expression of matrix metallopeptidase 2 (MMP‑2) and MMP‑9. As indicated by western blot analysis, the mitogen‑activated protein kinase (MAPK)/extracellular‑signal‑regulated kinase (ERK) signaling pathway and the phosphatidylinositol 3‑kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway was regulated by PTPN1, while knockdown of PTPN1 significantly suppressed the MAPK/ERK and PI3K/AKT pathways, in addition to the downstream oncogenic transcription factor MYC Proto‑Oncogene. In conclusion, it was demonstrated that PTPN1 is upregulated in glioma tissue and the overexpression of PTPN1 predicted the poor prognosis of patients with glioma. PTPN1 promotes the progression of glioma by activating the MAPK/ERK and PI3K/AKT pathways.

Background: As an essential member of the Polycomb group (PcG) proteins, chromobox homolog 7 (CBX7) is found deregulated in some human cancers, and is thought to be a contributing factor in carcinogenesis. However, the expression and role of CBX7 in hepatocellular carcinoma (HCC) is still not well characterized. Materials and Methods: The levels of the CBX7 protein were quantified in 75 paired HCC and adjacent nontumor tissues by immunohistochemistry; comparisons were made using McNemar's chi-square test. The Kaplan-Meier estimate was used for survival analysis. Results: We found that the expression of CBX7 in HCC tissues was significantly lower than that of adjacent nontumor tissues. In addition, decreased CBX7 expression levels were correlated with liver cirrhosis in HCC patients. Furthermore, the survival times of HCC patients who were CBX7-expression-negative were shorter than HCC patients who were CBX7-expression-positive. Conclusion: Our results show that downregulation of CBX7 is related to HCC progression and a poor prognosis in HCC patients.

Aim. Vitamin D plays an important role in water and salt homeostasis. The aim of our study was to investigate the underlying relationship of Vitamin D and Aquaporins (AQP). Methods. The behaviors of 1α (OH)-ase knockout mice and wild type mice were observed before analysis. The ICR mice were treated with vehicle or paricalcitol, a vitamin D analogue, followed by animals receiving a standard diet and free access to drinking water either with aliskiren (renin blocker; 37.5 mg aliskiren in 100 ml water), or telmisartan (a angiotensin II type I receptor blocker; 40 mg telmisartan in 100 ml water) a week before study. The expressions of AQP-1, AQP-4, and renin in mice kidneys were detected by western bolting, immunohistochemistry, and immunofluorescence. Results. Diuresis and polydipsia were observed in 1α (OH)-ase knockout mice, and a decreased water intake and urine output in ICR mice was observed after paricalcitol treatment. Compared with wild type, the AQP-1 expressions were increased in renal papilla and AQP-4 expressions were decreased in renal proximal tubule of 1α(OH) ase knockout mice. In addition, AQP-1 was decreased in renal papilla and AQP-4 expressions were increased in proximal tubule by suppressing renin activity or supplement of Vitamin D analogue. After injecting renin into the lateral ventricle of the 1α(OH)ase knockout mice, the renin expression level was decreased in the kidney, followed by the decrease of AQP-1 in renal papilla and increase of AQP-4 in proximal tubule. Conclusions. Overall, Vitamin D and renin inhibitors have synergistic effects in regulating water channels in mice kidneys.

This study aimed to examine the expression level and clinical significance of chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) in paired hepatocellular carcinoma (HCC) and adjacent nontumor tissues. The expression of CMTM6 was detected in 75 paired HCC and adjacent nontumor tissues by immunohistochemistry. Chi-square test was used to compare the difference of CMTM6 expression between HCC tissues and adjacent nontumor tissues. The clinic-pathological features and prognosis of HCC patients were collected to analyze the relationship with CMTM6 expression. The positive expression of CMTM6 in HCC tissues was significantly lower than that of adjacent nontumor tissues. The difference of CMTM6 expression between HCC tissues and paired adjacent nontumor tissues was statistically significant (p 0.05). Furthermore, CMTM6 expression was correlated with HCC metastasis and alpha-fetoprotein (AFP) (p 0.05). Multivariate logistic regression analysis showed tumor staging, metastasis, and AFP had a significant relationship with CMTM6 expression. In addition, the survival time of HCC patients was different between CMTM6 positive group and CMTM6 negative group by Kaplan-Meier survival analysis (p 0.05). Downregulation of CMTM6 is related to HCC metastasis and the prognosis of HCC patients.

To observe the inhibitory effect ofPolygonum capitatumextract on auricle swelling induced by xylene in mice, and explore the mechanism of anti-inflammatory action with the method of network pharmacology. Extract the total flavonoids, sugars and tannins fromPolygonum capitatum, and act on xylene induced auricular inflammation in mice. Use 8mm hole punch to lay down the ear piece and measure the quality of the ear piece. Through consulting CNKI, Wanfang, Vip and other databases, the chemical constituents related toPolygonum capitatumwere searched. Screening the active chemical constituents ofPolygonum capitatumby ADME parameters. Find a target with the active chemical composition and establish a target data set; Protein interaction network (PPI) was used to construct the protein interaction network of target and inflammatory target ofPolygonum capitatum.Cytoscape software was used to construct the complex network diagram of “component-target-pathway-disease”; DAVID was used for GO functional enrichment analysis and KEGG pathway enrichment analysis. Result: The experimental results of auricle inflammation induced by xylene in mice showed that the high dose group of total flavones, the low dose group of total flavones and the low dose group of tannin had inhibitory effects on auricle inflammation induced by minor xylene in mice. There were 37 reported compounds, 6 active compounds and 2 flavonoids compounds. A total of 268 targets were retrieved from 6 active compounds, and 41 potential targets were most closely related to the anti-inflammatory mechanism of thePolygonum capitatum.Through the biological function pathway enrichment and KEGG pathway enrichment analysis, 20 biological processes and 76 signal pathways were screened. Conclusion: The anti-inflammatory components of thePolygonum capitatumpredicted by the network pharmacology and the experimental results showed that the anti-inflammatory effect of the total flavonoids in the high-dose group was basically the same as that in the low-dose group. It is suggested that Quercetin and Kaempferol may be the anti-inflammatory flavonoids inPolygonum capitatum.

Moslae Herba has the function of inducing sweating to releasing exterior, removing dampness for regulating stomach. It is often used clinically in the treatment of summer heat dampness syndrome, fever in summer, acute enteritis, and herpes pharyngitis in children. There have been more studies on anti-inflammatory effects of Moslae Herba. However, research on the anti-inflammatory mechanism of Moslae Herba is rarely reported. Therefore, in this paper, a network pharmacologic approach was adopted to explore the potential molecular mechanism of the active ingredients in Moslae Herba for the anti-inflammatory. Firstly, all chemical components of Moslae Herba were searched through TCMSP, TDT, TCMID and other databases. According to ADME parameters (OB ≥ 30% and DL ≥ 0.18), the active ingredient in Moslae Herba was screened. Secondly, the targets of active chemical components were searched by traditional Chinese medicine target database, TCMSP database and BATMAN-TCM database, and the target data sets are established. PPI analysis and STRING database were used to construct a protein interaction network for the target of Moslae Herba active ingredients and inflammation. Finally, Cytoscape 3.6.1 software was used to construct a complex network diagram of “drug components-targets-disease”. GO functional and KEGG pathway enrichment analysis were performed by DAVID. As a result, 13 active compounds were screened out of 161 compounds. These active compounds were retrieved from 309 targets, and 143 potential targets were most closely related to the anti-inflammatory mechanism of action of Moslae Herba. Through GO biological function pathway enrichment analysis and KEGG pathway enrichment analysis, 20 biological processes and 20 signal pathways were screened. It is suggested that the active ingredients of Moslae Herba may regulate the inflammation mechanism through the main pathways such as Pathways in cancer, Tuberculosis, PI3K-Akt signaling pathway, HIF-1 signaling pathway, TNF signaling pathway.

Liver fibrosis may progress toward cirrhosis and cancer without effective therapy. Here, we investigated the underlying mechanism of Vitamin D as a therapeutic approach.Carbon tetrachloride (CCL4)-induced mice model and transforming growth factor-β1 (TGF-β1) induced human hepatic stellate cell line LX-2 were used in vivo and in vitro. The fibrotic profiles, degree of liver injury and HRC expression were assessed by histology, Western blot, immunohistochemistry and Real-Time PCR. The proliferation of cells transfected with HRCVitamin D significantly suppressed the expression of HRC in liver fibrosis model both in vivo and in vitro (P 0.01). The cell with overexpression of HRC significantly increased TGF-β1/Smad3 expressions and the percentage of the S peak in cell cycle (P 0.05). However, Vitamin D can significantly reverse the levels of TGF-β1, Smad3 and p-smad3 caused by HRC in vitro. Furthermore, the overexpression of HRC in cell lines can attenuate the function of Vitamin D, suggesting that VD played a role by regulating HRC. Mechanically, HRC as the target of VDR is detected by CHIP method.Vitamin D can delay hepatic fibrosis by reducing activation of hepatic stellate cells and TGF-β/Smad signaling through negative regulation of HRC. The findings revealed the important regulatory effect of Vitamin D in hepatic stellate cells and provided new insights into the therapeutic function of Vitamin D on liver fibrosis.

As a critical regulator of the cell cycle, cyclin-dependent kinase (CDK) inhibitor p21 or p21 is involved in the development of cardiac hypertrophy and heart failure. Calcitriol, or 1,25(OH)2D3, the bioactive form of vitamin D (VD), can activate p21 expression and attenuate cardiac hypertrophy. To simulate cardiac hypertrophy in vitro and ex vivo, respectively, mice and cardiomyocytes were treated with isoproterenol (ISO). Moreover, the p21 signaling pathway was examined in ISO + VD and ISO + VD p21 inhibitor-treated cardiomyocytes. We found that calcitriol treatment led to a significant decrease in cardiac size and the mRNA levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in ISO-treated mice. Furthermore, the surface area of cardiomyocytes and the expression of ANP and BNP were decreased, and the expression of p21 was increased in the ISO + VD group compared with those in the ISO group. Furthermore, the surface area of cardiomyocytes and the expression of ANP and BNP were markedly upregulated in the ISO + VD p21 inhibitor group relative to the ISO + VD group, whereas the difference was not statistically significant compared with those of the ISO p21 inhibitor group. Therefore, our findings indicate that 1,25(OH)2D3 protects against cardiac hypertrophy in mice through upregulating p21 expression.

There are still unmet medical needs for the treatment of glioblastoma (GBM), the most frequent and aggressive brain tumor worldwide. EGFRvIII, overexpressed in approximately 30% of GBM, has been regarded as a potential therapeutic target. In this study, we demonstrated that CH12, an anti-EGFRvIII monoclonal antibody, could significantly suppress the growth of EGFRvIII+ GBM in vivo; however, PTEN deficiency in GBM reduced the efficacy of CH12 by attenuating its effect on PI3K/AKT/mTOR pathway. To overcome this problem, CH12 was combined with the mTOR inhibitor rapamycin, leading to a synergistic inhibitory effect on EGFRvIII+PTEN− GBM in vivo. Mechanistically, the synergistic antitumor effect was achieved via attenuating EGFR and PI3K/AKT/mTOR pathway more effectively and reversing the STAT5 activation caused by rapamycin treatment. Moreover, the combination therapy suppressed angiogenesis and induced cancer cell apoptosis more efficiently. Together, these results indicated that CH12 and rapamycin could synergistically suppress the growth of EGFRvIII+PTEN− GBM, which might have a potential clinical application in the future.