A Bayesian network meta-analysis for acute thrombosis after lower extremity artery endovascular treatment.

BACKGROUND: Various endovascular treatment devices have been widely used in the lower extremity arterial disease (LEAD). Their patency efficiency for target lesions has been well studied and reported. Comparison of the risk of acute thrombosis events between the different endovascular treatment devices is unclear. AIMS: To rank the risk of acute thrombosis events when bare metal stents (BMSs), covered stents (CSs), drug-eluting stents (DESs), drug-coated balloons (DCBs), and conventional percutaneous transluminal balloon angioplasty (PTA) are used to treat LEAD through Bayesian network meta-analysis. METHODS: We performed a network meta-analysis of randomized controlled trials comparing the risk of 1-year postoperative acute thrombosis between BMSs, CSs, DESs, DCBs, and PTA for treating LEAD. Bayesian random models were used for pooled endovascular treatment modality comparisons. We ranked these treatment modalities via the Bayesian method according to their surface under the cumulative ranking curve (SUCRA) and estimated probabilities. RESULTS: Nineteen studies (38 study arms; 2758 patients) were included. The Bayesian network ranking of treatments indicated that DCB had the lowest risk of acute thrombosis, PTA had the second-lowest risk of thrombosis, and CS, BMS, and DES had the highest risk of thrombosis. Regarding the treatment efficacy, the OR values of the loss of primary patency were significantly lower for DCB (OR = 0.44, 95% CI: 0.30-0.62), DES (OR = 0.36, 95% CI: 0.14-0.94), and CS (OR = 0.31, 95% CI: 0.18,0.56) than for PTA. When BMS was used as a reference, only the OR for CS was significantly lower (OR = 0.41, 95% CI = 0.21-0.82). Correspondingly, the Bayesian ranking of treatments from better to worse target lesion primary patency was CS, DES, DCB, BMS, and PTA. CONCLUSION: With the available research evidence and according to the network analysis ranking, DES appears to have the highest risk of acute thrombosis and DCB appears to have the lowest risk.

The retina and retinal pigment epithelium differ in nitrogen metabolism and are metabolically connected.

Defects in energy metabolism in either the retina or the immediately adjacent retinal pigment epithelium (RPE) underlie retinal degeneration, but the metabolic dependence between retina and RPE remains unclear. Nitrogen-containing metabolites such as amino acids are essential for energy metabolism. Here, we found that 15N-labeled ammonium is predominantly assimilated into glutamine in both the retina and RPE/choroid ex vivo [15N]Ammonium tracing in vivo show that, like the brain, the retina can synthesize asparagine from ammonium, but RPE/choroid and the liver cannot. However, unless present at toxic concentrations, ammonium cannot be recycled into glutamate in the retina and RPE/choroid. Tracing with 15N-labeled amino acids show that the retina predominantly uses aspartate transaminase for de novo synthesis of glutamate, glutamine, and aspartate, whereas RPE uses multiple transaminases to utilize and synthesize amino acids. Retina consumes more leucine than RPE, but little leucine is catabolized. The synthesis of serine and glycine is active in RPE but limited in the retina. RPE, but not the retina, uses alanine as mitochondrial substrates through mitochondrial pyruvate carrier. However, when the mitochondrial pyruvate carrier is inhibited, alanine may directly enter the retinal mitochondria but not those of RPE. In conclusion, our results demonstrate that the retina and RPE differ in nitrogen metabolism and highlight that the RPE supports retinal metabolism through active amino acid metabolism.

A Novel Sirolimus-eluting Biodegradable Magnesium-based Alloy Scaffold: Six-month Results In Porcine Peripheral Arteries.

PURPOSE: Magnesium-based alloy scaffold is a promising biodegradable stent due to its intrinsic mechanical performance and biocompatibility. Based on our preliminary experiments, we designed a novel sirolimus-eluting magnesium-based alloy scaffold. This work aimed to assess its safety and degradation performance in vivo. METHODS: The scaffolds were implanted in the lower limb arteries of Bama mini-pigs. Safety was defined as no immediate thrombosis or >30% residual stenosis, which was assessed with optical coherence tomography and digital subtraction angiography. Blood biochemical analyses were performed to evaluate hepatorenal toxicity. The degradation process of the scaffolds, the endothelialization, and lumen loss of the stented-vessels were detected with scanning electron microscopy, immunohistochemical, hematoxylin-eosin staining and optical coherence tomography. RESULTS: Twenty-four scaffolds were successfully implanted in six pigs with no signs of immediate thrombosis or >30% residual stenosis. The scaffolds were covered by endothelium at one month and absolutely resorbed at six months post implantation. Blood analysis showed that the hepatorenal function except for alanine aminotransferase and γ-glutamyl transpeptidase was normal. Obvious intimal hyperplasia and lumen loss were found in the stented vessels at three months, while the diameters and inner lumen areas of stented segments had increased significantly at six months (p.

Perioperative baseline ß-blockers: An independent protective factor for post-carotid endarterectomy hypertension.

OBJECTIVE: Post-carotid endarterectomy hypertension is a well-recognized phenomenon closely related to surgical complications. This study aimed to determine whether different kinds of perioperative antihypertensive drugs had a protective effect on post-carotid endarterectomy hypertension and influence on intraoperative hemodynamics. METHOD: We retrospectively investigated 102 carotid stenosis patients who underwent conventional endarterectomy with a perioperative baseline antihypertensive regimen. Post-carotid endarterectomy hypertension was defined as a postoperative peak systolic blood pressure ≥160 mmHg and/or a requirement for any additional antihypertensive therapies. We compared the clinical characteristics and types of baseline perioperative antihypertensive drugs between patients with and without post-carotid endarterectomy hypertension and then determined the significant independent effect of antihypertensive drugs on post-carotid endarterectomy hypertension through multivariate regression and detected their influence on intraoperative hypertension (induction-related systolic blood pressure and vasodilators consumption) and hemodynamic depression (intra-arterial systolic blood pressure ≤100 mmHg and/or heart rate ≤50 beats/min). We also investigated adverse events such as stroke, death, myocardial infarction, and cerebral hyperperfusion syndrome during the postoperative hospitalization. RESULTS: A total of 52/102 (51.0%) patients were defined as having post-carotid endarterectomy hypertension during the first three days postoperative, including eight patients with a postoperative systolic blood pressure that exceeded 160 mmHg at least once, 31 patients requiring postoperative antihypertensive treatment in addition to their baseline regimen, and 13 patients with both. The incidence of stroke/death/myocardial infarction and cerebral hyperperfusion syndrome after conventional endarterectomy during hospitalization were both 1.9%. A significantly increased risk of composite postoperative complications (including cerebral hyperperfusion syndrome, hyperperfusion-related symptoms, transient ischemic attacks, stroke, death, and cardiac complications) was observed in patients with post-carotid endarterectomy hypertension than without (15.4% versus 2.0%, p = 0.032). Patients free of post-carotid endarterectomy hypertension had a higher incidence of perioperative baseline ß-blocker use than patients who suffered from post-carotid endarterectomy hypertension (46.0% versus 21%, p = 0.008). In multivariate analysis, ß-blocker use was a significant independent protective factor for post-carotid endarterectomy hypertension (OR = 0.356, 95% CI: 0.146-0.886, p = 0.028). Patients taking ß-blockers had a lower postoperative peak systolic blood pressure than the ß-blocker-naïve population (137.1 ± 12.1 mmHg versus 145.0 ± 11.2 mmHg, p = 0.008), but the postoperative mean systolic blood pressure showed no intergroup difference. However, the incidence of hemodynamic depression during conventional endarterectomy was higher in patients with perioperative ß-blocker use than in those without (44.1% versus 25.0%, p = 0.050). The difference in intraoperative hemodynamic depression became more prominent between the ß-blocker and non-ß-blocker groups (81.8% versus 33.3%, p = 0.014) for whose preoperative baseline heart rate was equal to or lower than 70 beats/min. CONCLUSION: The perioperative use of ß-blockers is a protective factor for post-carotid endarterectomy hypertension and contributes to stabilizing the postoperative peak systolic blood pressure three days after conventional endarterectomy. However, ß-blockers might also lead to intraoperative hemodynamic depression, especially for patients with a low baseline heart rate.

Serum hydroxybutyrate dehydrogenase as an early predictive marker of the severity of acute pancreatitis: a retrospective study.

BACKGROUND: To investigate the value of serum hydroxybutyrate dehydrogenase (HBDH) level, an isozyme of lactate dehydrogenase, in evaluating the severity of acute pancreatitis (AP). METHODS: Patients diagnosed with AP from January 2013 to December 2018 were included in this retrospective study. Patients were divided into the normal serum HBDH levels group (n-HBDH group) and the high serum HBDH levels group (h-HBDH group) according to the criteria HBDH ≥ 182 U/L after admission. The demographic parameters, laboratory data and the severity of AP in the two groups were compared. The receiver operating curve (ROC) was used to evaluate the efficacy of serum HBDH in predicting persistent organ failure and systemic inflammatory response syndrome (SIRS). RESULTS: A total of 260 AP patients were enrolled, including 176 cases in the n-HBDH group and 84 cases in the h-HBDH group. The incidence of SIRS and organ failure in the h-HBDH group were significantly higher than those in n-HBDH group (both P < 0.001). In addition, the HBDH level was significantly decreased in 110 patients who were re-measured after AP treatment. The serum HBDH levels were positively correlated with Atlanta classification, Ranson score, and BISAP score (all P < 0.05). ROC analysis showed that a serum HBDH cut-off point of 195.0 U/L had optimal predictive value for the development of persistent organ failure (AUC = 0.778) and 166.5 U/L for the development of SIRS (AUC = 0.724). CONCLUSION: The elevated serum HBDH in early stage of AP is closely related to the adverse prognosis of AP patients, which can be used as a potential early biomarker for predicting the severity of AP.

Outcomes of Total Aortoiliac Revascularization for TASC-II C&D Lesion with Kissing Self-Expanding Covered Stents.

BACKGROUND: The endovascular approach has been widely used for aortoiliac occlusive disease (AIOD), especially for aortic bifurcation and iliac artery Trans-Atlantic Inter-Society Consensus II (TASC-II) A and B lesions. However, the outcomes of self-expanding covered stents (SECSs) for extensive aortoiliac lesion remain unclear. This study aimed to assess the short-term patency of kissing covered stents for the revascularization of aortoiliac TASC-II C and D diseases. METHODS: Thirty-three patients with TASC-II C and D lesions of AIOD were treated with kissing covered stents. All patients were reviewed under a standard institutional review board protocol. Demographic variables, lesion location and characteristics, stenting configuration, and patency were analyzed. RESULTS: Thirty-one male and 2 female patients with a mean age of 65.1 ± 10.7 years underwent aortoiliac bifurcation reconstruction with kissing SECSs. Eight patients had TASC-II C lesions, and 25 patients had TASC-II D lesions. Among them, 8 patients had total infrarenal aortoiliac occlusion, of which 5 had juxtarenal aortoiliac lesions. The mean lesion length was 11.6 ± 2.1 cm. Mean diameters of aorta and common iliac artery were 18.3 ± 2.1 and 10.7 ± 1.5 mm, respectively. Among them, the abutting stent configuration was used in 11 patients with short or focal ostial lesions, whereas the crossing stent configuration was used in 22 patients with longer lesions extending into the distal aorta. The mean follow-up was 24.5 ± 7.8 months, the follow-up rate was 93.9% (31 of 33), and 29 patients had follow-up longer than 12 months. Primary patency rate at 12 months was 96.5%, and secondary patency rate was 100%. CONCLUSIONS: The use of kissing SECSs for the revascularization of extensive AIOD is safe and effective. The short-term primary patency rates of endovascular treatment of TASC-II C and D lesions were favorable.

Dynamic changes of proteasome and protective effect of bortezomib, a proteasome inhibitor, in mice with acute pancreatitis.

The proteasome is involved in the activation of NF-κB and can regulate the progression of inflammatory diseases. However, the role of proteasome in acute pancreatitis (AP) has not been demonstrated. In this study, we first observed that the protein level and activity of proteasome 20S were increased significantly in pancreatic injury tissues after caerulein-induced mild acute pancreatitis (MAP) induction, which was in consistent with the expression of the NF-κB nucleoprotein and positively correlated with the severity of AP. Then, bortezomib, a classical proteasome inhibitor, was used to intervene the progression of MAP in mice. The results showed that bortezomib administration reduced the serum amylase and lipase levels and mitigated histopathological manifestation of pancreatic injury in mice. Meanwhile, bortezomib decreased the expression of NF-κB p65 nucleoprotein as well as total proteasome 20S protein, and inhibited the activity of 20S in pancreatic tissues. In addition, we found that bortezomib could protect pancreatic acinar cell against necrosis and mitigate the severity of AP in a severe acute pancreatitis model induced by sodium taurocholate hydrate. Taken together, our study for the first time confirmed that the proteasome participated in the pathogenesis of AP and its inhibitor bortezomib could protect against AP in mice.

Prevalence and clinical characteristics of fatty pancreas in Yangzhou, China: A cross-sectional study.

OBJECTIVE: The aim of this study was to investigate the prevalence and risk factors of fatty pancreas in Yangzhou, China. METHODS: This was a cross-sectional study. Initially, 2093 subjects were included in the study. After the exclusion of 865 subjects based on incomplete information, a total of 1228 subjects were selected for further analysis. The subjects were stratified into two groups (the fatty pancreas group and the non-fatty pancreas group) based on the results. Anthropometric and biochemical findings were compared between the groups. RESULTS: Among the 2093 study subjects, 56 (2.7%) had fatty pancreas. Overall, 53 out of 1228 subjects were diagnosed with fatty pancreas and included into the fatty pancreas group. Univariate analysis showed significant differences in age and the prevalence of general obesity, central obesity, alcohol consumption, metabolic syndrome and fatty liver between the two groups (all p < 0.01). The fatty pancreas group had higher levels of aspartate aminotransferase, alanine aminotransferase, serum uric acid, fasting blood glucose, total cholesterol, triglycerides and low-density lipoprotein, and lower levels of high-density lipoprotein than did the non-fatty pancreas group (all p < 0.05). Multivariate logistic regression analysis showed that age (p = 0.007), central obesity (p = 0.002) and fatty liver (p = 0.006) were independent risk factors for fatty pancreas, with odds ratios (ORs) of 1.034 (95% confidence interval (CI): 1.009-1.059), 5.364 (95% CI: 1.890-15.227), and 2.666 (95% CI: 1.332-5.338), respectively. CONCLUSION: The prevalence of fatty pancreas in the examined population is approximately 2.7%. Increased age, central obesity and fatty liver disease are independent risk factors for fatty pancreas.

Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats.

Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing ß cell apoptosis, CD68-cell infiltration, ROS production, and caspase-3 expression. The siRNA-knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor-2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking-induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking-related diabetes, and the therapeutic regimens are absent currently.

High glucose induces the expression of osteopontin in blood vessels in vitro and in vivo.

Osteopontin (OPN) is involved in mineral metabolism and the inflammatory response while diabetes mellitus is associated with severe and extensive vascular calcification. Therefore, we speculated that OPN could be a key factor in the calcification and dysfunction of blood vessels exposed to high glucose. To identify the relationship between high glucose and OPN, we used high glucose medium to stimulate smooth muscle cells (SMCs) and vascular endothelial cells (VECs) in vitro and diabetic rats for in vivo analyses. As assessed by flow cytometry and western blots, SMC and VEC apoptosis levels increased with high glucose. Potassium and calcium uptake by cells were also increased with high glucose. These findings demonstrated the relationship between mineral metabolism and high glucose. Western blot and quantitative real time polymerase chain reaction analyses demonstrated that OPN increased in vitro with high glucose stimulation. The inflammatory factor ICAM1 and the inhibitory phosphorylation of endothelial nitric-oxide synthase (eNOS) (Thr495) were also upregulated by high glucose. In contrast, the anti-inflammatory factor Nrf2 and the activating phosphorylation of eNOS (Ser1177) were downregulated. Similar to the change of OPN, phosphorylated P38 was increased with high glucose. SB203580, an inhibitor of P38 phosphorylation, downregulated the expression of OPN and related inflammatory factors. Additionally, OPN was increased in the aortas and plasma of diabetic rats. In conclusion, our findings demonstrate that high glucose can induce the expression of OPN, which may be a key factor in the calcification and dysfunction of the vascular wall in diabetes.

Perivascular adipose tissue alleviates inflammatory factors and stenosis in diabetic blood vessels.

Adipose tissue can modulate disease processes in a depot-specific manner. However, the functional properties of perivascular adipocytes, and their influence on the pathophysiology of blood vessel walls, remain to be determined. In this study, we aimed to investigate whether perivascular adipose tissue could have an ameliorative effect on blood vessels damaged in diabetes. Using in vitro coculture, and in vivo transplantation model simulating diabetic angioplasty-induced injury, we showed that perivascular adipose tissue has an important function in protecting blood vessels from high glucose impairment. Levels of inflammatory cytokines, including intercellular cell adhesion molecule-1 and osteopontin, were markedly reduced, whereas that of endothelial nitric-oxide synthase was markedly elevated in vascular walls. These depot-specific differences in blood vessels exposed to high levels of glucose were demonstrable both in vivo, with transplanted adipose tissues, and in vitro, when vascular endothelial cells were cocultured with adipocytes. In addition, intimal hyperplasia was also decreased by transplanted perivascular adipose tissue after balloon injury combined with hyperglycemia. We conclude that perivascular adipocytes can reduce inflammation in blood vessels and promote the normal function of endothelium, which could afford a new therapeutic strategy in vascular walls damaged by diabetes.

Impact of the Action Time of Inducers on Differentiation of 3T3-L1 Cells.

Objective To explore the effect of the action time of inducers on the differentiation of 3T3-L1 cells to adipocytes. Methods According to the "Cocktail" method,3T3-L1 cells were divided into three groups according to the action time of inducers,with the action time being 2,3 or 4 days,respectively. Cell morphology was observed using inverted microscope and adipose content were detected by Oil red "O" staining and detection of triglyceride. The cell viability was identified by trypan blue staining method. Results The proportion of samples (n=12) with differentiation rate above 80% in group A was 66% (12/18),while the differentiation rate of all the samples (n=18)in group B and group C were above 80%. For the Oil red "O",the OD value at 510 nm in group C was 2.59±0.17,which was significantly higher than that in group A (2.12±0.47;F=6.62,P=0.0001)and group B (2.20±0.17;F=5.15,P=0.0001),while no significant difference was found between group A and group B (F=1.14,P=0.74). As for the triglyceride,the value in group C was (1351.04±119.01)ng/ml,which was significantly higher than that in group A[ (1077.88±272.75)ng/ml;F=6.73,P=0.001] and group B [(1089.38±115.39)ng/ml;F=5.78,P=0.001],while no difference was found between group A and group B (F=0.27,P=0.64). The cell viability in group A,B,and C was (98.3±1.2)%,(98.5±1.8)%,and (98.9±2.1)%,respectively,showing no significant difference (F=0.18,P=0.83). Conclusions The modified procedure for the differentiation of 3T3-L1 cells to adipocytes can increase the differentiation rate and thus may be applied for establishing adipocyte models. The recommended action time is three days.

The incidence of herpes zoster in China: A meta-analysis and evidence quality assessment.

This review aimed to estimate the disease burden of herpes zoster (HZ) in China and explore the application of the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach in studies of disease burden. We searched for the literature of observational studies analyzing HZ incidence in populations of all ages in China. Meta-analysis models were constructed to calculate the pooled incidence of HZ and pooled risks of postherpetic neuralgia (PHN), HZ recurrence, and hospitalization. Subgroup analysis was performed according to gender, age, and quality assessment score. The quality of evidence for incidence was rated using the GRADE system. Twelve studies with a total of 25,928,408 participants were included in this review. The pooled incidence for all ages was 4.28/1000 person years (95% CI 1.22-7.35). It increased with the increasing in age especially for individuals aged ≥60 y, which was 11.69/1000 person years (95% CI 6.56-16.81). The pooled risks of PHN, recurrence, and hospitalization were 12.6% (95% CI 10.1-15.1), 9.7% (95% CI 3.2-16.2), and 6.0/100,000 population (95% CI 2.3-14.2), respectively. The quality of the evidence assessment of the pooled incidence by the GRADE for all ages was 'low'; however, it was 'moderate' for the ≥60 yold subgroup. HZ is a serious public health problem in China and is more significant in individuals older than 60 y. Therefore, an immunization strategy for the zoster vaccine should be considered. The evidence quality assessment by the GRADE approach indicated that we had more confidence in the estimation of aged population.

Perfusion pressure of elastase impacts the formation ratio and diameters of abdominal aortic aneurysms in rats.

Intra-arterial perfusion with elastase is a common method used to create abdominal aortic aneurysms (AAA) models. The present study aimed to explore the impact of porcine pancreatic elastase (PPE) perfusion pressure on the morphology of abdominal aortic aneurysms. A total of 40 male Sprague Dawley rats were randomized into four groups. The elastase was perfused at pressures in the aortic lumen of 300, 100 and 0 mmHg in three groups, respectively. Rats perfused with saline at 300 mmHg were used as controls. The maximum diameters of the AAA were monitored with ultrasound at 7, 14 and 28 days after the operation. Elastin degradation and inflammatory cell counts were determined using histochemical staining. All rats were successfully perfused at the scheduled pressure. After 7 days, the AAA formation ratio of PPE-300, PPE-100 and PPE-0 was 100, 50 and 0%, respectively. After 14 days, the AAA formation ratio in PPE-100 and PPE-0 reached 90 and 20%, respectively. After 28 days, the diameters of the isolated aorta in PPE-300, PPE-100, PPE-0 and NaCl-300 were (mean ± standard deviation) 7.34±1.81, 4.02±0.40, 2.92±0.32 and 2.49±0.07 mm, respectively, and the difference between groups was statistically significant (P<0.05). The formation ratio in PPE-300, PPE-100, PPE-0 and NaCl-300 was 100, 100, 20 and 0%, respectively. Elastase perfusion pressure could impact the AAA formation ratio at an early stage and the maximum diameter of the aneurysm without increasing animal mortality. Elastase perfusion with high pressure could accelerate aneurysm formation and represents a potential method for building large-size abdominal aortic aneurysms. However, the underlying mechanisms need further investigation.

High circulating fibroblast growth factor-21 levels as a screening marker in fatty pancreas patients.

Background: The study aimed to detect the serum levels of fibroblast growth factor-21 (FGF-21) in fatty pancreas (FP) patients and to investigate their potential clinical value. Methods: We screened patients with FP using transabdominal ultrasound. The anthropometric, biochemical and serum levels of FGF-21 were compared between the FP group and the normal control (NC) group. A receiver operating characteristic (ROC) curve was used to evaluate the predictive value of serum FGF-21 for FP patients. Results: Compared with the NC group, body mass index, fasting blood glucose levels, uric acid levels and cholesterol levels of the FP group were significantly higher, while the high-density lipoprotein level was lower. In addition, levels of serum FGF-21, resistin, leptin and tumor necrosis factor-α were significantly higher than those in the NC group, while the serum adiponectin level was lower. Pearson analysis showed serum FGF-21 levels in FP patients were negatively correlated with leptin. The ROC curve showed the best critical value of the serum FGF-21 level in FP patients was 171 pg/mL (AUC 0.744, P = 0.002, 95% confidence intervals 0.636-0.852). Conclusion: Serum FGF-21 was closely related to fatty pancreas. Detecting serum FGF-21 levels may help identify the population susceptible to FP.

Causal relationship between gut microbiota and serum vitamin D: evidence from genetic correlation and Mendelian randomization study.

BACKGROUND: The gastrointestinal microbiota is emerging as an important mediator in intestinal metabolism, such as vitamin D absorption. METHODS: To elucidate the causality of microbiota and vitamin D, we used linkage disequilibrium score (LDSC) regression and two-sample Mendelian randomization (MR) methods with largest genome-wide association study (GWAS) summary statistics to identify specific taxa that are linked to serum 25-hydroxyvitamin D (25(OH)D). RESULTS: We found that Ruminiclostridium9 was significantly genetically correlated with 25(OH)D at nominal significance (rg = 0.43, P = 0.04). Applying the inverse variance weighted (IVW) method, we identified that doubling the genetic liability of abundance of Erysipelotrichia, Erysipelotrichaceae and Erysipelotrichales reduced the concentration of 25(OH)D by 0.06 standard deviation (SD) (ßIVW = -0.06, s.e. = 0.01, P = 1.48 × 10-6, PFDR = 1.93 × 10-4) and, in turn, one SD increment in genetically determined serum 25(OH)D caused a 0.16 SD decrease in the relative abundance of Phascolarctobacterium (ßIVW = -0.16, s.e. = 0.04, P = 2.48 × 10-4, PFDR = 0.02) after removing pleiotropic instruments and outliers. Moreover, four MR methods were also used to evaluate causality, the results of which supported these findings. Leave-one-out analyses showed that the results were robust with regard to alterations in the single nucleotide polymorphisms (SNPs) we selected. CONCLUSIONS: In conclusion, our results support the hypothesis that the gut microbiota mediates the absorption of serum vitamin D supplementation and interacts with it closely. These microbiota are potential therapeutic targets for promoting serum vitamin D homeostasis.

Wogonin Induces Cell Cycle Arrest and Apoptosis of Hepatocellular Carcinoma Cells by Activating Hippo Signaling.

BACKGROUND: Wogonin has been reported to exhibit pharmacological effects against cancer by regulating cell proliferation, metastasis and apoptosis, however, the role of wogonin in hepatocellular carcinoma (HCC) remains poorly elucidated. OBJECTIVE: The current study aimed to illustrate whether wogonin influences HCC cell cycle progression and apoptosis by regulating Hippo signaling. METHODS: The effects of wogonin on HCC cell viability, cell cycle progression and apoptosis were analyzed by utilizing CCK-8 and flow cytometry. RNA-seq was employed to analyze the expression profiles between wogonin-treated and control HCC cells, and the selected RNA-seq transcripts were validated by Reverse Transcription-quantitative realtime Polymerase Chain Reaction (RT-qPCR). Immunofluorescence staining was performed to detect the distribution of YAP/TAZ in the nucleus and cytoplasm in HCC cells. Western blotting and human apoptosis array were performed to examine the expression of the indicated genes. RESULTS: We demonstrated that wogonin induced cell cycle arrest and apoptosis of HCC cell lines SMMC7721 and HCCLM3. RNA-seq analysis showed enrichment in genes associated with cell cycle progression and apoptosis following incubation with wogonin in HCC cells, and the pathways analysis further identified that Hippo signaling pathways highly altered in wogonin-treated cells. Specifically, wogonin increased the phosphorylation of MOB1 and LATS1, promoted translocation of endogenous YAP and TAZ from the nucleus to the cytoplasm, and facilitated phosphorylation of YAP and TAZ. Notably, overexpression of YAP or TAZ partially abrogated the wogonin-mediated HCC cell cycle arrest and apoptosis, and reversed wogonin-mediated suppression of Claspin. CONCLUSION: Wogonin induced HCC cell cycle arrest and apoptosis probably by activating MOB1-LATS1 signaling to inhibit the activation of YAP and TAZ, and then decrease the expression of Claspin, suggesting that the understanding of the molecular mechanisms underlying wogonin-induced cell cycle arrest and apoptosis may be useful in HCC therapeutics.

Dose-Response Relationship Between Physical Activity and the Incidence of Peripheral Artery Disease in General Population: Insights From the National Health and Nutrition Examination Survey 1999-2004.

Purpose: A low ABI, ≦0.9, indicates peripheral artery disease (PAD) and physical activity (PA) represents an important non-surgical treatment for patients with PAD. However, as for the general population, the associations between PA, PAD, and their mutual dependence are not well-defined. Here we aimed to determine whether there is a dose-response relationship between PA and incidence of PAD in the general population using restricted cubic spline (RCS). Patients and methods: This study analyzed 1,370 adults aged ≧40 years who had participated in the National Health and Nutrition Examination Survey (NHANES) during 1999-2004. The ABI of the participants were measured by trained technicians, and PAD was defined as ABI ≦0.9. PA was obtained with a standard questionnaire, and metabolic equivalents (MET) were used to quantify the PA level. Logistic regression was used to assess the association between PA and incidence of PAD, and the dose-response relationship was analyzed with RCS. Results: PAD was present in 6.2% of the participants: 5.6% of males and 6.9% of females. After adjusting for potential confounders, compared with the first quartile (Q1) of MET, the odds ratios (ORs) of PAD for those with Q2, Q3, and Q4 of MET were 0.688 [95% confidence interval (CI) = 0.684-0.692], 0.463 (95% CI = 0.460-0.466), 0.816 (95% CI = 0.812-0.821), respectively (all p < 0.0001). The RCS regression showed that physical activity was related to the incidence of PAD in a non-linear manner (p for non-linearity < 0.0001). For females, the prevalence of PAD decreased as physical activity increased, reaching the minimum for activity at ~5,800 MET-min month-1 (OR = 0.425, 95% CI = 0.424-0.426), and for males, no plateau was found in this study. Conclusion: The prevalence of PAD is inversely associated with PA, and vigorous activities might help decrease PAD risk for general population. The prevalence of PAD reaches the minimum at ~5,800 MET-min month-1, representing a recommended PA value.

PD-1/PDL1 Blockade Exacerbates Pancreatic Damage and Immune Response in a Mouse Model of Acute Pancreatitis.

Programmed necrosis factor 1 (PD-1) is significantly overexpressed in lymphocytes, neutrophils, and macrophages and has been studied in depth in tumors. As a member of the negative costimulatory family of immune regulatory molecules, expression of PD-1 and its primary regulatory pathway are related to immune cells. Recently, PD-1 was demonstrated to be clinically important in inflammatory diseases, such as multiple sclerosis, glomerulonephritis, and inflammatory bowel disease. PD-1, a negative regulator molecule, was recently found to protect tissues from the inflammatory response and inflammatory cell infiltration. Conversely, PD-1 deficiency may contribute to the occurrence of a diverse array of inflammatory diseases. However, whether PD-1 regulates the pathogenesis of acute pancreatitis (AP) is unclear. AP is a noninfectious inflammatory disease with primary pathological manifestations that include edema, inflammatory cell infiltration, and acinar cell necrosis. Among these features, costimulatory molecules including PD-1/PDL1 play a critical role in the regulation of immune response and immune activation. Here, we first found that PD-1 is notably upregulated in neutrophils and macrophages in peripheral blood and pancreatic injury tissue in AP mice. PD-1 gene deficiency exacerbated pancreatic injury in an experimental mouse model of AP. We observed more severe pancreatic injury in PD-1-deficient mice than in control mice, including increased pancreatic edema, inflammatory cells, infiltration, and acinar cell necrosis. We also found that PD-1-deficient mice exhibited higher levels of serum enzymology and inflammatory factors in AP. Furthermore, PD-1/PDL1 neutralizing antibodies significantly aggravated pancreatic and lung injury and increased serum inflammatory cytokine levels. These findings were consistent with those in PD-1-deficient mice. In summary, PD-1 may protect against AP in mice and act as a potential target for the prevention of AP in the future.

Asiaticoside ameliorates acinar cell necrosis in acute pancreatitis via toll-like receptor 4 pathway.

Acinar cell necrosis is one of the most prominent pathophysiological changes of acute pancreatitis (AP). Asiaticoside (AS) is a triterpene compound with confirmed apoptosis-and necrosis-related activities. However, the specific effects of AS on AP have not been determined. In this study, we aimed to investigate the protective effect of AS on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, We found that AS administration reduced serum amylase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. And the levels of toll-like receptor 4 (TLR4) and necrotic related proteins (RIP3 and p-MLKL) of pancreatic tissue were reduced after AS administration. In addition, TLR4 deficiency eliminated the protective effect of AS on AP induced by caerulein in mice. Correspondingly, we elucidated the effect of AS in vitro and found that AS protected against pancreatic acinar cells necrosis and TAK-242 counteracted this protective effect. Meanwhile, we found that AS ameliorated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by l-arginine. Furthermore, Molecular docking results revealed interaction between AS and TLR4. Taken together, our data for the first time confirmed the protective effects of AS on AP in mice via TLR4 pathway.