Associations of Abdominal Visceral Fat Content and Plasma Adiponectin Level With Intracranial Atherosclerotic Stenosis: A Cross-Sectional Study.

Background: Abdominal obesity and adipocytokines are closely related to atherosclerosis, and adiponectin level is considered one of the important clinical indicators. This study aimed to analyze the associations of abdominal visceral fat content and adiponectin level with intracranial atherosclerotic stenosis (ICAS). Methods: A total of 186 patients were enrolled in this study. Patients were distributed into ICAS and non-ICAS by the degree of artery stenosis. Plasma adiponectin levels and the ratio of visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT) were measured. The related factors of intracranial atherosclerotic stenosis were determined using multivariable logistic regression analysis. Results: The VAT/SAT ratio (OR, 26.08; 95% CI, 5.92-114.83; p < 0.001) and adiponectin (OR, 0.61; 95% CI, 0.44-0.84; p = 0.002) were found to be the independent predictors of ICAS in a multivariable logistic regression analysis. The prevalence of ICAS increased (T1: 27.4%; T2: 50.0%; T3: 75.8%) as the VAT/SAT ratio tertile increased (p < 0.001). The prevalence of ICAS decreased (T1: 72.6%; T2: 54.8%; T3: 25.8%) as the adiponectin tertile increased (p < 0.001). In ROC curves analysis, VAT/SAT ratio had a sensible accuracy for the prediction of ICAS. The optimal cut-off value of VAT/SAT ratio to predict ICAS in this study was 1.04 (AUC: 0.747; p < 0.001; sensitivity: 67.4%; specificity: 74.7%). The optimal adiponectin cutoff was 3.03 ug/ml (AUC: 0.716; p < 0.001; sensitivity:75.8%; specificity: 61.5%). Conclusion: Higher VAT/SAT ratio and lower plasma adiponectin levels were closely related to the increased risk of intracranial atherosclerotic stenosis.

Adiponectin Levels Are Associated with White Matter Lesions (WMLs) and Cognitive Impairment.

METHOD: In the present study, 126 patients, 90 cases in the WML group and 36 cases in the control group, were analyzed to explore the relationship between adiponectin and WMLs. All patients underwent an MRI scan to assess whether white matter lesions happened. And the serum levels of adiponectin were detected by ELISA. RESULTS: In this study, according to Fazekas criteria, WMLs were divided into different severity groups. With the increase of WML score, the level of adiponectin decreased, and linear correlation analysis shows that adiponectin is negatively correlated with the severity of white matter lesions (p < 0.001). And adiponectin level was significantly positively correlated with MoCA score (p < 0.05). Moreover, adiponectin in the WMLs combined with the cognitive impairment group was significantly reduced (p < 0.01). CONCLUSION: The level of adiponectin is independently associated with WMLs and cognitive function, which suggests that adiponectin may be a protective factor for WMLs and cognitive function.

MiR-132 down-regulates high glucose-induced ß-dystroglycan degradation through Matrix Metalloproteinases-9 up-regulation in primary neurons.

Cognitive dysfunction is one of the complications of diabetes. Unfortunately, there is no effective methods to block its progression currently. One of the pathophysiological mechanisms is synaptic protein damage and neuronal signal disruption because of glucose metabolism disorder. Dystroglycan protein, located in the post-synaptic membrane of neurons, links the intracellular cytoskeleton with extracellular matrix. Abnormal expression of dystroglycan protein affects neuronal biological functions and leads to cognitive impairment. However, there are no relevant studies to observe the changes of ß-dystroglycan protein in diabetes rat brain and in primary neurons under high glucose exposure. Our data demonstrated the alterations of cognitive abilities in the diabetic rats; ß-dystroglycan protein degradation occurred in hippocampal and cortical tissues in diabetic rat brain. We further explored the mechanisms underlying of this phenomenon. When neurons are exposed to high glucose environment in long-term period, microRNA-132 (miR-132) would be down-regulated in neurons. Matrix Metalloproteinases-9 (MMP-9) mRNA, as a target of miR-132, could be up-regulated; higher expression and overlay activity of MMP-9 protein could increase ß-DG protein degradation. In this way, ß-DG degradation may affect structure and functions among the synapses, which related to cognition decline. It may provide some theoretical basis for elucidating the molecular mechanism of diabetes-induced cognitive dysfunction.

Comparison of the antiviral effect of Arbidol and Chloroquine in treating COVID-19.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) was broken out in December 2019 and soon became a global health emergency. Effective treatment for COVID-19 is urgently needed. In the present study, we aimed to evaluate the antiviral effect of Arbidol vs. Chloroquine in treating COVID-19. METHODS: We retrospectively analyzed 62 patients with COVID-19 diagnosed according to the guidelines for diagnosis and treatment of COVID-19 in China. They were divided into two groups depending on the antiviral drugs that they received. Participants in the Arbidol group (n=42) received 0.2 g Arbidol, tid for 10 days,and those in Chloroquine group (n=20) received 500 mg Chloroquine, bid for 10 days. The coronavirus negative conversion time and the length of hospital stay were analyzed and compared between the two groups. RESULTS: There was no significant difference in demographic and clinical characteristics between the two groups. After antiviral treatment, the nasopharyngeal specimen negative conversion time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the length of hospital stay in the Arbidol group were significantly shorter than those in the Chloroquine group (18.50 vs. 25.05 days, P=0.001; 23.52 vs. 28.75 days, P=0.001). Adverse events observed during the antiviral treatment period were comparable between the two groups. Overall, 3 (7.14%) participants in the Arbidol group and 4 (20.0%) in the Chloroquine group experienced adverse events during antiviral treatment. CONCLUSIONS: These results suggest that Arbidol is advantageous over Chloroquine in terms of the SARS-CoV-2 negative conversion and the length of hospital stay in treating COVID-19 patients.

Repressor Element 1 Silencing Transcription Factor (REST) Governs Microglia-Like BV2 Cell Migration via Progranulin (PGRN).

Microglia activation contributes to Alzheimer's disease (AD) etiology, and microglia migration is a fundamental function during microglia activation. The repressor element-1 silencing transcription factor (REST), a powerful transcriptional factor, was found to play a neuroprotective role in AD. Despite its possible role in disease progression, little is known about whether REST participates in microglia migration. In this study, we aimed to explore the function of REST and its molecular basis during microglia migration under Aß 1-42-treated pathological conditions. When treated by Aß 1-42 REST was upregulated through JAK2/STAT3 signal pathway in BV2 cells. And transwell coculture system was used to evaluate cell migration function of microglia-like BV2. Small interfering RNA (siRNA) targeting progranulin (PGRN) were delivered into BV2 cells, and results showed that PGRN functions to promote BV2 migration. REST expression was inhibited by sh-RNA, which induced BV2 cell migration obviously. On the contrary, REST was overexpressed by REST recombinant plasmid transfection, which repressed BV2 cell migration, indicating that REST may act as a repressor of cell migration. To more comprehensively examine the molecular basis, we analyzed the promoter sequence of PGRN and found that it has the potential binding site of REST. Moreover, knocking-down of REST can increase the expression of PGRN, which confirms the inhibiting effect of REST on PGRN expression. Further detection of double luciferase reporter gene also confirmed the inhibition of REST on the activity of PGRN promoter, indicating that REST may be an inhibitory transcription factor of PGRN which governs microglia-like BV2 cell migration. In conclusion, the present study demonstrates that transcription factor REST may act as a repressor of microglia migration through PGRN.

Aß-Induced Repressor Element 1-Silencing Transcription Factor (REST) Gene Delivery Suppresses Activation of Microglia-Like BV-2 Cells.

Compelling evidence from basic molecular biology has demonstrated the crucial role of microglia in the pathogenesis of Alzheimer's disease (AD). Microglia were believed to play a dual role in both promoting and inhibiting Alzheimer's disease progression. It is of great significance to regulate the function of microglia and make them develop in a favorable way. In the present study, we investigated the function of repressor element 1-silencing transcription factor (REST) in Aß 1-42-induced BV-2 cell dysfunction. We concluded that Aß 1-42 could promote type I activation of BV-2 cells and induce cell proliferation, migration, and proinflammation cytokine TNF-α, IL-1ß, and IL-6 expression. Meanwhile, REST was upregulated, and nuclear translocalization took place due to Aß 1-42 stimulation. When REST was knocked down by a specific short hairpin RNA (sh-RNA), BV-2 cell proliferation, migration, and proinflammation cytokine expression and secretion induced by Aß 1-42 were increased, demonstrating that REST may act as a repressor of microglia-like BV-2 cell activation.

Association Between PSD95 Gene 3'UTR Single Nucleotide Polymorphism and Risk of Acute Ischemic Stroke in Chinese Han Population.

To study the association between the 3'UTR single nucleotide polymorphism of PSD95 gene and the risk of acute ischemic stroke (AIS) in Chinese Han population. PSD95 gene 3'UTR rs191350575, rs314254, rs58197058, rs314253, rs314252, rs188777, rs11652753, rs79715480, and rs13331 genotypes of a total of 280 AIS patients and 280 healthy controls were analyzed. The prognosis outcomes of all AIS patients were analyzed after 3 years of follow-up. The risk of AIS in the rs58197058 locus A allele was 1.76 times higher than the G allele (95%CI 1.53-1.92, p < 0.01). The rs314252 locus A allele carrier was 1.29 times more likely to develop AIS than the G allele (95%CI 1.14-1.45, p < 0.01). The rs13331 locus A allele was a high-risk factor for ASI (adjusted OR = 1.18, 95%CI 1.05-1.33, p = 0.01). The interaction model between Alcohol, DM, Hypertension, rs58197058, and rs314252 predicted the highest accuracy of AIS, with a corresponding sensitivity of 75.36%, specificity of 85.00%, and cross-validation consistency (CVC) of 10/10 (p < 0.01). There was a significant correlation between rs58197058, rs314252, and rs13331 SNPs and plasma FG, TC, HDL-c, and LDL-c levels in AIS patients. The PSD95 gene 3'UTR rs58197058, rs314252, and rs13331 SNPs are associated with the occurrence and prognosis of Chinese Han AIS patients.

Enhanced liver-targeting via coadministration of 10-Hydroxycamptothecin polymeric micelles with vinegar baked Radix Bupleuri.

BACKGROUND: Vinegar baked Radix Bupleuri (VBRB) is a wildly used traditional Chinese medicine, it could be used as a meridian guided drug to enhance liver targeting efficiency of the delivered drug in addition to its therapeutic effect. PURPOSE: To investigate the liver targeting effect induced by VBRB via coadministration with 10-Hydroxycamptothecin loaded polymeric micelles. METHODS: First of all, the inhibitory effect of VBRB on the activity of glutathione S-transferase (GST) was investigated in vitro to select the most effective extract. After oral administration of 10-Hydroxycamptothecin (HCPT) polymeric micelles with low, medium and high doses of VBRB, pharmacokinetic parameters, including the ratio of Cmax in the liver (Ce) and the relative uptake efficiency (RUE), were employed to assess the liver targeting efficiency. RESULTS: It was found that VBRB extract BC1 has the strongest inhibition effect on GST activity in the five extracts. By coadministration of HCPT loaded micelles with three doses of BC1, the AUC0-t of HCPT in the liver raised by 42.5%, 23.0%, -0.2%, with RUE 1.45, 1.23, 1.02 for low, medium and high dose groups, respectively, indicating that low and medium dose of BC1 presented better liver-targeting enhancing effect than that of the high dose, which corresponded to the commonly used dose of VBRB in traditional Chinese medicine formulae. CONCLUSIONS: VBRB could effectively enhance the liver-targeting efficiency of HCPT loaded polymeric micelles after oral coadministration. Such a simple but effective strategy may enlighten on the potential use of meridian guided drug together with modern drug delivery system to achieve better active drug targeting.

Safety and Efficiency of Low Dose Intra-arterial Tirofiban in Mechanical Thrombectomy During Acute Ischemic Stroke.

OBJECTIVE: In this study, we aimed to evaluate the safety and efficiency of low dose intra- arterial tirofiban in mechanical thrombectomy of acute ischemic stroke patients to facilitate the reperfusion of distal vessel. METHODS: We retrospectively analyzed 54 consecutive acute ischemic patients who underwent mechanical thrombectomy for large-vessel occlusion. Patients were divided into two groups based on whether intra-arterial tirofiban was used during mechanical thrombectomy to facilitate the reperfusion of distal vessel. Patients in Non-tirofiban group (n=28) have received mechanical thrombectomy, while Patients in Tirofiban group (n=26) have received mechanical thrombectomy with a low dose intra-arterial tirofiban. We comparatively analyzed two groups of the bleeding complications, recanalization rate, 24-hour National Institutes of Health Stroke Scale score, functional independence of 90 day and mortality rate. RESULTS: Of 54 patients undergoing mechanical thrombectomy, baseline characteristics did not differ between the Tirofiban group and Non-tirofiban cohort. Symptomatic intracranial hemorrhage rates were not different between Tirofiban group and Non-tirofiban group (11.5 % vs. 14.3%). Total 47 (87.0%) patients have realized successful recanalization, no apparent difference between two groups (85.7% vs. 88.5%, P>0.05). Mean 24-hour National Institutes of Health Stroke Scale score was 9.24±6.85, 9.11±8.13 in the Non-tirofiban group and 9.39±5.31 in the Tirofiban group respectively, P>0.05. Total 20 (35.7%) patients have achieved functional independence (34.6% vs. 39.3%, P>0.05) at 90 days. Patients treated with tirofiban presented lower mortality when compared with those who were not treated with tirofiban without significant difference (10.7% versus 3.8%, P>0.05). CONCLUSION: Intra-arterial tirofiban may be safe in mechanical thrombectomy of acute ischemic stroke to facilitate the reperfusion of distal vessel, but has no beneficial effect on prognosis.

Insights into the mechanisms of chitosan-anionic polymers-based matrix tablets for extended drug release.

The aim of this study was to investigate drug release mechanisms from physical mixtures of chitosan-anionic polymers-based matrix tablets and to obtain a comprehensive understanding about release characteristics. Six types of anionic polymers (i.e., Eudragit(®) L100, sodium alginate, carrageenan, carboxymethylcellulose sodium, carbomer and xanthan gum) and two model drugs (i.e., theophylline and metoprolol succinate) with varied solubility were chosen. Texture analyzer, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were applied to better understand drug release mechanisms. In vitro release experiments were conducted in a pH-changing medium to simulate the physiological condition of the gastrointestinal tract. Interestingly, a common phenomenon was observed in all the CS-anionic polymers-based matrix tablets investigated here, that is, the inner layer of the swollen tablets was coated by CS-anionic polymer polyelectrolyte complexes (PEC)-based film formed by self-assembly. Formation of the in situ self-assembled film was further confirmed by texture analysis, DSC, and FTIR. It was further identified that properties of the film were influenced by the characteristics of anionic polymers and the physiological conditions of the gastrointestinal tract. Moreover, this novel structure could alter swelling and erosion-based release mechanisms of the tablets. In addition, drug release characteristics from CS-anionic polymer systems depended on the properties of anionic polymers and the drug solubility. In conclusion, our studies may broaden current views on cationic polymer-anionic polymer-based oral matrix tablets for extended release.

Modulatory effects of extracts of vinegar-baked Radix Bupleuri and saikosaponins on the activity of cytochrome P450 enzymes in vitro.

1. In this article, the modulatory effects of extracts from vinegar-baked Radix Bupleuri (VBRB) and saikosaponins on the activity of CYP1A2, CYP2C9 and CYP3A4 were investigated in vitro. 2. Microsomal in vitro incubation method was utilized to simulate metabolic reaction under physiological environment by incubating the marker with liver microsomes in the absence or presence of VBRB and saikosaponins. The contents of 4-acetamidophenol, 6ß-hydroxyltestosterone and 4-hydroxydiclofenac, the metabolites of phenacetin, testosterone and diclofenac, which were selected as specific probe drugs of CYP1A2, CYP2C9 and CYP3A4, respectively, were analyzed by high-performance liquid chromatography. 3. The production of the metabolites was incubation time dependent. The modulatory effects of different VBRB extracts and saikosaponins on CYP isoforms increased with concentration. Among all the extracts studied, BC1 has a strong inhibition effect compared to the three CYP isoforms tested, while the others have only significant inhibition on the activity of CYP2C9. 4. This in vitro study demonstrated that various extracts of VBRB tested in this study have negligible potential to interfere with CYP1A2- and CYP3A4-metabolized drugs; risk of herb-drug interaction might occur when VBRB is concurrently taken with CYP2C9 substrates.

Effect of saikosaponins and extracts of vinegar-baked Bupleuri Radix on the activity of ß-glucuronidase.

In Traditional Chinese Medicine, liver targeting is usually achieved by coadministration with Vinegar-baked Radix Bupleuri (VBRB), but the mechanism is unclear. In this paper, the influence of VBRB on the activity of ß-glucuronidase was investigated and compared with that of saikosaponins. The activity of ß-glucuronidase was measured by microplate reader using a 4-nitrophenyl-ß-d-glucuronide substrate. The change of 4-nitrophenol content was used to characterize the activity of ß-glucuronidase. Bupleurum chinenes were found to be the inhibitor of ß-glucuronidase. The inhibition rate of Bupleurum chinenes extracts BC1 (high molecular weight polysaccharides), BC2 (ethanol soluble/water insoluble component), BC3 (extracted by n-butanol, soluble in water), and BC4 (low molecular weight water soluble parts) on the activity of ß-glucuronidase was found to be 45.15%, 33.94%, 24.94%, and 34.54%, respectively, after 1 h incubation, with BC1 showing the highest inhibition rate. In contrast, the saikosaponins were demonstrated to be the promoter of ß-glucuronidase, with promotion rates of 333.56%, 217.04%, 247.87%, 149.75%, and 92.50% for saikosaponin standard samples A, B, B2, C, and D, respectively, (p<0.05). In conclusion, inhibiting the activity of ß-glucuronidase might be one of the reasons why VBRB could influence drug distribution upon its coadministration with other drugs. Since saikosaponins and VBRB extracts have opposite effect, more attention should be paid to the content of saikosaponins in the extracts upon its application.