Paroxetine alleviates dendritic cell and T lymphocyte activation via GRK2-mediated PI3K-AKT signaling in rheumatoid arthritis.

BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (Tregs), an increase in the cluster of differentiation 8 positive (CD8+) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8+ T cells, and induced the proportion of Tregs. Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION: Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cell in RA.

COVID-19 control accelerates the decline in illegal drug use in China.

This work illustrates the accelerated decline in illegal drug use during the COVID-19 pandemic in China. We first reviewed the global effects of the COVID-19 pandemic on the situation of illegal drugs. We then compared the data of the pre-pandemic (2016-2019) and pandemic period (2020-2022) for drug seizures, individuals identified as using drugs, registered and newly discovered illegal drug users and the number of community-treated drug users to demonstrate the fast decline in the use of illegal drugs in China. We then discussed the possible reasons and additional considerations for these changes. Overall, the COVID-19 controls in China, such as all-staff nucleic acid testing and ID-based dynamic monitoring, substantially reduced illegal drug use. Being wary of a possible rebound in drug use and preventing new types of drug crimes are still essential in post-COVID China.

Thermadapt Shape Memory Polymers Enabling Spatially Regulated Plasticity.

Converting planar polymer films into sophisticated 3D structures with a facile and effective method is highly challenging yet desirable for device applications in the real world. Dynamic covalent polymer networks enable permanent shape transformations from 2D sheets to 3D structures, but either sophisticated molecular design or a complex fabrication method is required. Here, we report a shape memory polymer cross-linked by ester bonds, which can be activated upon heating after photoexposure to release the catalyst for the transesterification. The region that is activated via the bond exchange can be patterned due to the spatial-temporal selectivity of the photoexposure. Accordingly, the material presents a localized heterogeneity in stress relaxation upon stretching. The exposed and the unexposed regions show respectively plastic deformation and elastic recovery after removal of the external force, which finally make the 2D sheet transform into a 3D structure. The decoupling of the activated region (photoexposure) and activated condition (heating) enables facile chemical design and fabrication for 2D-to-3D shape morphing.

Occupational class differences in outcomes after ischemic stroke: a prospective observational study.

BACKGROUND: Occupational class is an integral part of socioeconomic status. The studies focused on the occupational difference in ischemic stroke outcome in a Chinese population are limited. We aimed to investigate the associations between occupational class and the prognosis of patients with ischemic stroke in China. METHODS: We included 1484 ischemic stroke participants (mean age: 63.42 ± 11.26 years) from the prospective cohort study: Infectious Factors, Inflammatory Markers and Prognosis of Acute Ischemic Stroke (IIPAIS). Occupational class was categorized into white-collar workers, blue-collar workers and farmers in our study. Study outcomes were cardiovascular events and all-cause mortality within 12 months after ischemic stroke onset. We applied Cox proportional hazard model to evaluate the associations between the occupational class and study outcomes after ischemic stroke. RESULTS: Within 12 months after ischemic stroke, there were 106 (7.5%) cardiovascular events and 69 (4.9%) all-cause deaths. The Kaplan-Meier plots showed that white-collar workers had highest risk of cardiovascular events after 12-month follow-up (Log-rank P = 0.02). Multivariate adjusted hazard ratio and 95% confidence intervals (CIs) of farmers versus white-collar workers was 0.43(0.20-0.91) for cardiovascular events. No significant difference showed in blue-collar workers versus white-collar workers, with fully adjusted hazard ratio 0.62(95% CIs, 0.23-1.67). CONCLUSIONS: Compared with white-collar workers, farmers are associated with less risk of cardiovascular events at 12 months after ischemic stroke, while there are no significant differences in blue-collar workers.

Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression.

Enhancer of zeste homolog 2 (EZH2), an oncogene, is a commonly up-regulated epigenetic factor in human cancer. Hepatocellular carcinoma deletion gene 1 (DLC1) is an antioncogene that is either expressed at low levels or not expressed in many malignant tumours. Curcumin is a promising anticancer drug that has antitumour effects in many tumours, but its mechanism of action is unclear. Our research demonstrated that EZH2 was up-regulated in breast cancer (BC) tissues and cells, whereas DLC1 was down-regulated, and the expression of EZH2 and DLC1 was negatively correlated in BC. By analysing the characteristics of clinical cases, we found that positive expression of EZH2 and negative expression of DLC1 may be predictors of poor prognosis in patients with triple-negative breast cancer (TNBC). Moreover, knockdown of EZH2 expression restored the expression of DLC1 and inhibited the migration, invasion and proliferation, promoted the apoptosis, and blocked the cell cycle of MDA-MB-231 cells. Furthermore, we found that curcumin restored the expression of DLC1 by inhibiting EZH2; it also inhibited the migration, invasion and proliferation of MDA-MB-231 cells, promoted their apoptosis and blocked the cell cycle. Finally, xenograft tumour models were used to demonstrate that curcumin restored DLC1 expression by inhibiting EZH2 and also inhibited the growth and promoted the apoptosis of TNBC cells. In conclusion, our results suggest that curcumin can inhibit the migration, invasion and proliferation, promote the apoptosis, block the cycle of TNBC cells and restore the expression of DLC1 by inhibiting the expression of EZH2.

The synergistic action of phosphate and interleukin-6 enhances senescence-associated calcification in vascular smooth muscle cells depending on p53.

Cardiovascular calcification is associated with cardiovascular morbidity and mortality of patients with end-stage renal diseases (ESRD). Hyperphosphatemia and many of the inflammatory markers and mediators, including interleukin-6 (IL-6), are considered as the major risk factors of cardiovascular calcification. Although cellular senescence may be involved in cardiovascular calcification caused by phosphate overload and (or) IL-6 in patients with ESRD, less is known about the underlying mechanisms for phosphate- and IL-6-induced senescence-associated calcification of vascular smooth muscle cells (VSMCs). In the present study, we investigated the correlation between cellular senescence and vascular calcification induced by loading phosphate and (or) IL-6 in VSMCs. Our findings show that p53 plays a major role in senescence-associated vascular calcification induced by phosphate overload. IL-6 induces senescence-associated calcification in VSMCs depending upon activation of the IL-6/soluble IL-6 receptor (sIL-6R)/signal transducer and activator of transcription 3 (STAT3)/p53/p21 pathway. We demonstrate that the synergistic action of phosphate overload and IL-6 enhances senescence-associated calcification in a p53-dependent manner and is inhibited by an anti-aging agent (resveratrol) in a dose-dependent manner.

Viral quasispecies of hepatitis B virus in patients with YMDD mutation and lamivudine resistance may not predict the efficacy of lamivudine/adefovir rescue therapy.

The association between hepatitis B virus (HBV) quasispecies (QS) and the efficacy of nucleos(t)ide analog therapy is currently not well defined, particularly in the case of lamivudine (LAM)/adefovir (ADV) combination rescue therapy for patients with chronic HBV infection (CHB) presenting with LAM resistance. In the present study, 16 CHB patients with the rtM204I/V mutation in the tyrosine-methionine-aspartate-aspartate motif of the C domain of the polymerase gene who switched to LAM/ADV treatment due to LAM resistance were assessed. HBV DNA was isolated from these patients and the reverse transcriptase (RT) region was sequenced. The QS heterogeneity and distribution was analyzed, the mutation sites were recorded and the phylogenetic trees were constructed. The results indicated that QS heterogeneity and distribution in the RT and S regions were not significantly different between responders (RS) and non-RS (NRS) at baseline (P>0.05), except for the higher frequency of a dominant strain in the RT region at the nucleotide level in the RS group (P=0.039). In addition, in NRS, no significant difference in QS heterogeneity or distribution in these regions was identified at six months vs. the baseline. Furthermore, although in the non-responder group the frequency of the LAM resistance-associated mutations (rtM204V/I) decreased at 6 months compared with the baseline, it did not disappear in any of the patients after six months of treatment. Analysis of individual patients did not indicate any consistent selection of specific HBV mutants during LAM/ADV rescue therapy. In conclusion, the baseline HBV QS within the RT and S regions may not be a valid predictor of the response to LAM/ADV rescue treatment in CHB patients with LAM resistance.

Performance Characteristics and Clinical Value of the Lipoprotein-Associated Phospholipase A2 by an Enzymatic Kinetic Method.

OBJECTIVE: To analyze the performance characteristics, stability, and clinical value of lipoprotein-associated phospholipase A2 (Lp-PLA2) using an enzymatic kinetic method. METHODS: The performance characteristics included reference intervals, precision, and accuracy. We assessed Lp-PLA2 stability by comparing Lp-PLA2 changes under different conditions. Lp-PLA2 was determined in the following groups: control individuals, patients with coronary heart disease (CHD), patients of different lipid subgroups within CHD, and patients with high total cholesterol (TC). Also, correlations between Lp-PLA2 and traditional cardiovascular risk factors were assessed. RESULTS: The mean (SD) reference interval of serum Lp-PLA2 activity was 451 (113) U per L with sex differences. Inter- and intra-assay precision revealed coefficients of variance (CVs) of 1.81% to 2.63% and 1.43% to 1.77%. The average bias was 0.33%. Lp-PLA2 activity was stable. In the CHD group, high-lipid subgroups, and high-TC group, Lp-PLA2 was elevated, and correlation was observed between Lp-PLA2 and traditional risk factors. CONCLUSION: Lp-PLA2 activity has important clinical value in CHD.

Expression alterations of apoptosis repressor with caspase recruitment domain in Aß25-35-induced hippocampal neurotoxicity.

Many proapoptotic and antiapoptotic proteins have been involved in the pathology of Alzheimer's disease. As the first identified antiapoptotic protein, apoptosis repressor with caspase recruitment domain (ARC) is highly expressed in terminally differentiated cells, and its functions and expressions in striated muscles and cancer cells have been widely studied. However, the expression alterations of ARC in amyloid ß-induced early hippocampal neurotoxicity are less known. In this report, we not only confirm previous reports that ARC is expressed in the hippocampal neurons but also demonstrate for the first time that ARC is also expressed in the hippocampal astrocytes. Furthermore, we extend the findings to show that, contrary to the time-dependently decreased ARC levels in the hippocampal neurons, ARC in astrocytes is strikingly increased in Aß25-35-induced early neurotoxicity. Our data suggest that ARC has distinct roles based on cell type and stimuli. Our results provide valuable information for further exploring the complicated functions and related mechanisms of ARC in amyloid-related diseases.

Elevated Serum Human Cytomegalovirus IgM Levels in the Acute Phase of Ischemic Stroke are Associated with Increased Risk of Death and Major Disability.

BACKGROUND: There was a lack of studies on the association between Human Cytomegalovirus (HCMV) infection and prognosis of ischemic stroke, although it was indicated that human cytomegalovirus DNA has played a role in several cardiovascular disorders. OBJECTIVE: To examine the association between HCMV IgM levels in the acute phase and death and major disability after 2 weeks of acute ischemic stroke. METHODS: Serum HCMV IgM levels were measured in 1150 participants in China. Study outcome data on major disability and combined outcome of death and major disability were collected at 2 weeks after stroke onset or hospital discharge. RESULTS: After 2 weeks of follow-up, 351 participants (30.52%) suffered from a major disability or died. Serum HCMV IgM was correlated with the combined outcome of death and major disability significantly after adjustment confounding factors. For example, the highest quartile of HCMV IgM was related to an odds ratio (95% confidence interval) of 1.84 (1.12-3.11) for the combined outcome. Risk prediction of the combined outcome was improved by the addition of serum HCMV IgM to conventional risk factors (net reclassification index 25.41%, p＝0.0002; integrated discrimination improvement 0.70%, p＝0.04377). CONCLUSIONS: Elevated serum HCMV IgM levels in the acute phase of ischemic stroke were correlated with increased risk of combined outcome of death and major disability, indicating that serum HCMV IgM could be an important predictive factor for poor prognosis of ischemic stroke.

The establishment of biological reference intervals of nontraditional glycemic markers in a Chinese population.

BACKGROUND: We established the reference intervals for glycated albumin (GA), fructosamine (FA), and 1,5-anhydroglucitol (1,5-AG) in a Chinese healthy population. METHODS: This study enrolled a total of 458 eligible reference individuals, consisted of 226 men and 232 women, aged from 20~79 years (median age 43 years), who attending routine healthy checks. We stratified the subjects according to gender (males and females) and age (20-39, 40-59, and 60-79 years), and combined statistical methods with Lahti algorithm, as well as appropriate clinical consideration, to judge whether partitioning for data was needed. RESULTS: Glycated albumin levels between males and females were statistically different (P<.001), but the absolute difference between the upper reference limits was only 0.31%, which was too small to be clinically relevant. GA levels across the three age groups were statistically different (P<.001), and Lahti algorithm suggested partitioning for 20-59 and 60-79 years, which reference intervals were 10.38%-13.89% and 10.23%-14.79%, respectively. 1,5-AG levels in males were significant higher than females (P<.001), and absolute difference was 51 µmol/L (8.5 µg/mL) in mean level. Thus, partitioning for gender was needed. Reference intervals for 1,5-AG were 107-367 µmol/L for males and 79-306 µmol/L for females. The absolute difference of the lower reference limits for FA was only 7 µmol/L between males and females. FA levels across the three age groups were not statistically different (P>.05). The reference interval for FA was 220-298 µmol/L. CONCLUSION: New reference intervals for nontraditional glycemic markers were established based on a Chinese population.

Cerebral dopamine neurotrophic factor alleviates Aß25-35-induced endoplasmic reticulum stress and early synaptotoxicity in rat hippocampal cells.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease, and early stage AD is characterized by synaptic dysfunction generally ascribed to soluble oligomers of amyloid-beta (Aß). Neurotrophic factors are promising for AD treatment and are integrally involved in neuronal growth, survival and maintenance. Cerebral dopamine neurotrophic factor (CDNF) was recently discovered to have beneficial effects on long-term memory. The present study explored the synaptoprotective effects of CDNF in Aß-treated primary hippocampal cells. Immunofluorescent analysis of synaptophysin and postsynaptic density protein 95 (PSD95) puncta densities in the group of pretreatment with CDNF before Aß exposure revealed significant improvements compared to Aß group. In addition, pretreatment with CDNF reduced the expression levels of endoplasmic reticulum (ER) stress-related proteins, including Bip (also known as GRP78), phosphorylation of eukaryotic translation initiation factor 2 subunit α (peIF2α), phosphorylation of c-Jun N-terminal kinase (pJNK), and cleaved caspase 3, which are increased by Aß treatment at early stage. Our results revealed protective effects of CDNF on Aß-induced synaptotoxicity and ER stress, implying that CDNF may protect against Aß-induced synaptotoxicity through suppression of ER stress. CDNF could be a potential drug candidate for early AD treatment.

Association between vitamin D status and the risk of gestational diabetes mellitus: a meta-analysis.

PURPOSE: Vitamin D is widely used for bone growth and normal insulin secretion; however, the association between vitamin D status and gestational diabetes risk is controversial. This meta-analysis aimed to quantitatively evaluate the association between vitamin status and risk of gestational diabetes. METHODS: We performed a systematic search on the PubMed, EmBase, and Cochrane Library databases in January 2015 to obtain observational studies studying gestational diabetes risk in relation to vitamin D status. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to measure the association between vitamin D status and the risk of gestational diabetes. RESULTS: A total of 20 observational studies were included in the final analysis containing 16,515 individuals. Overall, maternal vitamin D insufficiency was found to be associated with a greater risk of gestational diabetes (RR 1.45; 95 % CI 1.15-1.83; P < 0.001). Subgroup analysis indicated that this association might differ based on countries, study design, assessment of vitamin D levels, sample size, age at baseline, adjusted models, and study quality. CONCLUSIONS: This meta-analysis revealed that maternal vitamin D insufficiency is associated with increased risk of gestational diabetes.

High homocysteine and blood pressure related to poor outcome of acute ischemia stroke in Chinese population.

OBJECTIVES: To assess the association between plasma homocysteine (Hcy), blood pressure (BP) and poor outcome at hospital discharge among acute ischemic stroke patients, and if high Hcy increases the risk of poor outcome based on high BP status in a northern Chinese population. METHODS: Between June 1, 2009 and May 31, 2013, a total of 3695 acute ischemic stroke patients were recruited from three hospitals in northern Chinese cities. Demographic characteristics, lifestyle risk factors, medical history, and other clinical characteristics were recorded for all subjects. Poor outcome was defined as a discharge modified Rankin Scale (mRS) score ≥3 or death. The association between homocysteine concentration, admission blood pressure, and risk of poor outcome following acute ischemic stroke was analyzed by using multivariate non-conditional logistic regression models. RESULTS: Compared with those in the lowest quartile of Hcy concentration in a multivariate-adjusted model, those in the highest quartile of Hcy concentration had increased risk of poor outcome after acute ischemic stroke, (OR = 1.33, P<0.05). The dose-response relationship between Hcy concentration and risk of poor outcome was statistically significant (p-value for trend  = 0.027). High BP was significantly associated with poor outcome following acute ischemic stroke (adjusted OR = 1.44, 95%CI, 1.19-1.74). Compared with non-high BP with nhHcy, in a multivariate-adjusted model, the ORs (95% CI) of non-high BP with hHcy, high BP with nhHcy, and high BP with hHcy to poor outcome were 1.14 (0.85-1.53), 1.37 (1.03-1.84) and 1.70 (1.29-2.34), respectively. CONCLUSION: The present study suggested that high plasma Hcy and blood pressure were independent risk factors for prognosis of acute ischemic stroke, and hHcy may further increase the risk of poor outcome among patients with high blood pressure. Additionally, the results indicate that high Hcy with high BP may cause increased susceptibility to poor outcome among acute ischemic stroke patients in a northern Chinese population.

Measurement of electrolyte concentrations in expressed prostatic secretion and urine from patients with chronic prostatitis and its implications.

This study was aimed at measuring concentration of electrolytes, especially K+ in expressed prostatic secretion (EPS) and urine from patients with chronic prostatitis. The concentration of potassium, sodium, chloride, calcium in EPS and urine of 31 controls and 79 patients with prostatitis were measured and analyzed. There was no significant difference in the concentrations of potassium, sodium, chloride and calcium between the patients and the controls. Among the patients treated effectively, potassium concentration was 40.66 +/- 17.10 mmol/l before treatment and 33.42 +/- 17.27 mmol/l after treatment. While among the patients treated ineffectively, potassium concentration was measured as 37.57 +/- 16.93 mmol/l and 50.66 +/- 18.77 mmol/l before and after treatment respectively. The concentrations of electrolytes in prostatic fluid varied greatly between individuals. Potassium concentration in EPS decreased significantly after treatment among the patients with obvious treatment effectiveness, while increased among those who failed the treatment. EPS potassium concentration was also found to be lower in patients with pain than those without pain. No significant difference was found between the normal group and the no-pain patients.