Synergistic dual cell therapy for atherosclerosis regression: ROS-responsive Bio-liposomes co-loaded with Geniposide and Emodin.

The development of nanomaterials for delivering natural compounds has emerged as a promising approach for atherosclerosis therapy. However, premature drug release remains a challenge. Here, we present a ROS-responsive biomimetic nanocomplex co-loaded with Geniposide (GP) and Emodin (EM) in nanoliposome particles (LP NPs) for targeted atherosclerosis therapy. The nanocomplex, hybridized with the macrophage membrane (Møm), effectively evades immune system clearance and targets atherosclerotic plaques. A modified thioketal (TK) system responds to ROS-rich plaque regions, triggering controlled drug release. In vitro, the nanocomplex inhibits endothelial cell apoptosis and macrophage lipid accumulation, restores endothelial cell function, and promotes cholesterol effluxion. In vivo, it targets ROS-rich atherosclerotic plaques, reducing plaque area ROS levels and restoring endothelial cell function, consequently promoting cholesterol outflow. Our study demonstrates that ROS-responsive biomimetic nanocomplexes co-delivering GP and EM exert a synergistic effect against endothelial cell apoptosis and lipid deposition in macrophages, offering a promising dual-cell therapy modality for atherosclerosis regression.

Trending prevalence of healthcare-associated infections in a tertiary hospital in China during the COVID-19 pandemic.

BACKGROUND: The purpose of this study was to demonstrate both the four-year prevalence trend of healthcare-associated infections (HAIs) in a large tertiary hospital and the trend regarding the prevalence of HAIs following the outbreak of coronavirus disease 2019 (COVID-19) in order to provide evidence of hospital infection management during the COVID-19 pandemic. METHODS: Based on the hospital's electronic nosocomial infection databases related to HAIs, we retrospectively identified the HAI cases to assess the epidemiological characteristics of HAIs from January 1, 2018, to December 31, 2021, in a large tertiary hospital in China. Similarly, the trends of HAIs after the COVID-19 outbreak and the seasonal variation of HAIs were further analyzed. RESULTS: The HAI cases (n = 7833) were identified from the inpatients (n = 483,258) during the 4 years. The most frequently occurring underlying cause of HAIs was respiratory tract infections (44.47%), followed by bloodstream infections (11.59%), and urinary tract infections (8.69%). The annual prevalence of HAIs decreased from 2.39% in 2018 to 1.41% in 2021 (P = 0.032), with the overall prevalence of HAIs significantly decreasing since the outbreak of COVID-19 (2.20% in 2018-2019 vs. 1.44% in 2020-2021, P < 0.001). The prevalence of respiratory tract infections decreased most significantly; whereas, overall, the prevalence of HAIs was significantly greater during the winter compared with the rest of the year. CONCLUSIONS: Not only did the annual prevalence of HAIs decrease from 2018 to 2021, but it also significantly decreased since the start of the COVID-19 pandemic, particularly respiratory tract infections. These results provide evidence for the need to prevent HAIs, especially during the winter season.

Evolocumab loaded Bio-Liposomes for efficient atherosclerosis therapy.

PCSK9, which is closely related to atherosclerosis, is significantly expressed in vascular smooth muscle cells (VSMCs). Moreover, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) mediated phenotypic transformation, abnormal proliferation, and migration of VSMCs play key roles in accelerating atherosclerosis. In this study, by utilizing the significant advantages of nano-materials, a biomimetic nanoliposome loading with Evolocumab (Evol), a PCSK9 inhibitor, was designed to alleviate atherosclerosis. In vitro results showed that (Lipo + M)@E NPs up-regulated the levels of α-SMA and Vimentin, while inhibiting the expression of OPN, which finally result in the inhibition of the phenotypic transition, excessive proliferation, and migration of VSMCs. In addition, the long circulation, excellent targeting, and accumulation performance of (Lipo + M)@E NPs significantly decreased the expression of PCSK9 in serum and VSMCs within the plaque of ApoE-/- mice.

FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE-/- mice atherosclerosis.

Atherosclerosis is a chronic inflammatory vascular disease, and inflammation plays a critical role in its formation and progression. Elevated serum homocysteine (Hcy) is an independent risk factor for atherosclerosis. Previous studies have shown that fatty acid binding protein 4 (FABP4) plays an important role in macrophage inflammation and lipid metabolism in atherosclerosis induced by Hcy. However, the underlying molecular mechanism of FABP4 in Hcy-induced macrophage inflammation remains unknown. In this study, we found that FABP4 activated the Janus kinase 2/signal transducer and activator of transcription 2 (JAK2/STAT2) pathway in macrophage inflammation induced by Hcy. Of note, we further observed that ras-related protein Rap-1a (Rap1a) induced the Tyr416 phosphorylation and membrane translocation of non-receptor tyrosine kinase (c-Src) to activate the JAK2/STAT2 pathway. In addition, the suppressor of cytokine signaling 1 (SOCS1)-a transcriptional target of signal transducer and activator of transcription (STATs) inhibited the JAK2/STAT2 pathway and Rap1a expression via a negative feedback loop. In summary, these results demonstrated that FABP4 promotes c-Src phosphorylation and membrane translocation via Rap1a to activate the JAK2/STAT2 pathway, contributing to Hcy-accelerated macrophage inflammation in ApoE-/- mice.

Efficacy and safety of oral Guanxinshutong capsules in patients with stable angina pectoris in China: a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial.

BACKGROUND: To assess the efficacy and safety of oral Guanxinshutong (GXST) capsules in Chinese patients with stable angina pectoris (SAP) in a prospective, multicenter, double-Blind, placebo-controlled, randomized clinical trial (clinicaltrials.gov Identifier: NCT02280850). METHODS: Eligible patients were randomized 1:1 to the GXST or placebo group. Current standard antianginal treatment except for nitrate drugs was continued in both groups, who received an additional 4-week treatment of GXST capsule or placebo. Primary endpoint was the change from baseline in angina attack frequency after the 4-week treatment. Secondary endpoints included the reduction of nitroglycerin dose, score of Seatntle Agina Questionnaire, exercise tolerance test defined as time to onset of chest pain and ST-segment depression at least 1 mm greater than the resting one. RESULTS: A total of 300 SAP patients from 12 centers in China were enrolled between January 2013 and October 2015, and they were randomly divided into the GXST group and the placebo group (150 patients in each group). Of whom, 287 patients completed the study (143 patients in the GXST group, 144 patients in the placebo group). The baseline characteristics of the two groups were comparable. After 4-week treatment with GXST capsules, the number of angina attacks and the consumption of short-acting nitrates were significantly reduced. In addition, the quality of life of patients were also substantially improved in the GXST group. No significant differences in the time of onset of angina and 1-mm ST segment depression were noted between the two groups. 7 patients (4.1%) in the GXST group and 3 patients (2.1%) in the placebo group reported at least one adverse event, respectively. CONCLUSIONS: GXST capsules are beneficial for the treatment of SAP patients.

Obstructive sleep apnoea and risks of all-cause mortality: preliminary evidence from prospective cohort studies.

PURPOSE: A meta-analysis of prospective cohort studies was conducted to clarify the association between obstructive sleep apnoea (OSA) and future risk of all-cause mortality. METHODS: Eligible studies were identified by searching the PubMed and EMBASE databases up to July 2015. Pooled hazard ratios (HRs) and their corresponding 95 % confidence intervals (CIs) were calculated to estimate the association between OSA and risk of all-cause mortality. Sources of heterogeneity were identified by subgroup and meta-regression analyses. RESULTS: Twelve prospective cohort studies involving 34,382 participants were included in this meta-analysis. The pooled HR of all-cause mortality was 1.262 (95 % CI 1.093-1.431) with significant heterogeneity. Subgroup analyses indicated that the pooled HRs of all-cause mortality in patients with mild, moderate and severe OSA were 0.945 (95 % CI 0.810-1.081), 1.178 (95 % CI 0.978-1.378) and 1.601 (95 % CI 1.298-1.902), respectively. OSA severity could be a possible sources of heterogeneity. Existing publication bias produced a minor contribution to effect size. CONCLUSION: Severe, but not mild to moderate, OSA is significantly associated with increased risk of all-cause mortality.

MiR-503 inhibited cell proliferation of human breast cancer cells by suppressing CCND1 expression.

Breast cancer is one of the most common malignancies and a major cause of cancer-related mortality all over the world. A growing body of reports revealed that microRNAs play essential roles in the progression of cancers. Aberrant expression of miR-503 has been reported in several kinds of cancer. The aim of the current study was to elucidate the role of miR-503 in the pathogenesis of breast cancer. In the present study, our results suggested that miR-503 expression was markedly downregulated in breast cancer tissues and cells. Overexpression of miR-503 in breast cancer cell lines reduced cell proliferation through inducing G0/G1 cell cycle arrest by targeting CCND1. Together, our findings provide new knowledge regarding the role of miR-503 in the progression of breast cancer and indicate the role of miR-503 as a tumor suppressor microRNA (miRNA) in breast cancer.

Effect of Inactivated SARS-CoV-2 Vaccine on Thyroid Function and Autoimmunity Within 28 Days After the Second Dose.

Background: The safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is widely appreciated. However, there is limited knowledge regarding the potential impact of SARS-CoV-2 vaccines on the thyroid. Methods: We performed two prospective clinical trials between April and June, 2021, enrolling recipients of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV and CoronaVac). Thyroid function, antithyroid antibody levels, and SARS-CoV-2 neutralizing antibody levels were detected for each participant before receiving the first vaccine dose and 28 days after receiving the second vaccine dose. Results: A total of 657 recipients participated in the study. The overall median thyroid function and levels of antithyroid antibodies before and after SARS-CoV-2 vaccination were within the normal range. Among the 564 participants with normal thyroid function at baseline, 36 (6.38% [confidence interval; CI 4.51-8.73]) developed thyroid dysfunction. Of the 545 recipients with negative antithyroid antibodies at baseline, none developed abnormal antibodies after vaccination. Notably, 75.27% (70/93 [CI 65.24-83.63]) of the 93 recipients with thyroid dysfunction returned to normal function after vaccination. The levels of antithyroid peroxidase antibody (96.20% [CI 89.30-99.21]) and antithyroglobulin antibody (TgAb; 88.31% [CI 78.97-94.51]) remained positive after vaccination in most patients with abnormal values at baseline. However, the TgAb levels in more than half of the patients (48/77) decreased. All of 11 abnormal thyrotropin receptor antibody levels at baseline decreased postvaccination. Conclusions: Vaccination with an inactivated SARS-CoV-2 vaccine had no significant adverse impact on thyroid function or antithyroid antibodies within the first 28 days after the second dose. Clinical Trial Registration: ChiCTR2100045109 and ChiCTR2100042222.

Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine.

SARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a nonrandomized trial among the healthcare workers (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccines and the potential need for a third booster dose. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 29.3 arbitrary units (AU)/mL to 8.8 AU/mL 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 63.6 AU/mL by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to two doses were not truly "non-responders" but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term immunological memory by the inactivated vaccine, which could be rapidly recalled and further boosted by a third dose.

Static pressure promotes rat aortic smooth muscle cell proliferation via upregulation of volume-regulated chloride channel.

Arterial smooth muscle cell proliferation is a key event in the development of hypertension associated vascular disease. Although previous studies have found that pressure itself can promote cell proliferation and DNA synthesis in vascular smooth muscle cells, the mechanisms are not clear. Recent accumulating evidence indicate that volume-regulated chloride channel plays an important role in the regulation of cell proliferation induced by numerous mitogenic factors. However, whether volume-regulated chloride channel is involved in hypertension-induced vascular smooth muscle cell proliferation remains to be determined. In this study, we found that static pressure promoted rat aortic smooth muscle cell proliferation and cell cycle progression. Static pressure treatment increased volume-regulated chloride currents and ClC-3 expression. Inhibition of chloride channel with pharmacological blockers or knockdown of ClC-3 with ClC-3 antisense transfection attenuated pressure-evoked cell proliferation and cell cycle progression. Static pressure enhanced the production of reactive oxygen species (ROS) in aortic smooth muscle cells. Diphenyleneiodonium (DPI) or apocynin pretreatment inhibited pressure-induced ROS production as well as cell proliferation. Furthermore, DPI or apocynin attenuated the pressure-induced upregulation of ClC-3 protein and hypoosmolarity-activated chloride current. Our data suggest that volume-regulated chloride channel plays a critical role in static pressure-induced cell proliferation and cell cycle progression, suggesting the therapeutic importance of volume-regulated chloride channel for treatment of hypertension attendant vascular complications.

[The value of regulated upon activation normal T cell expressed and secreted in the pathogenesis of varicose ulcer of lower limbs].

OBJECTIVE: To study the effectiveness of RANTES in the pathogenesis of venous ulceration. METHODS: 40 Chronic venous insufficiency (CVI) individuals were enrolled in the study and separated into the ulceration group (n=20) and non-ulceration group (n=20), according to CVI with or without ulceration, 10 healthy individuals were enrolled as control group. The expression of RANTES mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in blood. Immunohistochemical staining of RANTES were carried in normal skin, in the tissue at the brim of ulceration and in the tissue of cured or curing ulceration. RESULTS: In ulceration group, the expression of RANTES mRNA in blood increased obviously. Compared with the other two groups, they were significant different (P < 0.05). The difference was also significance in the other two groups (P < 0.05). The average number of RANTES positive expression in normal skin is 28 +/- 13, in the tissue at the brim of ulceration is 107 +/- 44, and in the tissue of cured or curing ulceration is 35 +/- 20. There are significant difference between normal skin and the tissue at the brim of ulceration (P < 0.05). The average number of RANTES positive expression in the tissue of cured or curing ulceration is lower than that's in the tissue at the brim of ulceration. CONCLUSION: The high expression of RANTES may be one of the important mechanisms of varicose ulcer.

Ulnar nerve sonography in leprosy neuropathy.

A 23-year-old woman presented with a half-year history of right forearm sensory and motor dysfunction. Ultrasound imaging revealed definite thickening of the right ulnar nerve trunk and inner epineurium, along with heterogeneous hypoechogenicity and unclear nerve fiber bundle. Color Doppler exhibited a rich blood supply, which was clearly different from the normal ulnar nerve presentation with a scarce blood supply. The patient subsequently underwent needle aspiration of the right ulnar nerve, and histopathological examination confirmed that granulomatous nodules had formed with a large number of infiltrating lymphocytes and a plurality of epithelioid cells in the fibrous connective tissues, with visible atypical foam cells and proliferous vascularization, consistent with leprosy. Our report will familiarize readers with the characteristic sonographic features of the ulnar nerve in leprosy, particularly because of the decreasing incidence of leprosy in recent years.

MicroRNA-210 interacts with FBXO31 to regulate cancer proliferation cell cycle and migration in human breast cancer.

BACKGROUND: In this study, we investigated the functional correlation between microRNA-210 (miR-210) and gene of F-box protein 31 (FBXO31) in regulating breast cancer. METHODS: Dual-luciferase assay and quantitative real-time polymerase chain reaction were used to investigate the binding of miR-210 with FBXO31 and their expression patterns in breast cancer. miR-210 was inhibited in breast cancer T47D and MCF-7 cells to assess its effect on cancer proliferation, cell cycle progression, and migration. FBXO31 was also downregulated in breast cancer cells to examine its effect on miR-210-mediated breast cancer regulation. The interaction between miR-210 and FBXO31 was further investigated by examining the effect of overexpressing miR-210 on FBXO31-induced suppression of breast cancer proliferation. RESULTS: FBXO31 was the downstream target gene of miR-210 in breast cancer. miR-210 and FBXO31 are inversely expressed in breast cancer cell lines. miR-210 downregulation reduced cancer progression, induced cell cycle arrest, and inhibited cancer migration in T47D and MCF-7 cells. Tumor suppression by miR-210 downregulation was reversed by downregulating FBXO31. In FBXO31-overexpressed breast cancer cells, upregulating miR-210 also reversed the tumor-suppressive effect of FBXO31 on breast cancer proliferation. CONCLUSION: Our work demonstrated that the expression pattern and tumor regulatory functions of miR-210 and FBXO31 are inversely correlated in breast cancer.

[Static pressure induces vascular smooth muscle cells proliferation and apoptosis].

OBJECTIVE: To study the role of static pressure on proliferation and apoptosis of the vascular smooth muscle cells. METHODS: Vascular smooth muscle cell line A10 were cultured at normal atmosphere, 80 mmHg, 100 mmHg, 200 mmHg static pressure respectively. Cell viability was determined by MTT assay, cell cycle and apoptosis rate were analyzed by flow cytometer. RESULTS: After exposure to lower static pressure (100 mmHg) for 48 hour, cell viability and proliferation index (PI) of A10 cell significantly increased, the percentage of A10 cell in G(0)/G(1) phase decreased significantly and the apoptosis rate showed no difference as compared with those exposed to atmospheric pressures. However after exposure of A10 cell to higher static pressure (200 mmHg) for 48 hours, cell viability and proliferation index (PI) significantly decreased, the percentage of A10 cell in G(0)/G(1) phase increased significantly, apoptosis rate significantly increased, as compared with cells exposed to atmospheric pressure. CONCLUSION: Lower static pressure can facilitate vascular smooth muscle cells proliferation, while higher pressure can induce cell apoptosis.

Elevation of serum procalcitonin in patients after chemical pleurodesis with intrapleural injection of OK-432.

INTRODUCTION: In patients with refractory pleural effusion or pneumothorax, fever and elevated level of white blood cell count (WBC) are frequently observed after chemical pleurodesis with intrapleural injection of OK-432, which make it difficult to differentiate whether it was from the side effects of OK-432 or concurrent bacterial infection. OBJECTIVE: Procalcitonin (PCT) levels were measured before and after pleurodesis so as to discuss whether PCT is useful for distinguishing between the side effects of OK-432 and concurrent bacterial infection. METHOD: Twenty-six patients with refractory pleural effusion or pneumothorax who underwent chemical pleurodesis with intrapleural injection of OK-432 at the First Affiliated Hospital of Sun Yat-sen University between August 2010 and August 2012 were included in our study. Levels of PCT and WBC were measured before and after pleurodesis. RESULT: Of all 26 patients, 22 patients were with refractory pleural effusion, and the other four were with pneumothorax. The median serum levels of PCT and WBC elevated from 0.155 to 1.470 ng/mL (P = 0.009) and from 5.920 to 10.475 × 10(9) /L (P = 0.000), respectively. No patient was given antibiotics and fever subsided. CONCLUSION: Intrapleural injection of OK-432 could increase the serum level of PCT and WBC with no bacterial infection. The serum PCT level may not be useful to distinguish whether fever was caused by the side effects of OK-432 or concurrent bacterial infection.

Tracing type 1 diabetic Tibet miniature pig's bone marrow mesenchymal stem cells in vitro by magnetic resonance imaging (1).

BACKGROUND: Traditional cell-tracking methods fail to meet the needs of preclinical or clinical research. Thus, the aim of the present study was to establish a new method of double labeling bone marrow mesenchymal stem cells (BMSCs) from type 1 diabetic (T1D) minipigs with super-paramagnetic iron oxide (SPIO) and enhanced green fluorescent protein (eGFP) and tracing them using MRI in vitro. METHODS: Isolated BMSCs from T1D minipigs were labeled with eGFP and different concentrations of SPIO. The effects of lentivirus (LV)-eGFP transfection and SPIO on the viability and growth curves of BMSCs were determined by Trypan blue exclusion, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry. Cellular ultrastructure was evaluated by transmission electron microscopy. Magnetic resonance imaging was used to evaluate BMSCs labeled with SPIO-eGFP complexes 6 weeks after labeling. RESULTS: Expression of eGFP in BMSCs peaked 96 h after transfection with LV-eGFP. Prussian blue staining revealed scattered blue granules in the cytoplasm of SPIO-labeled cells. Transmission electron microscopy revealed that the dense granules aggregated mainly in secondary lysosomes. On MRI, T2* -weighted imaging was far more sensitive for SPIO-labeled BMSCs than other image sequences 3 and 6 weeks after the cells had been labeled with SPIO-eGFP. CONCLUSIONS: We have developed a relatively simple and safe method for double labeling of BMSCs from T1D minipigs using SPIO and LV-eGFP and tracing them in vitro by MRI for 6 weeks.

Autografting of bone marrow mesenchymal stem cells alleviates streptozotocin­induced diabetes in miniature pigs: real-time tracing with MRI in vivo.

Cellular replacement therapy for diabetes mellitus (DM) has received much attention. In this study, we investigated the effect of transplantation of autologous bone marrow­derived mesenchymal stem cells (ABMSCs) in streptozotocin (STZ)­induced diabetic miniature pigs. Miniature pig BMSCs were cultured, labeled with superparamagnetic iron oxide (SPIO) and transplanted into the pancreas of diabetic miniature pigs through targeted intervention. Blood glucose levels, intravenous and oral glucose tolerance test (OGTT), serum insulin, C­peptide and islets histology were analyzed. These transplanted cells were then identified by magnetic resonance imaging (MRI). The results showed that transplantation of ABMSCs reversed STZ­induced diabetes in miniature pigs. Blood glucose levels, intravenous, OGTT, serum insulin and C­peptide were significantly recovered in the diabetic minipigs with the autologous BMSC (DMAB) transplantation group. In addition, the number of islets was significantly increased in this group compared to the diabetic minipig control (DMC) group with conventional therapy. These data suggested the implantation of autologous BMSCs for type 1 diabetes treatment can partially restore the function of islet ß cells and maintain blood glucose homeostasis. Transplanted autologous BMSCs may improve islet repairing by differentiating for new islets and change pancreatic microcirculation and be identified in a real­time manner using MRI in vivo.

Intensive statin therapy: a favorable adjunct to the improvement of small-diameter vascular grafts.

To assess the effect of intensive statins therapy on the outcome of small-diameter vascular prosthesis, we investigated whether atorvastatin treatment (30 mg/d) could accelerate the re-endothelialization process and improve the patency rate in a canine infrarenal abdominal aorta-expanded polytetrafluoroethylene (ePTFE) bypass model. Furthermore, we also evaluated the effect of atorvastatin on the migratory and adherent capacity of circulating endothelial progenitor cells (EPCs) in vitro. Improved patency was confirmed by Doppler sonography and arteriography. Histological and scanning electron microscopy illustrated enhanced re-endothelialization process. Treatment with atorvastatin enhanced the circulating pool of EPCs with fortified migratory and adherent capacity. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that atorvastatin treatment increased endothelial nitric oxide synthase (eNOS) and kinase insert domain receptor (KDR) messenger RNA (mRNA) expression in cultured EPCs and neointima. In conclusion, intensive statin therapy could be considered a favorable option to improve small-diameter vascular graft patency.