Effect and Safety of Herbal Medicine Foot Baths in Patients with Diabetic Peripheral Neuropathy: A Multicenter Double-Blind Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect and safety of foot baths with Tangbi Waixi Decoction (TW) in treating patients with diabetic peripheral neuropathy (DPN). METHODS: It is a multicenter double-blinded randomized controlled trial. Participants with DPN were recruited between November 18, 2016 and May 30, 2018 from 8 hospitals in China. All patients received basic treatments for glycemic management. Patients received foot baths with TW herbal granules either 66.9 g (intervention group) or 6.69 g (control group) for 30 min once a day for 2 weeks and followed by a 2-week rest, as a therapeutic course. If the Toronto Clinical Scoring System total score (TCSS-TS) ⩾6 points, the patients received a total of 3 therapeutic courses (for 12 weeks) and were followed up for 12 weeks. The primary outcome was change in TCSS-TS score at 12 and 24 weeks. Secondary outcomes included changes in bilateral motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the median and common peroneal nerve. Safety was also assessed. RESULTS: Totally 632 patients were enrolled, and 317 and 315 were randomized to the intervention and control groups, respectively. After the 12-week intervention, patients in both groups showed significant declines in TCSSTS scores, and significant increases in MNCV and SNCV of the median and common peroneal nerves compared with pre-treatment (P<0.05). The reduction of TCSS-TS score at 12 weeks and the increase of SNCV of median nerve at 24 weeks in the control group were greater than those in the intervention group (P<0.05). The number of adverse events did not differ significantly between groups (P>0.05), and no serious adverse event was related with treatment. CONCLUSION: Treatment of TW foot baths was safe and significantly benefitted patients with DPN. A low dose of TW appeared to be more effective than a high dose. (Registry No. ChiCTR-IOR-16009331).

A New and Practical Model of Human-like Ascending Aorta Aneurysm in Rats.

INTRODUCTION: Ascending aortic aneurysm is a serious health risk. In order to study ascending aortic aneurysms, elastase and calcium ion treatment for aneurysm formation are mainly used, but their aneurysm formation time is long, the aneurysm formation rate is low. Thus, this study aimed to construct a rat model of ascending aorta aneurysm with a short modeling time and high aneurysm formation rate, which may mimic the pathological processes of human ascending aorta aneurysm. METHODS: Cushion needles with different pipe diameters (1.0, 1.2, 1.4 and 1.6 mm) were used to establish a human-like rat model of ascending aortic aneurysm by narrowing the ascending aorta of rats and increasing the force of blood flow on the vessel wall. The vascular diameters were evaluated using color Doppler ultrasonography after two weeks. The characteristics of ascending aortic aneurysm in rats were detected by Masson's trichrome staining, Verhoeff's Van Gieson staining and hematoxylin and eosin staining while RT-PCR were utilized to assess the total RNA of cytokine interleukin-1ß, interleukin 6, transforming growth factor-beta1 and metalloproteinase 2. RESULTS: Two weeks after surgery, the ultrasound images and the statistical analysis demonstrated that the diameter of the ascending aorta in rats increased more than 1.5 times, similar to that in humans, indicating the success of animal modeling of ascending aortic aneurysm. Moreover, the optimal constriction diameter of the ascending aortic aneurysm model is 1.4 mm by the statistical analysis of the rate of ascending aortic aneurysm and mortality rate in rats with different constriction diameters. CONCLUSIONS: The human-like ascending aortic aneurysm model developed in this study can be used for the studies of the pathological processes and mechanisms in ascending aortic aneurysm in a more clinically relevant fashion.

Swin-Transformer -YOLOv5 for lightweight hot-rolled steel strips surface defect detection algorithm.

An essential industrial application is the examination of surface flaws in hot-rolled steel strips. While automatic visual inspection tools must meet strict real-time performance criteria for inspecting hot-rolled steel strips, their capabilities are constrained by the accuracy and processing speed of the algorithm used to identify defects. To solve the problems of poor detection accuracy, low detection efficiency, and unsuitability of low computing power platforms of the hot-rolled strip surface defect detection algorithm The Swin-Transformer-YOLOv5 model based on the improved one-stage detector is proposed. By employing GhostNet, the model's lightweight design, and guaranteed detection accuracy are both achieved. The C3 module introduces Swin-Transformer to address the issues of cluttered backdrops of defect photos and easily confused defect categories. With the addition of the CoordAttention module, the model's capacity to extract defective features is improved, and its performance keeps getting better. The issue of huge differences in different scales and poor detection of small flaws is resolved by employing BiFPN for feature fusion, and the detector's capacity to adapt to targets of different scales is improved. The experimental results demonstrate that the improved Swin-Transformer-Yolov5 model significantly outperforms the industry-standard target detection algorithms, and the model's mAP value still improves by 8.39% over the original model while reducing the number of parameters, GFLOPs, and weight by 36.6%, 40.0%, and 34.7%, respectively. The model is better suited for use on low-arithmetic platforms as a result.

Landscape of molecular crosstalk between SARS-CoV-2 infection and cardiovascular diseases: emphasis on mitochondrial dysfunction and immune-inflammation.

BACKGROUND: SARS-CoV-2, the pathogen of COVID-19, is a worldwide threat to human health and causes a long-term burden on the cardiovascular system. Individuals with pre-existing cardiovascular diseases are at higher risk for SARS-CoV-2 infection and tend to have a worse prognosis. However, the relevance and pathogenic mechanisms between COVID-19 and cardiovascular diseases are not yet completely comprehended. METHODS: Common differentially expressed genes (DEGs) were obtained in datasets of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2 and myocardial tissues from heart failure patients. Further GO and KEGG pathway analysis, protein-protein interaction (PPI) network construction, hub genes identification, immune microenvironment analysis, and drug candidate predication were performed. Then, an isoproterenol-stimulated myocardial hypertrophy cell model and a transverse aortic constriction-induced mouse heart failure model were employed to validate the expression of hub genes. RESULTS: A total of 315 up-regulated and 78 down-regulated common DEGs were identified. Functional enrichment analysis revealed mitochondrial metabolic disorders and extensive immune inflammation as the most prominent shared features of COVID-19 and cardiovascular diseases. Then, hub DEGs, as well as hub immune-related and mitochondria-related DEGs, were screened. Additionally, nine potential therapeutic agents for COVID-19-related cardiovascular diseases were proposed. Furthermore, the expression patterns of most of the hub genes related to cardiovascular diseases in the validation dataset along with cellular and mouse myocardial damage models, were consistent with the findings of bioinformatics analysis. CONCLUSIONS: The study unveiled the molecular networks and signaling pathways connecting COVID-19 and cardiovascular diseases, which may provide novel targets for intervention of COVID-19-related cardiovascular diseases.

Effect of Vitamin D and/or Calcium Supplementation on Pancreatic ß-Cell Function in Subjects with Prediabetes: A Randomized, Controlled Trial.

So far, the potential role of vitamin D in ß-cell function remains a matter of debate. Therefore, a randomized, placebo-controlled trial (RCT) was conducted to evaluate the effect of a vitamin D supplement with or without calcium on ß-cell function in a Chinese population with prediabetes. Two hundred and forty-three subjects were randomly assigned in a 2-by-2 factorial-design RCT to receive either 1600 IU/day vitamin D3 with/or 500 mg/day calcium for 24 weeks. The results showed that oral administration of vitamin D and calcium could increase the secretion of insulin. Vitamin D-insufficient individuals displayed an increment in the disposition index (adjusted change = 0.31, 95%CI: 0.07, 0.56) after treatment by vitamin D + calcium. It illustrated that supplementation with vitamin D and calcium might improve the function of pancreatic ß-cell in prediabetes with low serum 25(OH)D levels. However, further studies are needed to confirm the findings. Given the low vitamin D content in natural foods, it is necessary to fortify processed foods with vitamin D.

Fibrin-based cardiac patch containing neuregulin-1 for heart repair after myocardial infarction.

Cardiac patch, a scaffold layered on the surface of the heart that can provide mechanical and regeneration support for damaged myocardium, has provided a promising solution to treat severe myocardial infarction (MI). In this work, a fibrin based cardiac patch loaded with neuregulin-1 (NRG-1) is developed to attach locally to the infract area of heart. The composite patch exhibited good biocompatibility and promoted cardiomyocyte proliferation in vitro via NRG-1/ErbB signaling. Moreover, implantation of this patch to the infracted border zone reduced cell apoptosis, promoted angiogenesis and inhibited fibrosis, which reduced infraction size and improved cardiac function consequently. Thus, the combination of natural biomaterial fibrin and bioactive factor NRG-1 might have a promising potential for clinical application of MI treatment.

Serum cystatin C is a potential predictor of short-term mortality and acute kidney injury in acute aortic dissection patients: a retrospective cohort study.

Background: Serum cystatin C concentration is associated with cardiovascular disease. However, the relationship between cystatin C and acute aortic dissection (AAD) remains unclear. In the current study, we aim to evaluate the predictive value of cystatin C in the occurrence of acute kidney injury (AKI) and the prognosis of AAD patients. Methods: The patients with AAD admitted to our hospital from November 2019 through January 2022 were consecutively included in the retrospective cohort study. A complete blood cell count, serum biochemistry tests, including cystatin C and creatinine, in-hospital mortality and the incidence of AKI were recorded. All the patients were categorized into four groups according to the quartile of their serum cystatin C levels. Multivariate logistic and Cox regression analyses were conducted to determine the independent risk factors for the incidence of AKI and the prognosis of AAD patients, respectively. Kaplan-Meier analyses and log-rank tests were used to evaluate differences in survival. Receiver operating characteristic (ROC) curves were used to assess the predictive value of cystatin C for short-term mortality and the incidence of AKI in AAD patients. Results: A total of 357 patients were included in this study. The results showed that the higher the concentration of cystatin C, the higher the level of serum creatinine and the higher the incidence of AKI. Mortality was significantly higher in the group with serum cystatin C levels >1.18 mg/L. Type A AAD, white blood cell count >10×109/L, platelet count <100×109/L, and serum cystatin C concentration >1.18 mg/L [adjusted hazards ratio (HR) =2.405, 95% confidence interval (CI), 1.029-4.063, P=0.041] were independent risk factors for in-hospital mortality. Cystatin C levels >1.18 mg/L remained an independent predictor of AKI in AAD after adjusting for the confounding [odds ratio (OR) 76.489, 95% CI, 25.586-228.660]. The areas under the ROC curves of cystatin C in predicting the mortality and incidence of AKI in AAD patients were 0.655 (95% CI, 0.551-0.760) and 0.807 (95% CI, 0.758-0.856), respectively. Conclusions: In sum, serum cystatin C concentration is a potential predictor of short-term mortality and the incidence of AKI in AAD patients.

GC gene polymorphisms found with type 2 diabetes and low vitamin D status among rural Chinese in Henan province.

BACKGROUND AND OBJECTIVES: Accumulating evidence suggests that vitamin D may be involved in the pathogenesis of type 2 diabetes (T2D). Group-specific component (GC) gene is the most important transporter of vitamin D and plays a regulatory role in vitamin D metabolism. We aimed to evaluate the association of GC gene polymorphisms with T2D susceptibility and vitamin D status in the Chinese rural population. METHODS AND STUDY DESIGN: A total of 1372 subjects were eligible in this cross-sectional study. Three SNPs of the GC gene (rs7041, rs4588, and rs2282679) were genotyped by TaqMan probe assays. Logistic regression and Kruskal-Wallis one-way analysis were performed to determine the possible risk genotype for T2D and vitamin D metabolite concentrations, respectively. RESULTS: The serum 25-hydroxyvitamin D3 [25(OH)D3] and vitamin D binding protein (DBP) concentrations were significantly lower in the T2D group than the non-T2D group. GG genotype carriers of rs7041 (T>G) were more likely to have T2D compared with AA carriers (OR=2.00, 95% CI: 1.19-3.37). Variants of rs4588 (C>A) and rs2282679 (A>C) were associated with a lower risk of T2D under the dominant inheritance model (OR=0.65, 95% CI: 0.48-0.88; OR=0.66, 95% CI: 0.49-0.90, respectively). We further found that non-T2D subjects with the AA genotype of rs4588 had significantly higher 25(OH)D3 concentrations than the CC genotype (p=0.022). In contrast, the T2D cases with the CC genotype of rs2282679 had lower DBP concentrations compared to the AA genotype (p=0.020). CONCLUSIONS: Our study indicates a potential role for GC gene polymorphisms in T2D susceptibility and vitamin D metabolite concentrations in the Chinese rural population.

Fucoidan protects the pancreas and improves glucose metabolism through inhibiting inflammation and endoplasmic reticulum stress in T2DM rats.

It is important to maintain the normal function of the pancreas in the prevention and intervention of type 2 diabetes mellitus (T2DM). This study was undertaken to explore the protective effects of fucoidan on the pancreas in T2DM rats induced by using a high fat diet (HFD) and low dose of streptozotocin (STZ) injection. The results showed fucoidan remarkably decreased the levels of fasting blood glucose, serum insulin and glycated serum protein, and increased the level of glucagon-like peptide-1 in T2DM rats. Also, fucoidan improved insulin sensitivity and reduced the postprandial blood glucose level. Meanwhile, fucoidan alleviated pancreas damage and improved the islet ß cell function in T2DM rats. Additionally, fucoidan activated the PI3K/AKT signaling pathway and regulated glucose homeostasis, which seemed to be related to the protection of the pancreas from damage by inhibiting inflammation and endoplasmic reticulum stress in T2DM rats. Collectively, these results indicated that fucoidan had a potential protective effect on the pancreas, which enriched ideas for the use of fucoidan as a nutritional agent in the cure of T2DM.

The Association Between GC Gene Polymorphisms and Metabolic Syndrome in Chinese Rural Population: A Case-Control Study.

BACKGROUND: GC (group-specific component globulin) encoding VDBP (Vitamin D binding protein) polymorphisms have been associated with susceptibility to some diseases such as diabetes, obesity, osteoporosis, and polycystic ovary syndrome, but the evidence for metabolic syndrome (MetS) in the Chinese rural population is inconclusive. Therefore, we investigated the relationship between GC variants (rs7041, rs4588, rs2282679, and rs705117) and MetS risk as well as VDBP levels in the Chinese rural population. PATIENTS AND METHODS: The participants (range of age: 20-90 years) of this case-control study were recruited from the northern Chinese Han rural population. We matched 445 MetS cases with non-MetS controls in a 1:1 ratio by sex, age (within 5 years). Real-time PCR technology was carried out by TaqMan assays to examine the four variants of rs7041, rs4588, rs2282679, and rs705117 within the GC gene. To identify the association of GC gene polymorphisms with MetS, we calculated ORs using a conditional logistic regression model adjusted for potential confounding factors. RESULTS: We observed inverse associations of CA and AA genotypes of rs4588 with risk of MetS (OR = 0.678, 95% CI 0.505-0.910, P = 0.010; 0.603, 95% CI 0.373-0.973, P = 0.039, respectively) compared with carriers of CC genotype. A similar relationship was also found between rs2282679 and MetS, showing that carrying AC genotype of rs2282679 can decrease the risk of MetS (OR = 0.683, 95% CI 0.509-0.917, P = 0.011) compared with carriers of AA genotype. The results of correlation analysis between MetS components and GC polymorphisms showed that the ORs of AA genotype of rs4588 with high level of TG (triglycerides) and low level of HDL-C (high-density lipoprotein cholesterol) were 0.473 (95% CI 0.245-0.911, P = 0.025) and 0.268 (95% CI 0.117-0.615, P = 0.002), respectively; the ORs of CC genotype of rs2282679 with high level of TG and low level of HDL-C were 0.428 (95% CI 0.217-0.842, P = 0.014) and 0.263 (95% CI 0.110-0.628, P = 0.003), respectively. However, there was no significant association between the concentration of VDBP and MetS risk. CONCLUSION: Among the Chinese rural population, GC polymorphism was associated with lower metabolic syndrome susceptibility, which might be through affecting blood lipid levels (TG and HDL-C).

Fucoidan ameliorates glucose metabolism by the improvement of intestinal barrier and inflammatory damage in type 2 diabetic rats.

It has been reported that fucoidan possesses anti-diabetic activities by inhibiting α-glucosidase activity, improving ß-cell dysfunction, and enhancing insulin sensitivity. However, as a macromolecular carbohydrate, fucoidan is rarely absorbed and indigestible in gastrointestinal tract. The study aimed to explore whether the fucoidan can regulate glucose metabolism by improving intestinal barrier and inflammation in type 2 diabetes mellitus (T2DM) rats. A high-fat diet combined with streptozotocin was used to induce T2DM rats. Different doses of fucoidan (50, 100 and 200 mg/kg) were administered respectively by lavage to T2DM rats for 8 weeks and saline was given to controls. The results showed that in addition to hyperglycemia and hyperlipidemia, T2DM rats were also characterized by increased intestinal permeability and proinflammatory cytokines. Notably, fucoidan reduced fasting blood glucose and insulin resistance index along with alleviated the accumulation of proinflammatory cytokines in T2DM rats. Furthermore, fucoidan repaired the intestinal barrier function, which was accompanied by the up-regulation of tight junction proteins and the improvement of intestinal inflammation via inhibiting TLR4/NF-κB signaling. Meanwhile, fucoidan also mitigated the liver damage, and alleviated insulin resistance by activating PI3K/AKT signaling. Collectively, these findings supported the potential of fucoidan to be used as a functional ingredient to prevent T2DM.

Evaluation of Circulating Endothelial Progenitor Cells in Abdominal Aortic Aneurysms after Endovascular Aneurysm Repair.

Background and Objectives: Circulating endothelial progenitor cells (EPCs) participate in vascular repair and predict cardiovascular outcomes. The aim of this study was to investigate the correlation between EPCs and abdominal aortic aneurysms (AAAs). Methods and Results: Patients (age 67±9.41 years) suffering from AAAs (aortic diameters 58.09±11.24 mm) were prospectively enrolled in this study. All patients received endovascular aneurysm repair (EVAR). Blood samples were taken preoperatively and 14 days after surgery from patients with aortic aneurysms. Samples were also obtained from age-matched control subjects. Circulating EPCs were defined as those cells that were double positive for CD34 and CD309. Rat models of AAA formation were generated by the peri-adventitial elastase application of either saline solution (control; n=10), or porcine pancreatic elastase (PPE; n=14). The aortas were analyzed using an ultrasonic video system and immunohistochemistry. The levels of CD34＋/CD309＋ cells in the peripheral blood mononuclear cell populations were measured by flow cytometry. The baseline numbers of circulating EPCs (CD34＋/CD309＋) in the peripheral blood were significantly smaller in AAA patients compared with control subjects. The number of EPCs doubled by the 14th day after EVAR. A total of 78.57% of rats in the PPE group (11/14) formed AAAs (dilation ratio ＞150%). The numbers of EPCs from defined AAA rats were significantly decreased compared with the control group. Conclusions: EPC levels may be useful for monitoring abdominal aorta aneurysms and rise after EVAR in patients with aortic aneurysms, and might contribute to the rapid endothelialization of vessels.

Urine proteomics identifies biomarkers for diabetic kidney disease at different stages.

BACKGROUND: Type 2 diabetic kidney disease is the most common cause of chronic kidney diseases (CKD) and end-stage renal diseases (ESRD). Although kidney biopsy is considered as the 'gold standard' for diabetic kidney disease (DKD) diagnosis, it is an invasive procedure, and the diagnosis can be influenced by sampling bias and personal judgement. It is desirable to establish a non-invasive procedure that can complement kidney biopsy in diagnosis and tracking the DKD progress. METHODS: In this cross-sectional study, we collected 252 urine samples, including 134 uncomplicated diabetes, 65 DKD, 40 CKD without diabetes and 13 follow-up diabetic samples, and analyzed the urine proteomes with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We built logistic regression models to distinguish uncomplicated diabetes, DKD and other CKDs. RESULTS: We quantified 559 ± 202 gene products (GPs) (Mean ± SD) on a single sample and 2946 GPs in total. Based on logistic regression models, DKD patients could be differentiated from the uncomplicated diabetic patients with 2 urinary proteins (AUC = 0.928), and the stage 3 (DKD3) and stage 4 (DKD4) DKD patients with 3 urinary proteins (AUC = 0.949). These results were validated in an independent dataset. Finally, a 4-protein classifier identified putative pre-DKD3 patients, who showed DKD3 proteomic features but were not diagnosed by clinical standards. Follow-up studies on 11 patients indicated that 2 putative pre-DKD patients have progressed to DKD3. CONCLUSIONS: Our study demonstrated the potential for urinary proteomics as a noninvasive method for DKD diagnosis and identifying high-risk patients for progression monitoring.

Long non-coding RNA RP11-465L10.10 promotes vascular smooth muscle cells phenotype switching and MMP9 expression via the NF-κB pathway.

BACKGROUND: Thoracic aortic aneurysm/dissection (TAA/D) are complicated vascular disorders with rapid development and high mortality. Vascular smooth muscle cells (VSMCs) phenotype switching plays an important role in the pathological process of TAA/D. Previous studies have indicated a potential correlation between long non-coding RNA (lncRNA) RP11-465L10.10 and matrix metallopeptidase 9 (MMP9) involved in the development of TAA/D. This study aims to investigate the role of lncRNA RP11-465L10.10 in VSMCs phenotype switching and the molecular mechanism in regulating MMP9 expression. METHODS: The expression of RP11-465L10.10 in vascular tissues and in VMSCs was detected by RT-qPCR. To investigate the role of RP11-465L10.10 on VSMCs phenotype switching, an RP11-465L10.10-overexpressed lentiviral vector was constructed and transfected into VSMCs. Through EdU staining, migration assay, flow cytometry analysis, the roles of RP11-465L10.10 were estimated. Bioinformatics indicated that RP11-465L10.10 upregulating MMP9 expression via NF-κB signaling, and SN50 (a specific inhibitor of NF-κB pathway) was used to inhibit the NF-κB pathway activation, then the expression of MMP9 was detected in RP11-465L10.10 overexpressed VMSCs. RESULTS: In this study, we found RP11-465L10.10 and MMP9 were highly increased in TAD patient tissues, which was consistent in angiotensin II-induced VSMCs phenotype switching. RP11-465L10.10 overexpression facilitated VSMCs phenotype switching and MMP9 expression. Mechanismly, NF-κB signal pathway was involved in RP11-465L10.10 induced VSMCs phenotype switching and MMP9 expression by transcriptome data analysis and experimental confirm. CONCLUSION: This study demonstrated that RP11-465L10.10 induces VSMCs phenotype switching and MMP9 expression via the NF-κB signal pathway, suggesting that RP11-465L10.10 might be a potential therapeutic target for TAA/D treatment.

Reducing the prevalence of low-back pain by reducing the prevalence of psychological distress: Evidence from a natural experiment and implications for health care providers.

OBJECTIVE: To determine whether exogenously reduced psychological distress reduces reported low-back pain (LBP) and is associated with reduced medical visits for LBP. DATA SOURCES: National Health Interview Survey, National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, 1998-2004. STUDY DESIGN: We estimate a fuzzy regression discontinuity model in which a discontinuity in the prevalence of psychological distress is identified by exogenous national events. We examine whether this discontinuity induced a corresponding discontinuity in the prevalence of LBP. We additionally estimate a regression discontinuity model to determine associated changes in medical visits with LBP as the primary complaint. PRINCIPAL FINDINGS: The prevalence of LBP was discontinuously reduced by one-fifth due to the exogenous national discontinuous reduction in psychological distress. This discontinuity in LBP cannot be explained by discontinuities in employment, insurance, injuries/poisoning, general health status, or other factors. We find an associated three-fifth discontinuous reduction in medical visits with LBP as the primary complaint. CONCLUSIONS: On a monthly basis, 2.1 million (P < .01) adults ceased to suffer LBP due to the national reduction in psychological distress, and associated medical visits with LBP as the primary complaint declined by 685 000 (P < .01).

Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis.

Wound healing is a multistep phenomenon that relies on complex interactions between various cell types. Calpains are a well-known family of calcium-dependent cysteine proteases that regulate several processes, including cellular adhesion, proliferation, and migration, as well as inflammation and angiogenesis. CAPNS1, the common regulatory subunit of Calpain-1 and 2, is indispensable for catalytic subunit stabilization and activity. Calpain inhibition has been shown to reduce organ damage in various disease models. Here, we report that endothelial calpain-1/2 is crucially involved in skin wound healing. Using a mouse genetic model where Capns1 is deleted only in endothelial cells, we showed that calpain-1/2 disruption is associated with reduced injury-activated inflammation, reduced CD31+ blood vessel density, and delayed wound healing. Moreover, in cultured HUVECs, inhibition of calpain reduced TNF-α-induced proliferation, migration, and tube formation. Deletion of Capns1 was associated with elevated levels of IκB and downregulation of ß-catenin expression in endothelial cells. These observations delineate a novel mechanistic role for calpain in the crosstalk between inflammation and angiogenesis during skin repair.

The Application of Induced Pluripotent Stem Cells in Pathogenesis Study and Gene Therapy for Vascular Disorders: Current Progress and Future Challenges.

Vascular disorders are complex diseases with high morbidity and mortality. Among them, the dilated macrovascular diseases (MVD), such as aortic aneurysm and aortic dissection, have presented a huge threat to human health. The pathogenesis of vascular diseases is mostly associated with property alteration of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). Studies have confirmed that induced pluripotent stem cells (iPSCs) can be proliferated and differentiated into other somatic cells, such as VECs and VSMCs. And patient-specific cells could provide detailed human-associated information in regard to pathogenesis or drug responses. In addition, differentiated ECs from iPSC have been widely used in disease modeling as a cell therapy. In this review, we mainly discussed the application of hiPSCs in investigating the pathological mechanism of different inherited vascular diseases and provide a comprehensive understanding of hiPSCs in the field of clinical diagnosis and gene therapy.

MicroRNA-134-5p Regulates Media Degeneration through Inhibiting VSMC Phenotypic Switch and Migration in Thoracic Aortic Dissection.

Abnormal phenotypic switch, migration, and proliferation of vascular smooth muscle cells (VSMCs) are hallmarks for pathogenesis of thoracic aortic dissection (TAD). In the current study, we identified miR-134-5p as a critical regulator controlling human VSMC phenotypic switch and migration to investigate whether miR-134-5p affects human VSMC functions and development of TAD. Using miRNA microarray of aorta specimens from 12 TAD and 12 controls, we identified miR-134-5p, which was significantly downregulated in TAD tissues. With qPCR detection, we found that miR-134-5p was also evidently decreased in human AoSMCs. Ectopic expression of miR-134-5p obviously promoted VSMC differentiation and expression of contractile markers, such as α-SMA, SM22α, and MYH11. miR-134-5p potently inhibited PDGF-BB-induced VSMC phenotypic switch and migration. We further identified STAT5B and ITGB1 as downstream targets of miR-134-5p in human VSMCs and proved them to be mediators in VSMC phenotypic switch and progression of TAD. Finally, Ad-miR-134-5p obviously suppressed the aorta dilatation and vascular media degeneration by 39% in TAD mice after vascular injury induced by Ang II. Our findings revealed that miR-134-5p was a novel regulator in vascular remodeling and pathological progress of TAD via targeting STAT5B/ITGB1 expression. Targeting miR-134-5p or its downstream molecules in VSMCs might develop new avenues in clinical treatment of TAD.

A functional variant of SMAD4 enhances macrophage recruitment and inflammatory response via TGF-ß signal activation in Thoracic aortic aneurysm and dissection.

Thoracic aortic aneurysm and dissection (TAAD) is the most fatal macro vascular disease. The mortality of 48h after diagnosis of dissection is up to approximately 50-68%. However, the genetic factors and potential mechanism underlying sporadic TAAD remain largely unknown. Our previous study suggested rs12455792 variant of SMAD4 gene significantly contributed to the increased risk and might participated the pathological progression of TAAD. This investigation aims to test (1) the associations between rs12455792 and MØ recruitment, inflammatory response in aggressiveness of TAAD, and (2) the molecular mechanism accounting for their effects. In TGF-ß signaling molecular detection, rs12455792 C>T variant activated the canonical and non-canonical TGF-ß mediators. It also increased the secretion of chemotactic factors of HASMCs. To confirm the impact of this change, we detected MØ recruitment and infiltration in HASMCs and aortic tissues of TAAD patients. We found that MØ recruitment in cells and tissues with rs12455792 variant genotypes was increased than that in wild type groups. Moreover, rs12455792 variant increased M1 type inflammatory response, which might contribute much to TAAD progression. To mimic the SMAD4 suppression effect of rs12455792 in vivo, we constructed the SMAD4 KD mouse. After induction with Ang II for 4w, the thoracic aorta dilatation and vascular remodeling were more serious than that of wild type group. In conclusion, rs12455792 increased MØ recruitment, M1 type inflammatory response via activated TGF-ß signaling, and further promoted vascular remodeling and pathological progress of TAAD.