Application of adipose-derived stem cells in ischemic heart disease: theory, potency, and advantage.

Adipose-derived mesenchymal stem cells (ASCs) represent an innovative candidate to treat ischemic heart disease (IHD) due to their abundance, renewable sources, minor invasiveness to obtain, and no ethical limitations. Compared with other mesenchymal stem cells, ASCs have demonstrated great advantages, especially in the commercialization of stem cell-based therapy. Mechanistically, ASCs exert a cardioprotective effect not only through differentiation into functional cells but also via robust paracrine of various bioactive factors that promote angiogenesis and immunomodulation. Exosomes from ASCs also play an indispensable role in this process. However, due to the distinct biological functions of ASCs from different origins or donors with varing health statuses (such as aging, diabetes, or atherosclerosis), the heterogeneity of ASCs deserves more attention. This prompts scientists to select optimal donors for clinical applications. In addition, to overcome the primary obstacle of poor retention and low survival after transplantation, a variety of studies have been dedicated to the engineering of ASCs with biomaterials. Besides, clinical trials have confirmed the safety and efficacy of ASCs therapy in the context of heart failure or myocardial infarction. This article reviews the theory, efficacy, and advantages of ASCs-based therapy, the factors affecting ASCs function, heterogeneity, engineering strategies and clinical application of ASCs.

Case Report: Giant left atrial cystic tumor: myxoma or intracardiac blood cyst?

Background: Primary cardiac tumors are uncommon, with the majority being benign myxomas. Cystic myxoma, a particularly rare type of benign cardiac tumor, demands cautious differential diagnosis from other cardiac tumors. Case summary: A 43-year-old male patient presenting with intermittent dyspnea was referred to our department for surgical evaluation. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) unveiled an intra-left atrial cyst, which was subsequently found to be blood-filled during a video-assisted microinvasive heart surgery. Pathological examination depicted a cyst wall filled with small stellate and fat spindle cells, along with a mucoid matrix, indicating a diagnosis of cystic myxoma. Conclusions: We herein presented a rare case of an adult patient with cystic myxoma, initially misdiagnosed as an intracardiac blood cyst (CBC) prior to surgery, and ultimately verified via pathological findings.

An immunometabolic patch facilitates mesenchymal stromal/stem cell therapy for myocardial infarction through a macrophage-dependent mechanism.

Mesenchymal stromal/stem cells (MSCs) have emerged as a promising approach against myocardial infarction. Due to hostile hyperinflammation, however, poor retention of transplanted cells seriously impedes their clinical applications. Proinflammatory M1 macrophages, which rely on glycolysis as their main energy source, aggravate hyperinflammatory response and cardiac injury in ischemic region. Here, we showed that the administration of an inhibitor of glycolysis, 2-deoxy-d-glucose (2-DG), blocked the hyperinflammatory response within the ischemic myocardium and subsequently extended effective retention of transplanted MSCs. Mechanistically, 2-DG blocked the proinflammatory polarization of macrophages and suppressed the production of inflammatory cytokines. Selective macrophage depletion abrogated this curative effect. Finally, to avoid potential organ toxicity caused by systemic inhibition of glycolysis, we developed a novel chitosan/gelatin-based 2-DG patch that directly adhered to the infarcted region and facilitated MSC-mediated cardiac healing with undetectable side effects. This study pioneered the application of an immunometabolic patch in MSC-based therapy and provided insights into the therapeutic mechanism and advantages of this innovative biomaterial.

Analgesic effect of intercostal nerve block given preventively or at the end of operation in video-assisted thoracic surgery: a randomized clinical trial

Abstract Objective To compare the analgesic effect of intercostal nerve block (INB) with ropivacaine when given preventively or at the end of the operation in patients undergoing video-assisted thoracic surgery (VATS). Methods A total of 50 patients undergoing VATS were randomly divided into two groups. The patients in the preventive analgesia group (PR group) were given INB with ropivacaine before the intrathoracic manipulation combined with patient-controlled analgesia (PCA). The patients in the post-procedural block group (PO group) were administered INB with ropivacaine at the end of the operation combined with PCA. To evaluate the analgesic effect, postoperative pain was assessed with the visual analogue scale (VAS) at rest and Prince Henry Pain Scale (PHPS) scale at 6, 12, 24, 48, and 72 hours after surgery. Results At 6 h and 12 h post-surgery, the VAS at rest and PHPS scores in the PR group were significantly lower than those in the PO group. There were no significant differences in pain scores between two groups at 24, 48, and 72 hours post-surgery. Conclusion In patients undergoing VATS, preventive INB with ropivacaine provided a significantly better analgesic effect in the early postoperative period (at least through 12 h post-surgery) than did INB given at the end of surgery.

Calming egress of inflammatory monocytes and related septic shock by therapeutic CCR2 silencing using macrophage-derived extracellular vesicles.

Uncontrolled inflammation, featuring the aggravated mobilization of Ly6Chigh inflammatory monocytes (Mos), may cause high morbidity and mortality in the pathogenesis of sepsis-associated immune disorders. Inspired by the similar membrane protein profile of extracellular vehicles (EVs) and their parent cells, EVs are generated from immortalized bone marrow-derived macrophages (Mps) for Mo/Mp-targeting drug delivery. Compared with MSC-EVs, Mac-EVs are more efficiently internalized by inflammatory Mo/Mps in vitro as well as by septic spleen in vivo. By loading with siRNA targeting the chemokine receptor CCR2, the mediator for chemotaxis of inflammatory Mo/Mps, Mac-EVsiCCR2 not only restrains chemotaxis of inflammatory Mo/Mps but also relieves septic symptoms in mice by limiting the mobilization of splenic inflammatory monocytes and calming the subsequent serum cytokine storm. The current study provides functional evidence for the successful therapeutic targeting of septic inflammatory Mos, mandating the clinical development of CCR2 inhibition in patients with infectious diseases.

Analgesic effect of intercostal nerve block given preventively or at the end of operation in video-assisted thoracic surgery: a randomized clinical trial.

OBJECTIVE: To compare the analgesic effect of intercostal nerve block (INB) with ropivacaine when given preventively or at the end of the operation in patients undergoing video-assisted thoracic surgery (VATS). METHODS: A total of 50 patients undergoing VATS were randomly divided into two groups. The patients in the preventive analgesia group (PR group) were given INB with ropivacaine before the intrathoracic manipulation combined with patient-controlled analgesia (PCA). The patients in the post-procedural block group (PO group) were administered INB with ropivacaine at the end of the operation combined with PCA. To evaluate the analgesic effect, postoperative pain was assessed with the visual analogue scale (VAS) at rest and Prince Henry Pain Scale (PHPS) scale at 6, 12, 24, 48, and 72 hours after surgery. RESULTS: At 6 h and 12 h post-surgery, the VAS at rest and PHPS scores in the PR group were significantly lower than those in the PO group. There were no significant differences in pain scores between two groups at 24, 48, and 72 hours post-surgery. CONCLUSION: In patients undergoing VATS, preventive INB with ropivacaine provided a significantly better analgesic effect in the early postoperative period (at least through 12 h post-surgery) than did INB given at the end of surgery.

ROS­mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC.

Deoxyribonucleic acid (DNA) epigenetic modification has been linked to specific sequences of CpG islands and plays roles in the progression of lung cancer. In this study, it was found that peroxiredoxin­5 (PRDX5) was highly expressed in non­small cell lung cancer (NSCLC) tissues; however, its specific regulatory mechanisms and functions in NSCLC remain unknown. The present study therefore explored the regulatory mechanism of PRDX5 under conditions of oxidative stress (OS) in NSCLC. The results revealed that 79 of 121 NSCLC patients exhibited demethylation in the PRDX5 promoter region, which was related to the tumor, node and metastasis (TNM) stage (P=0.027). PRDX5 messenger ribonucleic acid (mRNA) expression positively correlated with the demethylation status of the promoter region. The results of bisulfite sequencing polymerase chain reaction (BSP) revealed lower demethylation frequencies in H1299 cells treated with 0 µM H2O2, but maximum demethylation following treatment with 100 µM H2O2. Using chromatin immunoprecipitation (ChIP) and luciferase detection assays, the effective binding of STAT3 to the transcriptional binding sites of the PRDX5 promoter region was confirmed (2 sites confirmed: Site 1, ­444 to ­434 bp; and site 4, ­1,417 to ­1,407 bp). STAT3 knockdown significantly decreased the protein expression of PRDX5, while the overexpression of STAT3 significantly increased the protein levels of PRDX5. When PRDX5 was overexpressed in lung cancer cells under conditions of OS, the levels of the epithelial­mesenchymal transition (EMT) biomarkers, E­cadherin and vimentin, were significantly decreased and increased, respectively. By contrast, PRDX5 knockdown resulted in significantly increased E­cadherin and decreased vimentin protein expression levels. Ultimately, when PRDX5­small interfering RNA (siRNA) or pcDNA3.1­PRDX5 expression vector were constructed and transfected into H1299 cells pre­treated with 100 µM H2O2, the nuclear factor (erythroid­derived 2)­like 2 (Nrf2) signaling pathway was inhibited or activated. All these results suggested that the reactive oxygen species (ROS)­mediated hypomethylation of PRDX5 enhanced STAT3 binding affinity with the promoter region, and resulted in the promotion of cell migration and invasion, as well as in the activation of the Nrf2 signaling pathway in NSCLC. The demethylation status of the PRDX5 promoter may thus be used as an epigenetic biomarker in NSCLC. STAT3/PRDX5 signaling may also prove to be a potential strategy for the treatment of this type of cancer.

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.

LncRNA Sox2ot modulates the progression of thoracic aortic aneurysm by regulating miR-330-5p/Myh11.

Thoracic aortic aneurysm (TAA) has been causing the death of elder people. Myosin heavy chain 11 (Myh11) has been reported associated with aortic aneurysm, but there is no specific study on its function on TAA. Here we aimed to explore the function of Myh11 on mouse aortic smooth muscle cells (SMCs) for studying the inner mechanism of TAA. H2O2 treatment was implemented on mouse aortic SMCs for detecting cell apoptosis. Meanwhile, functional assays were conducted to verify the function of Myh11 on mouse aortic SMCs. Also, pull-down assay, RIP assay were implemented to identify the potential RNAs for study. Quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay were implemented to identify the expression and binding relationships of RNAs. Myh11 expression was increased by treatment of H2O2. Myh11 could decrease proliferation and enhance apoptosis of mouse aortic SMCs. At the same time, mmu-miR-330-5p could bind to Myh11 and Sox2ot, forming a competing endogenous RNA (ceRNA) pathway to regulate the proliferation and apoptosis of mouse aortic SMCs. Moreover, both Sox2ot and Myh11 were proved to be up-regulated whereas miR-330-5p down-regulated in Fbn1C1039G/+ mice, the in vivo model of TAA. In a word, long noncoding RNA (lncRNA) Sox2ot modulates the progression of TAA by regulating miR-330-5p/Myh11 axis.

PRDX5 as a novel binding partner in Nrf2-mediated NSCLC progression under oxidative stress.

Non-small-cell lung cancer (NSCLC) is one of the most common malignant tumors in the world. Reactive oxidative species (ROS) and nuclear factor-related factor 2 (Nrf2) -antioxidant response element (ARE) signal pathway are known to play important roles in the development of NSCLC. In this study, we identified Peroxiredoxin 5 (PRDX5) as a novel binding partner for Nrf2. PRDX5 was significantly increased in human NSCLC specimens and cell lines. Nrf2 interacted with PRDX5 in H2O2-stimulated NCSLC cells, and the interaction promoted the expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) protein in NSCLC cells. Further, high expression of Nrf2 and PRDX5 were associated with worsened prognosis in patients with NSCLC significantly. Moreover, animal studies showed that the growth of tumors treated with Nrf2 and PRDX5 shRNA was significantly lower than that of the other groups. All these data indicated that overexpressed PRDX5 in NSCLC promoted binding with Nrf2 and enhanced NQO1 expression and NSCLC development. Overall, our studies demonstrated that PRDX5 can be a novel binding partner of Nrf2 in promoting NCSLC development under oxidative stress and provide potential opportunity for improving NSCLC therapy.

Relationship of tidal volume to peak flow, breath rate, I: E and plateau time: mock study.

BACKGROUND: The purpose of this study was to determine the functional relationship between tidal volume (VT) and 4 other ventilator parameters. METHODS: The following parameters were collected from an AVEA ventilator operating in the volume-controlled ventilation mode: VT (in L), peak flow (Vmax, in L/min), breath rate (f, in bpm), inspiratory-to-expiratory time ratio (I:E) and plateau time (TP, in s). The relationship between VT and each of the other variables was determined. RESULTS: When the other parameters were held constant, VT was positively correlated with Vmax and I:E, but negatively correlated with f and TP. When the velocity versus time curve was a 50% linearly decreasing wave, the functional relationship among the 5 parameters was governed by the equation: VT = 180 Vmax (60f - 60f [1 + I:E] - TP). CONCLUSIONS: The functional relationship among the 5 parameters for the AVEA ventilator in the volume-controlled ventilation mode was determined. The parameters should be controlled in accordance with the patient's pathophysiological needs.