Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 µm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.

Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts.

BACKGROUND: Heart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair. METHODS: We applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling. RESULTS: In vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group. CONCLUSIONS: We developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model.

Asiatic acid protects against pressure overload-induced heart failure in mice by inhibiting mitochondria-dependent apoptosis.

BACKGROUND: Mitochondrial dysfunction and subsequent cardiomyocyte apoptosis significantly contribute to pressure overload-induced heart failure (HF). A highly oxidative environment leads to mitochondrial damage, further exacerbating this condition. Asiatic acid (AA), a proven antioxidant and anti-hypertrophic agent, might provide a solution, but its role and mechanisms in chronic pressure overload-induced HF remain largely unexplored. METHODS: We induced pressure overload in mice using transverse aortic constriction (TAC) and treated them with AA (100 mg/kg/day) or vehicle daily by oral gavage for 8 weeks. The effects of AA on mitochondrial dysfunction, oxidative stress-associated signaling pathways, and overall survival were evaluated. Additionally, an in vitro model using hydrogen peroxide-exposed neonatal rat cardiomyocytes was established to further investigate the role of AA in oxidative stress-induced mitochondrial apoptosis. RESULTS: AA treatment significantly improved survival and alleviated cardiac dysfunction in TAC-induced HF mice. It preserved mitochondrial structure, reduced the LVW/BW ratio by 20.24%, mitigated TAC-induced mitochondrial-dependent apoptosis by significantly lowering the Bax/Bcl-2 ratio and cleaved caspase-9/3 levels, and attenuated oxidative stress. AA treatment protected cardiomyocytes from hydrogen peroxide-induced apoptosis, with concurrent modulation of mitochondrial-dependent apoptosis pathway-related proteins and the JNK pathway. CONCLUSIONS: Our findings suggest that AA effectively combats chronic TAC-induced and hydrogen peroxide-induced cardiomyocyte apoptosis through a mitochondria-dependent mechanism. AA reduces cellular levels of oxidative stress and inhibits the activation of the JNK pathway, highlighting its potential therapeutic value in the treatment of HF.

Effects of Irrational Use of Antibiotics on Intestinal Health of Children with Extraintestinal Infectious Diseases.

The effects of different antibiotic treatment regimens on intestinal function and flora distribution in children with extraintestinal infectious diseases are explored. A total of 150 cases of extraintestinal infectious diseases admitted to our hospital from January 2021 to January 2022 and 50 healthy subjects during the same period were selected for the study. These 150 children were randomly divided into cephalosporin group, piperacillin group, and combined group and were successively treated with ceftazidime, piperacillin, and two drug combination regimens. The efficacy of the drug, intestinal microflora, intestinal mucosal barrier function, and incidence of antibiotic-associated diarrhea (AAD) were compared among the different groups. The experimental results showed that ceftazidime combined with piperacillin can effectively improve the intestinal health of children with extraintestinal infectious diseases but destroy the microecological environment of intestinal flora, affect the intestinal mucosal barrier function, and increase the risk of AAD.

Subtyping of hepatocellular adenoma: a machine learning-based approach.

Subtyping of hepatocellular adenoma (HCA) is an important task in practice as different subtypes may have different clinical outcomes and management algorithms. Definitive subtyping is currently dependent on immunohistochemical and molecular testing. The association between some morphologic/clinical features and HCA subtypes has been reported; however, the predictive performance of these features has been controversial. In this study, we attempted machine learning based methods to select an efficient and parsimonious set of morphologic/clinical features for differentiating a HCA subtype from the others, and then assessed the performance of the selected features in identifying the correct subtypes. We first examined 50 liver HCA resection specimens collected at the University of Washington and Kobe University/Kings College London, including HNF1α-mutated HCA (H-HCA) (n = 16), inflammatory HCA (I-HCA) (n = 20), beta-catenin activated HCA (ß-HCA) (n = 8), and unclassified HCA (U-HCA) (n = 6). Twenty-six morphologic/clinical features were assessed. We used LASSO (least absolute shrinkage and selection operator) to select key features that could differentiate a subtype from the others. We further performed SVM (support vector machine) analysis to assess the performance (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy) of the selected features in HCA subtyping in an independent cohort of liver resection samples (n = 20) collected at the University of Wisconsin-Madison. With some overlap, different combinations of morphologic/clinical features were selected for each subtype. Based on SVM analysis, the selected features classified HCA into correct subtypes with an overall accuracy of at least 80%. Our findings are useful for initial diagnosis and subtyping of HCA, especially in clinical settings without access to immunohistochemical and molecular assays.

Off-pump versus on-pump coronary artery bypass grafting for octogenarians: A meta-analysis involving 146 372 patients.

There is an ongoing debate concerning the optimal surgical option of myocardial revascularization for octogenarians. The current meta-analysis aimed to compare clinical outcomes following off-pump coronary artery bypass grafting (OPCABG) or conventional coronary artery bypass grafting (CCABG) in octogenarians. PubMed, Cochrane, Web of Science, and EMBASE databases were searched to identify eligible studies from inception to March 2021. The analysis was performed using STATA 15.1. A literature search yielded 18 retrospective studies involving 146 372 patients (OPCABG = 44 522 vs. CCABG = 101 850). Pooled analysis showed a strong trend toward reducing mortality risk in the OPCABG group (odds ratio: 0.75, 95% confidence interval: 0.56-1.00, p = .05). However, it did not reach statistical significance. The sensitive analysis demonstrated that OPCABG was less likely to cause death than CCABG. There were comparable data in myocardial infarction, renal failure, deep sternal wound infection, and hospital stays between the two groups, although the incidence of stroke, atrial fibrillation, prolonged ventilation, and reoperation for bleeding was significantly lower in the OPCAGB group. OPCABG may be an effective surgical strategy for myocardial revascularization, especially in reducing the incidence of postoperative stroke, atrial fibrillation, prolonged ventilation, and reoperation for bleeding.

Asiatic Acid Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting the ROS-Mediated Mitochondria-Dependent Apoptosis Pathway.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of heart failure in patients with coronary heart disease (CHD). Mitochondrial dysfunction is the crucial factor of MIRI; oxidative stress caused by mitochondrial reactive oxygen species (ROS) aggravates myocardial cell damage through the mitochondria-dependent apoptosis pathway. Asiatic acid (AA) is a type of pentacyclic triterpene compound purified from the traditional Chinese medicine Centella asiatica, and its protective pharmacological activities have been reported in various disease models. This study is aimed at investigating the protective effects of AA and the underlying mechanisms in MIRI. To achieve this goal, an animal model of MIRI in vivo and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) in vitro were established. The results show that AA exerts a protective effect on MIRI by improving cardiac function and reducing cardiomyocyte damage. Due to its antioxidant properties, AA alleviates mitochondrial oxidative stress, as evidenced by the stable mitochondrial structure, maintained mitochondrial membrane potential (MMP), and reduced ROS generation, otherwise due to its antiapoptotic properties. AA inhibits the mitogen-activated protein kinase (MAPK)/mitochondria-dependent apoptosis pathway, as evidenced by the limited phosphorylation of p38-MAPK and JNK-MAPK, balanced proportion of Bcl-2/Bax, reduced cytochrome c release, inhibition of caspase cascade, and reduced apoptosis. In conclusion, our study confirms that AA exerts cardiac-protective effects by regulating ROS-induced oxidative stress via the MAPK/mitochondria-dependent apoptosis pathway; the results provide new evidence that AA may represent a potential treatment for CHD patients.

Resilience as a Mediator of the Association Between Perceived Stigma and Quality of Life Among People With Inflammatory Bowel Disease.

Background: Improving Quality of Life (QOL) is an essential objective in the management of inflammatory bowel disease. An accumulating body of research has been conducted to explore the association between perceived stigma and QOL among patients with chronic illness. Still, underlying mechanisms behind this pathway have not been thoroughly examined. Objective: To investigate (a) the effect of perceived stigma on QOL among patients with inflammatory bowel disease; and (b) the mediating role of resilience in the association between perceived stigma and QOL. Methods: This cross-sectional study included a convenient sample of patients diagnosed with inflammatory bowel disease from four tertiary hospitals in Jiangsu Province, China. Patients completed the Perceived Stigma Scale in Inflammatory Bowel Disease (PSS-IBD), the Resilience Scale for Patients with Inflammatory Bowel Disease (RS-IBD), and the Inflammatory Bowel Disease Questionnaire (IBDQ). A bootstrapping analysis was implemented using the SPSS macro PROCESS. Results: A total of 311 patients with Cohn's disease and ulcerative colitis participated in this study, and 57.6% were men. The mean disease duration was 3.51 ± 1.04 years. Approximately 40% of the sample exceeded the criterion score for moderate stigma. Patients who perceived moderate or severe stigma reported lower QOL compared with those with mild stigma. After controlling for sociodemographic and clinical variables, we observed that perceived stigma was negatively associated with resilience. Moreover, resilience was found to mediate the relationship between perceived stigma and all aspects of QOL. Conclusions: These findings suggested that QOL of patients with inflammatory bowel disease was associated with perceived stigma and resilience and identified the mediating effects of resilience in the relationship between perceived stigma and QOL. Furthermore, this suggests that integrating intervention techniques to target resilience into the QOL improvement program of individuals with perceived stigma is possible.

Resveratrol activates PI3K/AKT to reduce myocardial cell apoptosis and mitochondrial oxidative damage caused by myocardial ischemia/reperfusion injury.

Resveratrol is a kind of iPolyphenols widely existing in herbal medicine. Here we aim to investigate whether resveratrol can reduce the degree of myocardial ischemia/reperfusion (IR) injury and inhibit the development of oxidative stress, and elucidate the molecular mechanism of resveratrol in protecting myocardial cells. The primary rat cardiomyocytes were used to establish an ischemia/reperfusion model in vitro, and a series of routine biochemical experiments were conducted to explore the antioxidant and anti-apoptotic effects of resveratrol in myocardial ischemia-reperfusion injury. Compared with that of the simulated ischemia-refusion (SIR) group, cell viability in the SIR and resveratrol co-treatment groups increased significantly (P < 0.001), the release of lactate dehydrogenase (LDH) and creatine kinase MB (CKMB) decreased, the positive rate of reactive oxygen species (ROS) in cardiomyocytes decreased, and the concentration of catalase and glutathione peroxidase increased significantly (P < 0.001). Besides, resveratrol can activate PI3K/AKT signaling pathway. PI3K siRNA can inhibit the PI3K/AKT signaling mediated by resveratrol. The addition of resveratrol can significantly increase the activity of mitochondrial superoxide dismutase (SOD) and reduce the malondialdehyde (MDA), which indicates that the oxidative damage of mitochondria induced by resveratrol was significantly weakened. The mitochondrial functional changes induced by resveratrol can be reversed by PI3K siRNA. In conclusion, our study shows that resveratrol can reduce ROS in cardiomyocytes by PI3K/AKT signaling pathway activation, and effectively inhibit the apoptosis of cardiomyocytes, thus having a direct protective effect on cardiomyocytes under SR.

Root-associated fungi of Vaccinium carlesii in subtropical forests of China: intra- and inter-annual variability and impacts of human disturbances.

Ericoid mycorrhiza (ERM) are expected to facilitate establishment of ericaceous plants in harsh habitats. However, diversity and driving factors of the root-associated fungi of ericaceous plants are poorly understood. In this study, hair-root samples of Vaccinium carlesii were taken from four forest types: old growth forests (OGF), secondary forests with once or twice cutting (SEC I and SEC II), and Cunninghamia lanceolata plantation (PLF). Fungal communities were determined using high-throughput sequencing, and impacts of human disturbances and the intra- and inter-annual variability of root-associated fungal community were evaluated. Diverse fungal taxa were observed and our results showed that (1) Intra- and inter-annual changes in root-associated fungal community were found, and the Basidiomycota to Ascomycota ratio was related to mean temperature of the sampling month; (2) Human disturbances significantly affected structure of root-associated fungal community of V. carlesii, and two secondary forest types were similar in root-associated fungal community and were closer to that of the old growth forest; (3) Plant community composition, edaphic parameters, and geographic factors significantly affected root-associated fungal communities of V. carlesii. These results may be helpful in better understanding the maintenance mechanisms of fungal diversity associated with hair roots of ERM plants under human disturbances.

Different distribution patterns between putative ercoid mycorrhizal and other fungal assemblages in roots of Rhododendron decorum in the Southwest of China.

Fungal diversity within plant roots is affected by several factors such as dispersal limitation, habitat filtering, and plant host preference. Given the differences in life style between symbiotic and non-symbiotic fungi, the main factors affecting these two groups of fungi may be different. We assessed the diversity of root associated fungi of Rhododendron decorum using internal transcribed spacer (ITS) sequencing and terminal restriction fragment length polymorphism (T-RFLP) analysis, and our aim was to evaluate the role of different factors in structuring ericoid mycorrhizal (ERM) and non-ericoid mycorrhizal (NEM) fungal communities. Thirty-five fungal operational taxonomic units (OTUs) were found in roots of R. decorum, of which 25 were putative ERM fungal species. Of the two main groups of known ERM, helotialean fungi were more abundant and common than sebacinalean species. Geographic and host patterning of the fungal assemblages were different for ERM and NEM. The distribution of putative ERM fungal terminal restriction fragments (TRFs) showed that there were more common species within ERM than in the NEM fungal assemblages. Results of Mantel tests indicated that the composition of NEM fungal assemblages correlated with geographic parameters while ERM fungal assemblages lacked a significant geographic pattern and instead were correlated with host genotype. Redundancy analysis (RDA) showed that the NEM fungal assemblages were significantly correlated with latitude, longitude, elevation, mean annual precipitation (MAP), and axis 2 of a host-genetic principle component analysis (PCA), while ERM fungal assemblages correlated only with latitude and axis 1 of the host-genetic PCA. We conclude that ERM and NEM assemblages are affected by different factors, with the host genetic composition more important for ERM and geographic factors more important for NEM assemblages. Our results contribute to understanding the roles of dispersal limitation, abiotic factors and biotic interactions in structuring fungal communities in plant roots.