Extracellular Vesicles Derived from Type 2 Diabetic Mesenchymal Stem Cells Induce Endothelial Mesenchymal Transition under High Glucose Conditions via the TGFb/Smad2-3 Signaling Pathway.

Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, which results in delayed wound healing. Mesenchymal stem cells (MSC) play a vital role in supporting endothelial cells (EC) and promoting wound healing via paracrine effects through their secretome-containing extracellular vesicles. We previously reported the impaired wound healing ability of adipose tissue-derived MSC from T2DM donors; however, whether extracellular vesicles isolated from T2DM adipose tissue-derived MSC (dEV) exhibit altered functions in comparison to those derived from healthy donors (nEV) is still unclear. In the present study, we found that nEV induced EC survival and angiogenesis, whereas dEV lost these abilities. In addition, under high glucose conditions, nEV protected EC from endothelial mesenchymal transition (EndMT), whereas dEV significantly induced EndMT by activating the TGF/Smad3 signaling pathway, which impaired the tube formation and in vivo wound healing abilities of EC. Interestingly, the treatment of dEV-internalized EC with nEV rescued the induced EndMT effects. Of note, the internalization of nEV into T2DM-derived adipose tissue-MSC resulted in the production of an altered n-dEV, which inhibited EndMT and supported the survival of T2DM db/db mice from severe wounds. Taken together, our findings suggest the role of dEV in endothelial dysfunction and delayed wound healing in T2DM by the promotion of EndMT. Moreover, nEV treatment can be considered as a promising candidate for cell-free therapy to protect EC in T2DM.

Extracellular vesicles derived from SARS-CoV-2 M-protein-induced triple negative breast cancer cells promoted the ability of tissue stem cells supporting cancer progression.

Introduction: SARS-CoV-2 infection increases the risk of worse outcomes in cancer patients, including those with breast cancer. Our previous study reported that the SARS-CoV-2 membrane protein (M-protein) promotes the malignant transformation of triple-negative breast cancer cells (triple-negative BCC). Methods: In the present study, the effects of M-protein on the ability of extracellular vesicles (EV) derived from triple-negative BCC to regulate the functions of tissue stem cells facilitating the tumor microenvironment were examined. Results: Our results showed that EV derived from M-protein-induced triple-negative BCC (MpEV) significantly induced the paracrine effects of adipose tissue-derived mesenchymal stem cells (ATMSC) on non-aggressive BCC, promoting the migration, stemness phenotypes, and in vivo metastasis of BCC, which is related to PGE2/IL1 signaling pathways, in comparison to EV derived from normal triple-negative BCC (nEV). In addition to ATMSC, the effects of MpEV on endothelial progenitor cells (EPC), another type of tissue stem cells, were examined. Our data suggested that EPC uptaking MpEV acquired a tumor endothelial cell-like phenotype, with increasing angiogenesis and the ability to support the aggressiveness and metastasis of non-aggressive BCC. Discussion: Taken together, our findings suggest the role of SARS-CoV-2 M-protein in altering the cellular communication between cancer cells and other non-cancer cells inside the tumor microenvironment via EV. Specifically, M-proteins induced the ability of EV derived from triple-negative BCC to promote the functions of non-cancer cells, such as tissue stem cells, in tumorigenesis.

Twisting of HeartMate II outflow graft 2.5 years after implantation-HM2 is still ongoing.

A 47-year-old woman with dilated cardiomyopathy underwent HeartMate II (HM2) implantation as a bridge-to-transplantation. Her postoperative course was good. However, 2.5 years after surgery, the outflow graft was found to be twisted and the graft and pump was exchanged. While HeartMate 3(HM3) twisting of the outflow graft is well documented, such malfunctions in HM2 are almost unknown. Although HM2 has since been discontinued, there are a significant number of patients using HM2 who are awaiting heart transplants or destination therapy. We caution that, even with HM2, the possibility of late-phase twisting requires vigilance.

Natto consumption suppresses atherosclerotic plaque progression in LDL receptor-deficient mice transplanted with iRFP-expressing hematopoietic cells.

Natto, known for its high vitamin K content, has been demonstrated to suppress atherosclerosis in large-scale clinical trials through a yet-unknown mechanism. In this study, we used a previously reported mouse model, transplanting the bone marrow of mice expressing infra-red fluorescent protein (iRFP) into LDLR-deficient mice, allowing unique and non-invasive observation of foam cells expressing iRFP in atherosclerotic lesions. Using 3 natto strains, we meticulously examined the effects of varying vitamin K levels on atherosclerosis in these mice. Notably, high vitamin K natto significantly reduced aortic staining and iRFP fluorescence, indicative of decreased atherosclerosis. Furthermore, mice administered natto showed changes in gut microbiota, including an increase in natto bacteria within the cecum, and a significant reduction in serum CCL2 expression. In experiments with LPS-stimulated macrophages, adding natto decreased CCL2 expression and increased anti-inflammatory cytokine IL-10 expression. This suggests that natto inhibits atherosclerosis through suppression of intestinal inflammation and reduced CCL2 expression in macrophages.

Effect of cardiopulmonary bypass on coagulation factors II, VII and X in a primate model: an exploratory pilot study.

OBJECTIVES: The use of cardiopulmonary bypass (CPB) in cardiac surgery is a major risk factor for postoperative bleeding. We hypothesized that consumptive coagulopathy and haemodilution influence the coagulation factors; therefore, we aimed to estimate the activity profiles of coagulation factors II, VII and X during CPB circulation. METHODS: A 120-min bypass was surgically established in cynomolgus monkeys (n = 7). Activities of coagulation factors II, VII and X were measured at 6 time points during the experiment (baseline, 0, 30, 60, 120 min of bypass and 60 min after bypass). To assess the influence of consumptive coagulopathy, the values were adjusted for haemodilution using the haematocrit values. Data were expressed as mean (standard deviation). RESULTS: Activities of coagulation factors decreased during the experiment. In particular, the activities for II, VII and X were decreased the most by 44.2% (5.0), 61.4% (4.3) and 49.0% (3.7) at 30 min following CPB initiation (P < 0.001, P < 0.001 and P < 0.001, respectively). Following adjustments for haemodilution, change magnitudes lessened but remained significant for factor VII. The adjusted concentration of factor VII was observed to decrease from the baseline to the initiation of bypass circulation. CONCLUSIONS: In conclusion, coagulation factor II, VII and X concentrations decreased during CPB. Following adjustment for haemodilution, a decrease in concentration was observed with factor VII.

Impairment of HIF-2α Expression Induced the Compensatory Overexpression of the HIF-1α/SDF-1 Axis to Promote Wound Healing.

Glucocorticoids are common anti-inflammatory factors; however, they have been reported to have side effects that delay the wound healing process. In a previous study, we found that mesenchymal stem cells isolated from the adipose tissue of patients with long-term glucocorticoid treatment (sAT-MSC) showed impaired wound healing ability due to the downregulation of SDF-1. In this study, we aimed to clarify the mechanisms by which SDF-1 is regulated in sAT-MSC by focusing on the roles of hypoxia-inducible factors (HIFs). Our data suggested that sAT-MSC showed impairment of HIF-1α and the upregulation of HIF-2α. Notably, HIF-2α impairment resulted in the compensatory overexpression of HIF-1α and its target gene SDF-1, which improved the wound healing ability of sAT-MSC. In addition, using knockdown/knockout heterozygous HIF-2α kd/null mice (kd/null), the functions of HIF-2α in the ischemic wound healing process were clarified. With a 50% reduction in the expression of HIF-2α, kd/null mice showed significantly induced wound healing effects, which are involved in the promotion of the inflammatory phase. Specifically, kd/null mice showed the compensatory overexpression of HIF-1α, which upregulated the expression of SDF-1 and enhanced the recruitment of inflammatory cells, such as neutrophils. Our study highlighted the novel function of HIF-2α in the inflammation phase of the wound healing process through the HIF-1α/SDF-1 axis, suggesting that the physiological state of the impaired expression of HIF-2α is a new concept for wound therapy.

Differences in the components of metabolic syndrome by age and sex: a cross-sectional and longitudinal analysis of a cohort of middle-aged and older Japanese adults.

BACKGROUND: The prevalence of metabolic syndrome (MetS) in Japan, a super-aged society, is increasing and poses a major public health issue. Several studies have reported sex differences in the association between age and MetS prevalence. This study aimed to examine the association between age and the prevalence of MetS based on multiple screening criteria and MetS components by sex. METHODS: We used 6 years of individual-level longitudinal follow-up data (June 2012 to November 2018; checkup year: 2012-2017) of middle-aged and older adults aged 40-75 years in Japan (N = 161,735). The Joint Interim Statement criteria, International Diabetes Federation criteria, and another set of criteria excluding central obesity were used as the screening criteria for MetS. The prevalence of MetS and MetS components was cross-sectionally analyzed according to sex and age. A longitudinal association analysis of age, MetS, and MetS components by sex was performed using a multilevel logistic model, adjusted for lifestyle- and regional-related factors. RESULTS: Sex differences were observed in the prevalence and association of MetS and MetS components. In all age groups, the prevalence of central obesity was higher among women, and the prevalence of high blood pressure and fasting glucose was higher among men (P < 0.001). The prevalence of high triglyceride and low high-density lipoprotein cholesterol was higher among women aged > 60 years (P < 0.05). Based on the criteria of the Joint Interim Statement and International Diabetes Federation, the prevalence of MetS was higher among women than in men aged > 55 years (P < 0.001). Men had a higher prevalence of MetS without central obesity than women in all age groups (P < 0.001). The odds ratio for MetS and MetS components with aging was greater among women than in men. CONCLUSIONS: Medical management should be based on the prevalence of MetS and its components according to sex and age. In particular, the high prevalence of MetS without central obesity in middle-aged and older Japanese men suggests that the adoption of the Joint Interim Statement criteria, which do not precondition central obesity, should be considered.

Associations of Lifestyle-Related Factors With Body Mass Index and Blood Pressure in the Middle-Aged and Older Population-Based Cohort in Japan: A Longitudinal Study.

This study aims to analyze associations between lifestyle-related factors and body mass index (BMI) and blood pressure (BP) in middle-aged and older people in Japan. An association analysis using a multilevel model with demographic and lifestyle-related factors as variables and with BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP) as outcomes was conducted. Among the modifiable lifestyle factors, we found a significant dose-response association for BMI and slower eating (fast: reference; normal: -0.123 kg/m2 and slow: -0.256 kg/m2). Consuming >60 g/d ethanol was significantly associated, before and after adjustment for BMI, with an increase in SBP of 3.109 and 2.893 mm Hg, respectively. These findings suggested that health guidance should focus on factors such as the eating rate and drinking habits.

Multicenter Study of Surgical Ablation for Atrial Fibrillation in Aortic Valve Replacement.

There is controversy regarding appropriate surgical ablation procedures concomitant with nonmitral valve surgery. We retrospectively investigated the impact of surgical ablation for atrial fibrillation during aortic valve replacement between 2010 and 2015 in 16 institutions registered through the Japanese Society for Arrhythmia Surgery. Clinical data of 171 patients with paroxysmal and nonparoxysmal atrial fibrillation undergoing aortic valve replacement were collected and classified into full maze operation (n = 79), pulmonary vein isolation (PVI) (n = 56), and no surgical ablation (n = 36) groups. All patients were followed up and electrocardiograms were recorded in 68% at 2 years. The myocardial ischemia time was significantly longer in the maze group than the others during isolated aortic valve replacement (p ≤ 0.01), but there were no significant differences in 30-day or 2-year mortality rates between groups. The ratios of sinus rhythm at 2 years in paroxysmal and nonparoxysmal atrial fibrillation in the maze group versus PVI group were 87% versus 97%, respectively (p = 0.24) and 53% versus 42%, respectively (p = 0.47). No patients with nonparoxysmal atrial fibrillation in the no surgical ablation group maintained sinus rhythm at 2 years. In conclusion, both maze and PVI during aortic valve replacement are valuable strategies to restore sinus rhythm at 2 years and result in favorable early and midterm survival rates.

Risk of fetal undergrowth in the management of gestational diabetes mellitus in Japan.

AIMS/INTRODUCTION: In Japan, the increasing frequency of underweight among women of reproductive age and the accompanying increase in the rate of low birth weight (LBW) are social issues. The study aimed to establish a prospective registry system for gestational diabetes mellitus (GDM) in Japan and to clarify the actual status of GDM according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. MATERIALS AND METHODS: Pregnant women with gestational diabetes mellitus and those in the normal glucose tolerance (NGT) group were enrolled in the Diabetes and Pregnancy Outcome for Mother and Baby study from October 2015. Pregnant women with positive glucose screening in early and mid-to-late pregnancy underwent a 75 g oral glucose tolerance test by gestational week 32. Gestational diabetes mellitus was diagnosed according to IADPSG criteria. Women with a positive glucose screening test at mid-to-late pregnancy but NGT were enrolled as references (NGT group). Treatment for gestational diabetes mellitus and maternal and neonatal pregnancy data were prospectively collected on outcomes. RESULTS: In total 1,795 singleton pregnancies (878 women with GDM and 824 NGT women) were analyzed. The risk of LBW and small-for-gestational age in the GDM group was significantly higher than in the NGT group. A similar relationship was found for LBW risk in the non-overweight/obese group but not in the overweight/obese group. CONCLUSIONS: We established a prospective GDM registry system in Japan. In the management of GDM in Japan, suppression of maternal weight gain may be associated with reduced fetal growth, especially in non-overweight/obese women with GDM; however, further investigation is required.

Metabolically Healthy Obesity: Are Interventions Useful?

PURPOSE OF REVIEW: This review aims to detail the current global research state of metabolically healthy obesogenesis with regard to metabolic factors, disease prevalence, comparisons to unhealthy obesity, and targeted interventions to reverse or delay progression from metabolically healthy to unhealthy obesity. RECENT FINDINGS: As a long-term condition with increased risk of cardiovascular, metabolic, and all-cause mortality risks, obesity threatens public health on a national level. The recent discovery of metabolically healthy obesity (MHO), a transitional condition during which obese persons carry comparatively lower health risks, has added to confusion about the true effect of visceral fat and subsequent long-term health risks. In this context, the evaluation of fat loss interventions, such as bariatric surgery, lifestyle changes (diet/exercise), and hormonal therapies require re-evaluation in light of evidence that progression to high-risk stages of obesity relies on metabolic status and that strategies to protect the metabolism may be useful in the prevention of metabolically unhealthy obesity. Typical calorie-based exercise and diet interventions have failed to reduce the prevalence of unhealthy obesity. Holistic lifestyle, psychological, hormonal, and pharmacological interventions for MHO, on the other hand, may at least prevent progression to metabolically unhealthy obesity.

Myeloid Progenitor Inhibitory Factor-1 (CCL23) Inhibits Lung Leukocyte Recruitment in a Primate Cardiopulmonary Bypass-Induced Pulmonary Ischaemia Model.

BACKGROUND: Bone marrow (BM)-derived polymorphonuclear leukocytes (PMNs) and monocytes (MO) induced by cardiopulmonary bypass (CPB) are highly proteolytic and cause postoperative lung injury. Although CCL23/Myeloid progenitor inhibitory factor-1 is a human CC chemokine with potent suppressor effects on myeloid progenitor cells, in vivo inhibitory effects on BM-derived leukocyte kinetics associated with CPB are unknown. METHODS: Two-hour CPB was surgically performed in cynomolgus monkeys and BM-derived leukocytes kinetics were monitored postoperatively by flow cytometry with 5'-bromo-2'-deoxyuridine (BrdU) and cytokine ELISA. Monkeys were given CCL23 (n=5) or saline (control, n=5) intravenously daily for 3 days before BrdU labelling and peripheral blood/bronchoalveolar lavage fluid (BALF) timepoint sampling to reveal BrdU-labelled cells. Levels of cytokines, CD11b, and L-selectin were considered leukocytic activation markers. RESULTS: The CCL23 treatment significantly prolonged BM transit of leukocytes (PMNs, 118.4±11.7-95.5±4.1 hours [control]; MO, 91.6±5.0-62.0±3.0 hours [control]) and reduced their alveolar appearance. The BM pool size of MO was decreased by CCL23 but PMNs were unaffected. CD11b, L-selectin expression of PMNs and MO during CPB, and post-surgical increases of interleukin (IL)-6, IL-8, TNF-α, MCP-1, and PMN elastase in the BALF were not suppressed. CONCLUSIONS: CCL23 treatment slows turnover of PMN and MO progenitors in BM and suppresses their circulatory release and lung recruitment. CCL23 has inhibitory effects specifically on the CPB-induced BM response and could hold value for preventing CPB-induced lung injury.

Effect of procedural volume on the outcomes of congenital heart surgery in Japan.

OBJECTIVES: The present study developed a new risk model for congenital heart surgery in Japan and determined the relationship between hospital procedural volume and mortality using the developed model. METHODS: We analyzed 47,164 operations performed between 2013 and 2018 registered in the Japan Cardiovascular Surgery Database-Congenital and created a new risk model to predict the 90-day/in-hospital mortality using the Japanese congenital heart surgery mortality categories and patient characteristics. The observed/expected ratios of mortality were compared among 4 groups based on annual hospital procedural volume (group A [5539 procedures performed in 90 hospitals]: ≤50, group B [9322 procedures in 24 hospitals]: 51-100, group C [13,331 procedures in 21 hospitals]: 101-150, group D [18,972 procedures in 15 hospitals]: ≥151). RESULTS: The overall mortality rate was 2.64%. The new risk model using the surgical mortality category, age-weight categories, urgency, and preoperative mechanical ventilation and inotropic use achieved a c-index of 0.81. The observed/expected ratios based on the new risk model were 1.37 (95% confidence interval, 1.18-1.58), 1.21 (1.08-1.33), 1.04 (0.94-1.14), and 0.78 (0.71-0.86) in groups A, B, C, and D, respectively. In the per-procedure analysis, the observed/expected ratios of the Rastelli, coarctation complex repair, and arterial switch procedures in group A were all more than 3.0. CONCLUSIONS: The risk-adjusted mortality rate for low-volume hospitals was high for not only high-risk but also medium-risk procedures. Although the overall mortality rate for congenital heart surgeries is low in Japan, the observed volume-mortality relationship suggests potential for improvement in surgical outcomes.

Induction of Cardiac Pathology: Endogenous versus Exogenous Nrf2 Upregulation.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the endogenous antioxidant response to reactive oxygen species as well as a controller of Phase II detoxification in response to xenobiotics. This amenity to specific external manipulation exploits the binding affinity of Nrf2 for its constitutive repressor and degradation facilitator Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1). Derived from both natural and synthesized origins, these compounds have been extensively tested without definitive beneficial results. Unfortunately, multiple terminated trials have shown a negative side to Nrf2 with regard to cardiac pathologies while animal-based studies have demonstrated cardiomyocyte hypertrophy and heart failure after chronic Nrf2 upregulation. Putatively based on autophagic control of Nrf2 activity-modulating upstream factors, new evidence of miRNA involvement has added complexity to this mechanism. What follows is an extensive survey of Nrf2-regulating exogenous compounds that may promote cardiomyopathy, clinical trial evidence, and a comparison to exercise-induced factors that also upregulate Nrf2 while preventing cardiac pathologies.

TMPRSS2 gene polymorphism common in East Asians confers decreased COVID-19 susceptibility.

COVID-19 has a wide range of clinical presentations, and the susceptibility to SARS-CoV-2 infection and the mortality rate also vary by region and ethnicity. Here, we found that rs12329760 in the TMPRSS2 gene, a missense variant common in East Asian populations, contributes to protection against SARS-CoV-2 infection. TMPRSS2 is a protease responsible for SARS-CoV-2 entry and syncytium formation. rs12329760 (c.478G>A, p. V160M) was associated with a reduced risk of moderate symptoms. The enzymatic activity of Met160-TMPRSS2 was lower than that of Val160-TMPRSS2, and thus the viral entry and the syncytium formation of SARS-CoV-2 were impaired. Collectively, these results indicate that the genetic variation in TMPRSS2, which is common in East Asians, is one of the molecular determinants of COVID-19 susceptibility.

Arterial switch operation with coronary button extension and neo-pulmonary trunk realignment for a rare coronary pattern.

Coronary anatomy is key for arterial switch operations as reimplantation for coronary artery patterns originating from the same sinus is often challenging. We experienced an extremely rare coronary artery anatomy case (Leiden convention: 1 R, 1LCx) and successfully performed an arterial switch operation with coronary button extension and neo-pulmonary trunk realignment maneuver.

Pediatric delirium is associated with increased brain injury marker levels in cardiac surgery patients.

Despite global consensus on the importance of screening pediatric delirium, correlations between pediatric delirium during acute brain injury and adult delirium are unclear. Therefore, we hypothesized that similar pediatric biomarkers reflect acute brain injury as in adult delirium. We observed pediatric cardiac surgery patients from neonatal age to 18 years, who were admitted to our pediatric intensive care unit after cardiovascular operations between October 2019 to June 2020, up to post-operative day 3 (4 days total). We recorded age, sex, risk score (Risk Adjustment in Congenital Heart Surgery [RACHS-1]), midazolam/dexmedetomidine/fentanyl dosage, and pediatric Sequential Organ Failure Assessment (pSOFA). Richmond Agitation-Sedation Scale (RASS), Cornell Assessment of Pediatric Delirium (CAPD), Face, Leg, Activity, Consolability (FLACC) behavioral scale, and Withdrawal Assessment Tool (WAT-1) scales were used and serum sampling for neuron specific enolase (NSE) was conducted. Consciousness status was considered hierarchical (coma > delirium > normal) and associations between conscious status and NSE were conducted by hierarchical Bayesian modeling. We analyzed 134 data points from 40 patients (median age 12 months). In the multi-regression model, NSE was positively associated with coma [posterior odds ratio (OR) = 1.1, 95% credible interval (CrI) 1.01-1.19] while pSOFA [posterior OR = 1.63, 95% CrI 1.17-2.5], midazolam [posterior OR = 1.02, 95% CrI 1.01-1.04], and dexmedetomidine [posterior OR = 9.52, 95% CrI 1.02-108.85] were also associated. We also evaluated consciousness state probability at each NSE concentration and confirmed both that consciousness was hierarchically sorted and CAPD scores were also associated with NSE [posterior OR = 1.32, 95% CrI 1.09-1.58]. "Eye contact" (r = 0.55) was the most correlated component with NSE within the pain, withdrawal syndrome, and PD items. PD within the hierarchy of consciousness (coma, delirium, normal) and CAPD scores are associated with brain injury marker levels. Using pediatric delirium assessment tools for monitoring brain injury, especially eye contact, is a reliable method for observing PD.

Endogenous and exogenous protection from surgically induced reactive oxygen and nitrogen species.

Surgical intervention creates reactive oxygen species through diverse molecular mechanisms, including direct stimulation of immune-mediated inflammation necessary for wound healing. However, dysregulation of redox homeostasis in surgical patients overwhelms the endogenous defense system, slowing the healing process and damaging organs. We broadly surveyed reactive oxygen species that result from surgical interventions and the endogenous and/or exogenous antioxidants that control them. This study assimilates current reports on surgical sources of reactive oxygen and nitrogen species along with literature reports on the effects of endogenous and exogenous antioxidants in human, animal, and clinical settings. Although exogenous antioxidants are generally beneficial, endogenous antioxidant systems account for over 80% of total activity, varying based on patient age, sex, and health or co-morbidity status, especially in smokers, the diabetic, and the obese. Supplementation of exogenous compounds for support in surgical patients is thus theoretically beneficial, but a lack of persuasive clinical evidence has left this potential patient support strategy without clear guidelines. A more thorough understanding of the mechanisms of exogenous antioxidants in patients with compromised health statuses and pharmacokinetic profiling may increase the utility of such support in both the operating and recovery rooms.

Factors of Obesity and Metabolically Healthy Obesity in Asia.

The East Asian region (China, Japan, and South Korea) is comprised of almost 1.5 billion people and recent industrialization has brought with it a pandemic of rising obesity, even in children. As these countries are rapidly aging and functioning at sub-replacement birthrates, the burgeoning costs of obesity-related care may threaten socialized healthcare systems and quality of life. However, a condition called metabolically healthy obesity (MHO) has been found to be without immediate cardiopulmonary or diabetic risk. Thus, maintenance of the MHO condition for the obese in East Asia could buffer the burden of long-term obesity care on medical systems and knowledge of the biochemical, genetic, and physiological milieu associated with it could also provide new targets for intervention. Diverse physiological, psychological, environmental, and social factors play a role in obesogenesis and the transition of MHO to a metabolically unhealthy obesity. This review will give a broad survey of the various causes of obesity and MHO, with special emphasis on the East Asian population and studies from that region.

Transformed extracellular vesicles with high angiogenic ability as therapeutics of distal ischemic tissues.

Introduction: The therapeutic effects of endothelial progenitor cells (EPC) in neovascularization have been suggested; however, to date, few studies have been conducted on the ability of EPC-derived extracellular vesicles (EV) to rescue the ischemic tissues. In order to examine the functional sources of EV for cell-free therapy of ischemic diseases, we compared the functions of EPC-EV and those of Wharton's Jelly-derived mesenchymal stem cell (WJ-EV) in the flap mouse model. Results and conclusion: Our results demonstrated that in the intravenous injection, EPC-EV, but not WJ-EV, were uptaken by the ischemic tissues. However, EPC-EV showed poor abilities to induce neovascularization and the recovery of ischemic tissues. In addition, compared to EPC-EV, WJ-EV showed a higher ability to rescue the ischemic injury when being locally injected into the mice. In order to induce the secretion of high-functional EPC-EV, EPC were internalized with hypoxic pre-treated WJ-EV, which resulted in a transformed hwEPC. In comparison to EPC, hwEPC showed induced proliferation and upregulation of angiogenic genes and miRNAs and promoted angiogenic ability. Interestingly, hwEPC produced a modified EV (hwEPC-EV) that highly expressed miRNAs related to angiogenesis, such as miR-155, miR-183, and miR-296. Moreover, hwEPC-EV significantly induced the neovascularization of the ischemic tissues which were involved in promoting the proliferation, the expression of VEGF and miR-183, and the angiogenic functions of endothelial cells. Of note, hwEPC-EV were highly uptaken by the ischemic tissues and showed a greater effect with regard to inducing recovery from ischemic injury in the intravenous administration, compared to EPC-EV. Therefore, hwEPC-EV can be considered a functional candidate for cell-free therapy to treat the distal ischemic tissues.