The role of extracellular vesicles in non-alcoholic steatohepatitis: Emerging mechanisms, potential therapeutics and biomarkers.

Non-alcoholic steatohepatitis (NASH), an emerging global healthcare problem, has become the leading cause of liver transplantation in recent decades. No effective therapies in the clinic have been proven due to the incomplete understanding of the pathogenesis of NASH, and further studies are expected to continue to delve into the mechanisms of NASH. Extracellular vesicles (EVs), which are small lipid membrane vesicles carrying proteins, microRNAs and other molecules, have been identified to play a vital role in cell-to-cell communication and are involved in the development and progression of various diseases. In recent years, there has been increasing interest in the role of EVs in NASH. Many studies have revealed that EVs mediate important pathological processes in NASH, and the role of EVs in NASH is distinct and variable depending on their origin cells and target cells. This review outlines the emerging mechanisms of EVs in the development of NASH and the preclinical evidence related to stem cell-derived EVs as a potential therapeutic strategy for NASH. Moreover, possible strategies involving EVs as clinical diagnostic, staging and prognostic biomarkers for NASH are summarized.

Biochar and zero-valent iron alleviated sulfamethoxazole and tetracycline co-stress on the long-term system performance of bioretention cells: Insights into microbial community, antibiotic resistance genes and functional genes.

Antibiotics and antibiotic resistance genes (ARGs), known as emerging contaminants, have raised widespread concern due to their potential environmental and human health risks. In this study, a conventional bioretention cell (C-BRC) and three modified bioretention cells with biochar (BC-BRC), microbial fuel cell coupled/biochar (EBC-BRC) and zero-valent iron/biochar (Fe/BC-BRC) were established and two antibiotics, namely sulfamethoxazole (SMX) and tetracycline (TC), were introduced into the systems in order to thoroughly investigate the co-stress associated with the long-term removal of pollutants, dynamics of microbial community, ARGs and functional genes in wastewater treatment. The results demonstrated that the SMX and TC co-stress significantly inhibited the removal of total nitrogen (TN) (C-BRC: 37.46%; BC-BRC: 41.64%; EBC-BRC: 55.60%) and total phosphorous (TP) (C-BRC: 53.11%; BC-BRC: 55.36%; EBC-BRC: 62.87%) in C-BRC, BC-BRC and EBC-BRC, respectively, while Fe/BC-BRC exhibited profoundly stable and high removal efficiencies (TN: 89.33%; TP: 98.36%). Remarkably, greater than 99% removals of SMX and TC were achieved in three modified BRCs compared with C-BRC (SMX: 30.86 %; TC: 59.29%). The decreasing absolute abundances of denitrifying bacteria and the low denitrification functional genes (nirK: 2.80 × 105-5.97 × 105 copies/g; nirS: 7.22 × 105-1.69 × 106 copies/g) were responsible for the lower TN removals in C-BRC, BC-BRC and EBC-BRC. The amendment of Fe/BC successfully detoxified SMX and TC to functional bacteria. Furthermore, the co-stress of antibiotics stimulated the propagation of ARGs (sulI, sulII, tetA and tetC) in substrates of all BRCs and only Fe/BC-BRC effectively reduced all the ARGs in effluent by an order of magnitude. The findings contribute to developing robust ecological wastewater treatment technologies to simultaneously remove nutrients and multiple antibiotics.

Stem Cell Transplantation in the Treatment of Type 1 Diabetes Mellitus: From Insulin Replacement to Beta-Cell Replacement.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that attacks pancreatic ß-cells, leading to the destruction of insulitis-related islet ß-cells. Islet ß-cell transplantation has been proven as a curative measure in T1DM. However, a logarithmic increase in the global population with diabetes, limited donor supply, and the need for lifelong immunosuppression restrict the widespread use of ß-cell transplantation. Numerous therapeutic approaches have been taken to search for substitutes of ß-cells, among which stem cell transplantation is one of the most promising alternatives. Stem cells have demonstrated the potential efficacy to treat T1DM by reconstitution of immunotolerance and preservation of islet ß-cell function in recent research. cGMP-grade stem cell products have been used in human clinical trials, showing that stem cell transplantation has beneficial effects on T1DM, with no obvious adverse reactions. To better achieve remission of T1DM by stem cell transplantation, in this work, we explain the progression of stem cell transplantation such as mesenchymal stem cells (MSCs), human embryonic stem cells (hESCs), and bone marrow hematopoietic stem cells (BM-HSCs) to restore the immunotolerance and preserve the islet ß-cell function of T1DM in recent years. This review article provides evidence of the clinical applications of stem cell therapy in the treatment of T1DM.

A systematic summary of survival and death signalling during the life of hair follicle stem cells.

Hair follicle stem cells (HFSCs) are among the most widely available resources and most frequently approved model systems used for studying adult stem cells. HFSCs are particularly useful because of their self-renewal and differentiation properties. Additionally, the cyclic growth of hair follicles is driven by HFSCs. There are high expectations for the use of HFSCs as favourable systems for studying the molecular mechanisms that contribute to HFSC identification and can be applied to hair loss therapy, such as the activation or regeneration of hair follicles, and to the generation of hair using a tissue-engineering strategy. A variety of molecules are involved in the networks that critically regulate the fate of HFSCs, such as factors in hair follicle growth and development (in the Wnt pathway, Sonic hedgehog pathway, Notch pathway, and BMP pathway), and that suppress apoptotic cues (the apoptosis pathway). Here, we review the life cycle, biomarkers and functions of HFSCs, concluding with a summary of the signalling pathways involved in HFSC fate for promoting better understanding of the pathophysiological changes in the HFSC niche. Importantly, we highlight the potential mechanisms underlying the therapeutic targets involved in pathways associated with the treatment of hair loss and other disorders of skin and hair, including alopecia, skin cancer, skin inflammation, and skin wound healing.

Enhanced removal of sulfamethoxazole and tetracycline in bioretention cells amended with activated carbon and zero-valent iron: System performance and microbial community.

Antibiotics, heavily used as medicine, enter the environment inevitably and raise concerns of the risk to the ecosystems. In this study, we explored the removal efficiency and mechanism of sulfamethoxazole (SMX) and tetracycline (TC) in activated carbon (AC) and AC-zero-valent iron amended bioretention cells (AC-BRC and AC-Fe-BRC) compared with a conventional bioretention cell (BRC). Moreover, the system performance of BRCs, the shifts of the microbial community, as well as the fate of corresponding antibiotic resistance genes (ARGs) were comprehensively investigated. The results showed that, exposed to antibiotics notwithstanding, AC-BRC and AC-Fe-BRC significantly outperformed BRC on total nitrogen (TN) removal (BRC: 70.36 ± 13.61%; AC-BRC: 91.43 ± 6.41%; AC-Fe-BRC: 83.44 ± 12.13%). Greater than 97% of the total phosphorous (TP) was removed in AC-Fe-BRC, remaining unimpacted despite of the selective pressure from SMX/TC. Excellent removals of antibiotics (above 99%) were achieved in AC-BRC and AC-Fe-BRC regardless of the types and initial concentrations (0.8 mg/L, 1.2 mg/L and 1.6 mg/L) of antibiotics, dwarfing the removal performance of BRC (12.2 ± 4.4%-64.2 ± 5.5%). The illumina high throughput sequencing analysis demonstrated the concomitant variations of microbial communities as SMX/TC was loaded. AC layers tended to alleviate the adverse effect of SMX/TC on microbial biodiversity. Proteobacteria (34.55-68.47%), Chloroflexi (7.13-33.54%), and Bacteroidetes (6.20-21.03%) were the top three dominant phyla in the anaerobic zone of the BRCs. The abundance of antibiotic resistance genes (ARGs) sulI, sulII and tetA genes were dramatically higher in AC-BRC and AC-Fe-BRC when exposed to 0.8 mg/L SMX/TC, which indicated that relatively low concentrations of SMX/TC induced the production of these three ARGs in the presence of AC. Although the amendment of AC led to highly efficient SMX/TC removals, further investigation is still required to improve the retention of ARGs in BRCs.

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications.

Stem cell-based therapy raises hopes for a better approach to promoting tissue repair and functional recovery. However, transplanted stem cells show a high death percentage, creating challenges to successful transplantation and prognosis. Thus, it is necessary to investigate the mechanisms underlying stem cell death, such as apoptotic cascade activation, excessive autophagy, inflammatory response, reactive oxygen species, excitotoxicity, and ischemia/hypoxia. Targeting the molecular pathways involved may be an efficient strategy to enhance stem cell viability and maximize transplantation success. Notably, a more complex network of cell death receives more attention than one crucial pathway in determining stem cell fate, highlighting the challenges in exploring mechanisms and therapeutic targets. In this review, we focus on programmed cell death in transplanted stem cells. We also discuss some promising strategies and challenges in promoting survival for further study.

Extracellular AMP Suppresses Endotoxemia-Induced Inflammation by Alleviating Neutrophil Activation.

Intracellular adenosine monophosphate (AMP) is indispensable for cellular metabolic processes, and it is interconverted to ADP and/or ATP or activates AMP-activated protein kinase (AMPK). However, the specific biological function of extracellular AMP has not been identified. We evaluated the effect of extracellular AMP using in vivo and in vitro models of endotoxemia. We found that AMP inhibited inflammation and neutrophil activation in lipopolysaccharide (LPS)-induced endotoxemic mice. The effects of extracellular AMP were abolished by an adenosine 1 receptor (A1R) antagonist but were not influenced by inhibiting the conversion of AMP to adenosine (ADO), indicating that AMP inhibited inflammation by directly activating A1R. In addition, in vitro experiments using LPS-stimulated mouse neutrophils showed that AMP inhibited LPS-induced reactive oxygen species (ROS) production, degranulation, and cytokine production, while the effects were reversed by an A1R antagonist. Further research showed that AMP regulated LPS-stimulated neutrophil functions by inhibiting the p38 MAPK pathway. These findings were also confirmed in primary neutrophils derived from healthy human blood. Moreover, we collected serum samples from septic patients. We found that AMP levels were increased compared with those of healthy volunteers and that AMP levels were negatively correlated with disease severity. Together, these data provide evidence that extracellular AMP acts on A1R to suppress endotoxemia-induced inflammation by inhibiting neutrophil overactivation and that the p38 MAPK signaling pathway is involved.

Evaluation of effectiveness of treatment paradigm for newly diagnosed type 2 diabetes patients in Chin: A nationwide prospective cohort study.

AIMS/INTRODUCTION: Data of nationwide glycemic control and hypoglycemic treatment patterns in newly diagnosed type 2 diabetes patients in China are absent. The aim of this study was to assess the evolution of treatment patterns for newly diagnosed type 2 diabetes patients and the clinical outcomes during 12-month follow up. MATERIALS AND METHODS: This is an observational prospective cohort study with 12 months of follow up. Patients with a diagnosis of type 2 diabetes for <6 months were enrolled. Glycated hemoglobin A1c (HbA1c) levels and hypoglycemic treatment patterns were collected at baseline and at every 3 months of follow up. RESULTS: A total of 79 hospitals were recruited, consisting of 5,770 participants. The mean HbA1c was 8.4 ± 2.5% at baseline, and decreased to 6.7 ± 1.2% at 12 months with 68.5% of patients achieving HbA1c <7%. At baseline, 44.6% of the patients were without hypoglycemic medications, 37.7% had oral hypoglycemic agents and 17.7% received insulin treatment. Determinants of change in HbA1c were treatment patterns, comorbidities, baseline characteristics such as obesity and smoking, regions, and tiers of hospitals. Associated factors with treatment alterations were time of follow up, treatment patterns, patient-reported reasons such as the economic factors and poor efficacy. CONCLUSIONS: In newly diagnosed type 2 diabetes patients, compared with patients without medications, patients with one oral hypoglycemic agent had higher possibilities of reaching glycemic control, whereas patients using insulin had lower possibilities of reaching the target. Factors associated with change in HbA1c and treatment alterations were also revealed.

The risk factors of glycemic control, blood pressure control, lipid control in Chinese patients with newly diagnosed type 2 diabetes _ A nationwide prospective cohort study.

Nationwide data on glycemic control, blood pressure (BP) control and lipid control in patients with newly diagnosed type 2 diabetes were vacant in China. The aim of this study was to assess the clinical outcomes for these patients. This is an observational prospective cohort study with 12 months of follow up. Patients with a diagnosis of type 2 diabetes less than 6 months were enrolled. Hemoglobin A1c (HbA1c) levels, BP levels and lipid levels were collected at baseline and the follow-ups. This study was registered at www.clinicaltrials.gov (NCT01525693). A total of 5770 participants from 79 hospitals across six geographic regions of China were recruited. After 12 months of treatment, 68.5% of these patients achieved HbA1c <7.0%; 83.7% reached BP <140/90 mmHg; 48.2% met low density lipoprotein cholesterol (LDL-c) <2.6 mmol/L; and 29.5% of patients reached the combined three therapeutic targets. Compared to those patients with baseline HbA1c <7.0%, patients with baseline HbA1c ≥7.0% had higher failure rate to reach glycemic control (relative risk (RR) = 2.04, p < 0.001), BP control (RR = 1.21, p < 0.001) and LDL-c control (RR = 1.11, p < 0.001). Obese patients had higher possibilities of failure in glucose control (RR = 1.05, p = 0.004), BP control (RR = 1.62, p < 0.001) and lipid control (RR = 1.09, p = 0.001) than patients with normal weight. The active smokers were more likely to fail in glycemic control than non-smokers (RR = 1.06, p = 0.002), and patients with physical activities were less likely to fail in lipid control than patients without exercises (RR = 0.93, p = 0.008). This study outlined the burdens of glycemic control, blood pressure control, lipid control in newly diagnosed type 2 diabetic patients in China, identified gaps in the quality of care and risk-factor control and revealed the factors influencing these gaps.

Simultaneously increased expression of glucocorticoid­induced tumor necrosis factor receptor and its ligand contributes to increased interleukin­5/13­producing group 2 innate lymphocytes in murine asthma.

Glucocorticoid­induced tumor necrosis factor receptor (GITR) is expressed at high levels on CD4+CD25+ regulatory T cells (Tregs). Following activation by its ligand (GITRL), GITR influences the activity of effector T cells and Tregs and participates in the development of numerous autoimmune and inflammatory diseases, including asthma. However, the GITR/GITRL expression level in lung tissue and its influence on group 2 innate lymphocytes (ILC2s) in asthma remains unclear. The present study detected the number of ILC2s and the expression levels of GITR and GITRL in the lung tissues of asthmatic mice by flow cytometry analysis, immunofluorescence staining and reverse transcription quantitative polymerase chain reaction. The results demonstrated that the number of ILC2s and the expression levels of ILC2­associated molecules (interleukin­33 receptor ST2, RAR related orphan receptor A and inducible T cell costimulator) were increased in the lung tissues of asthmatic mice. The upregulated ILC2s were accompanied by an increased number of GITR­positive cells in the spleen and lung tissues, and additionally an increased level of GITRL mRNA in lung tissue in asthma. In addition, increased mRNA expression levels of interleukin (IL)­5 and IL­13 were observed in the asthmatic lung, and there was a significant, positive correlation between the mRNA levels of GITR/GITRL and ILC2­associated molecules. Therefore, GITRL treatment may increase the number of ILC2s and/or GITR­positive cells in lung tissue. These results indicated that the activity of GITR­expressing ILC2s may be enhanced via interaction of GITRL and GITR, which may contribute to pathogenesis of asthma. These findings present potential therapeutic targets for the treatment of asthma.

IL-17B activated mesenchymal stem cells enhance proliferation and migration of gastric cancer cells.

Mesenchymal stem cells are important cells in tumor microenvironment. We have previously demonstrated that IL-17B/IL-17RB signal promoted progression of gastric cancer. In this study, we further explored the effect of IL-17B on mesenchymal stem cells in tumor microenvironment and its impact on the tumor progression. The results showed that IL-17B induced the expression of stemness-related genes Nanog, Sox2, and Oct4 in mesenchymal stem cells and enhanced its tumor-promoting effect. The supernatant from cultured mesenchymal stem cells after treating with exogenous rIL-17B promoted the proliferation and migration of MGC-803, therefor suggesting that rIL-17B might promote mesenchymal stem cells to produce soluble factors. In addition, rIL-17B also activated the NF-κΒ, STAT3, ß-catenin pathway in mesenchymal stem cells. Our data revealed a new mechanism that IL-17B enhanced the progression of gastric cancer by activating mesenchymal stem cells.

Prevalence of Obesity and Its Influence on Achievement of Cardiometabolic Therapeutic Goals in Chinese Type 2 Diabetes Patients: An Analysis of the Nationwide, Cross-Sectional 3B Study.

BACKGROUND: There are few data on the prevalence of obesity and its influence on achieving blood glucose, blood pressure, and blood lipid (3B) goals in Chinese type 2 diabetes outpatients. METHODS: Patient demographic data, anthropometric measurements, medications, and blood glucose and lipid profiles of 24,512 type 2 diabetes patients from a large, geographically diverse study (CCMR-3B) were analyzed. Using cut-points for body mass index (BMI) and waist circumference (WC) recommended by the Working Group on Obesity in China, overweight and obesity were defined as BMIs of 24-27.9 kg/m2 and ≥28.0 kg/m2. Central obesity was defined as a waist circumference ≥80 cm in women and ≥85 cm in men. The 3B therapeutic goals were HbA1c<7.0%, BP<140/90 mmHg and LDL-C<2.6 mmol/L. RESULTS: Overall, 43.0% of type 2 diabetes patients were overweight and 16.7% were obese; 13.3% of overweight and and 10.1% of obese patients achieved all the 3B target goals. Overweight or obese patients were less likely to achieve 3B goals than those with normal BMIs. More than a half the overweight or obese patients (69.6%) were centrally obese. Patients with abdominal obesity were less likely to achieve cardiometabolic targets than those without abdominal obesity. In multivariate logistic regression analysis, female, higher BMI and waist circumference, smoking, drinking, sedentary lifestyle, and longer diabetes duration were significantly correlated with failure to achieve 3B control goals. CONCLUSIONS: Obesity is highly prevalent and associated with poor 3B control in Chinese type 2 diabetes patients. In clinical practice, more attention and resources should focus on weight loss for such patients.

Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study.

BACKGROUND: The age of onset of type 2 diabetes is decreasing. Because non-Chinese patients with early-onset type 2 diabetes (defined here as diagnosis at <40 years) have increased risk of vascular complications, we investigated effects of early-onset versus late-onset type 2 diabetes on risk of non-fatal cardiovascular diseases in China. METHODS: We did a cross-sectional survey using data from the China National HbA1c Surveillance System (CNHSS), including 222,773 Chinese patients with type 2 diabetes in 630 hospitals from 106 cities in 30 provinces of China in 2012. We documented demographic information and clinical profiles. Non-fatal cardiovascular disease was defined as non-fatal coronary heart disease or non-fatal stroke. Prevalence of non-fatal cardiovascular diseases was standardised to the Chinese population in 2011. We did logistic regression analysis to obtain odds ratios (ORs) for the risk of cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Because the CNHSS did not contain patients on diet or lifestyle treatment alone, and did not capture information on smoking or lipid or antihypertensive treatment, we validated our findings in another dataset from a cross-sectional, multicentre observational study (the 3B study) of outpatients with type 2 diabetes to confirm that exclusion of patients with diet treatment only and non-adjustment for lipid-lowering and antihypertensive drugs did not introduce major biases in the main analysis. FINDINGS: Of 222,773 patients recruited from April 1, 2012, to June 30, 2012, 24,316 (11%) had non-fatal cardiovascular disease. Patients with early-onset diabetes had a higher age-adjusted prevalence of non-fatal cardiovascular disease than did patients with late-onset diabetes (11·1% vs 4·9%; p<0·0001). After adjustment for age and sex, patients with early-onset type 2 diabetes had higher risk of non-fatal cardiovascular disease than did those with late-onset type 2 diabetes (OR 1·91, 95% CI 1·81-2·02). Adjustment for duration of diabetes greatly attenuated the effect size for risk of non-fatal cardiovascular disease (1·13, 1·06-1·20). Results of the validation study showed that exclusion of patients with diet only and non-adjustment for lipid-lowering and antihypertensive drugs resulted in marginal changes in ORs for risk of non-fatal cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Early-onset type 2 diabetes remained associated with increased risk of cardiovascular disease, attributable to longer duration of diabetes. INTERPRETATION: Chinese patients with early-onset type 2 diabetes are at increased risk of non-fatal cardiovascular disease, mostly attributable to longer duration of diabetes. FUNDING: Novo Nordisk China (for the China National HbA1c Surveillance System [CNHSS]) and Merck Sharp & Dohme China (for the 3B study).

Primacy of the 3B approach to control risk factors for cardiovascular disease in type 2 diabetes patients.

BACKGROUND: Individually, diabetes mellitus, hypertension, and dyslipidemia have been shown to increase the risk of cardiovascular disease. While traditional management of Type 2 diabetes has focused mainly on glycemic control, robust evidence supports the integration of hypertension and dyslipidemia management to reduce the risk of cardiovascular disease. The primary objective of this study was to assess the level of control of blood glucose, blood pressure, and blood lipids (3Bs) among patients with type 2 diabetes. An additional objective was to investigate the impact of hospital type, physician specialty, treatment pattern, and patient profile on clinical outcomes. METHODS: This was a cross-sectional, multicenter observational study. A nationally representative sample of outpatients with established type 2 diabetes were enrolled at hospitals representative of geographic regions, tiers, and physician specialties in China. Main clinical measurements were the levels of glycosylated hemoglobin (HbA1c), blood pressure, and total serum cholesterol in reference to target goals. RESULTS: A total of 25,817 adults with type 2 diabetes (mean age 62.6 years, 47% male) were enrolled at 104 hospitals. Seventy-two percent reported comorbid hypertension, dyslipidemia, or both. Patients with concurrent type 2 diabetes, hypertension, and dyslipidemia were 6 times more likely to report a prior history of cardiovascular disease compared with those with type 2 diabetes alone. The mean HbA1c level was 7.6%. While 47.7%, 28.4%, and 36.1% of patients achieved the individual target goals for control of blood glucose (HbA1c <7%), blood pressure (systolic blood pressure <130 mm Hg, diastolic blood pressure <80 mm Hg), and blood lipids (total cholesterol <4.5 mmol/L), respectively, only 5.6% achieved all 3 target goals. Lower body mass index (<24 kg/m(2)), no active smoking or drinking, higher education, and diabetes duration <5 years were independent predictors of better cardiovascular disease risk control. CONCLUSION: Achieving adequate control of risk factors for cardiovascular disease in patients with type 2 diabetes remains a clinical challenge. Interventions to achieve control of 3Bs coupled with modification of additional cardiovascular disease predictors are crucial for optimization of clinical outcomes in patients with type 2 diabetes.