Severe liver injury and clinical characteristics of occupational exposure to 2-amino-5-chloro-N,3-dimethylbenzamide: A case series.

BACKGROUND: The 2-amino-5-chloro-N,3-dimethylbenzamide is a key intermediate in the synthesis of pesticides and pharmaceuticals. However, no literature currently exists on 2-amino-5-chloro-N,3-dimethylbenzamide poisoning in humans. This study aimed to reveal the health hazard of this chemical for humans and summarize the clinical characteristics of patients with occupational 2-amino-5-chloro-N,3-dimethylbenzamide poisoning. METHODS: This observational study included four patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning from June 2022 to July 2022. The entire course of the incidents was described in detail. Blood 2-amino-5-chloro-N,3-dimethylbenzamide concentrations were detected by a mass spectrometer. Hematoxylin and eosin staining was performed to assess liver injury, and immunofluorescence was used to evaluate hepatic mitophagy. RESULTS: The 2-amino-5-chloro-N,3-dimethylbenzamide powder (99% purity) entered the human body mainly via the skin and respiratory tract due to poor personal protective measures. The typical course of 2-amino-5-chloro-N,3-dimethylbenzamide poisoning was divided into latency, rash, fever, organic damage, and recovery phases in accordance with the clinical evolution. Rash and fever may be the important premonitory symptoms for further organ injuries. The chemical was detected in the blood of all patients and caused multiple organ injuries, predominantly liver injury, including kidney, myocardium, and microcirculation. Three patients recovered smoothly after comprehensive treatments, including artificial liver therapy, continuous renal replacement therapy, glucocorticoids, and other symptomatic and supportive treatments. One patient survived by liver transplantation. The postoperative pathological findings of the removed liver showed acute liver failure, and immunofluorescence staining confirmed the abundance of mitophagy in residual hepatocytes. CONCLUSIONS: This study is the first to elaborate the clinical characteristics of patients with 2-amino-5-chloro-N,3-dimethylbenzamide poisoning. The chemical enters the body through the respiratory tract and skin during industrial production. The 2-amino-5-chloro-N,3-dimethylbenzamide poisoning causes multiple-organ dysfunction with a predominance of liver injury. Liver transplantation may be an effective option for patients with severe liver failure. The mechanisms of liver injury induced by 2-amino-5-chloro-N,3-dimethylbenzamide might involve abnormal mitochondrial function and mitophagy.

Hypoxic bone marrow mesenchymal stem cell-derived exosomal lncRNA XIST attenuates lipopolysaccharide-induced acute lung injury via the miR-455-3p/Claudin-4 axis.

Mesenchymal stem cell-derived exosomes and long non-coding RNAs (lncRNAs) have been identified to play a role in acute lung injury (ALI). In this study, we investigated whether exosomal lncRNAs could regulate ALI and the underlying mechanisms. Bone marrow mesenchymal stem cells (BM-MSCs) were pretreated with hypoxia or normoxia, and exosomes were subsequently extracted from normoxic BM-MSCs (Nor-exos) and hypoxic BM-MSCs (Hypo-exos). A rat model of ALI was established via an airway perfusion of lipopolysaccharide (LPS). Exosomes were administered via the tail vein to evaluate the in vivo effect of exosomes in ALI. LPS-exposed RLE-6TN cells were incubated with exosomes to explore their in vitro effect in ALI. A luciferase reporter assay was used to evaluate the interaction between lncRNA XIST and miR-455-3p, as well as miR-455-3p and Claudin-4. We found that the exosomes attenuated LPS-induced ALI and Hypo-Exos exerted a greater therapeutic effect compared with Nor-exos both in vitro and in vivo. Moreover, an abundance of lncRNA XIST was observed in Hypo-exos compared with Nor-exos. Mechanistically, LncRNA XIST functioned as a miR-455-3p sponge and targeted Claudin-4 in ALI. Our results provide novel insight into the role of exosomal lncRNA XIST for the treatment of ALI. Thus, hypoxic pretreatment may represent an effective method for improving the therapeutic effects of exosomes.

Inflammatory granuloma of the trachea: a rare case with Epstin-Barr virus infection. / 气管炎性肉芽肿： 1例罕见的EBç— æ¯’æ„ŸæŸ“çš„EBç— æ¯’æ„ŸæŸ“.

Epstein-Barr virus (EBV), a double-stranded DNA virus with an envelope, is a ubiquitous pathogen that is prevalent in humans, although most people who contract it do not develop symptoms (Kerr, 2019). While the primary cells EBV attacks are epithelial cells and B lymphocytes, its target range expands to a variety of cell types in immunodeficient hosts. Serological change occurs in 90% of infected patients. Therefore, immunoglobulin M (IgM) and IgG, serologically reactive to viral capsid antigens, are reliable biomarkers for the detection of acute and chronic EBV infections (Cohen, 2000). Symptoms of EBV infection vary according to age and immune status. Young patients with primary infection may present with infectious mononucleosis; there is a typical triad of symptoms including fever, angina, and lymphadenectasis (Houen and Trier, 2021). In immunocompromised patients, response after EBV infection may be atypical, with unexplained fever. The nucleic acid of EBV can be detected to confirm whether high-risk patients are infected (Smets et al., 2000). EBV is also associated with the occurrence of certain tumors (such as lymphoma and nasopharyngeal carcinoma) because it transforms host cells (Shannon-Lowe et al., 2017; Tsao et al., 2017).

Tripterygium wilfordii Hook.f. ameliorates paraquat-induced lung injury by reducing oxidative stress and ferroptosis via Nrf2/HO-1 pathway.

Paraquat (PQ) poisoning can induce acute lung injury and fibrosis and has an extremely high mortality rate. However, no effective treatments for PQ poisoning have been established. In this study, the potential efficacy of Tripterygium wilfordii Hook.f. (TwHF) in alleviating PQ-induced lung injury and fibrosis was investigated in a mouse model. Mice were randomly assigned to the control, PQ, PQ + TwHF1 (pretreatment before inducing poisoning), and PQ + TwHF2 (treatment after poisoning) groups. The mice in the PQ + TwHF1 group were pretreated with TwHF for 5 days before receiving one dose of PQ (120 mg/kg) and then received a daily oral gavage of the indicated dosages of TwHF until sacrifice. The mice in the PQ + TwHF2 group were treated with TwHF 2 h after PQ exposure until sacrifice. The pathological analysis and Fapi PET/CT showed that treatment with TwHF attenuated lung injury. And TwHF reduced pulmonary oxidative stress, as indicated by the reduction in, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels, as well as by the increase in superoxide dismutase (SOD) levels. Accordingly, the Perls DAB staining showed increased iron concentrations and western blotting revealed a decreased GPX4 expression after PQ exposure, as well as the mitigation of the overexpression of Nrf2 and HO-1 induced by PQ. In conclusion, our study demonstrated the potential of TwHF as a treatment for PQ-induced lung injury and fibrosis. The protective mechanism of this medicinal herb may involve the regulation of ferroptosis.

Upregulation of claudin­4 by Chinese traditional medicine Shenfu attenuates lung tissue damage by acute lung injury aggravated by acute gastrointestinal injury.

CONTEXT: Many studies have explored new methods to cure acute lung injury (ALI); however, none of those methods could significantly change the high mortality rate of ALI. Shenfu is a Chinese traditional medicine that might be effective against ALI. OBJECTIVE: Our study explores the therapeutic potential of Shenfu in ALI. MATERIALS AND METHODS: Male C57BL/6 mice were assigned to control, lipopolysaccharide (LPS) (500 µg/100 µL per mouse), and LPS + Shenfu (30 mL/kg) groups. Shenfu (10 µL/mL) was added to LPS (10 µg/mL) treated MLE-12 cells for 48 h in vitro. Male C57BL/6 mice were divided into four groups: LPS, LPS + 3% dextran sulphate sodium (DSS), 3% DSS + Shenfu, and LPS + 3% DSS + Shenfu. RESULTS: Compared with the ALI group, Shenfu reduced wet/dry weight ratio (19.8%, 36.2%), and reduced the IL-2 (40.9%, 61.6%), IFN-γ (43.5%, 53.3%) TNF-α (54.1%, 42.1%), IL-6 (54.8%,70%), and IL-1ß (39.9%, 65.1%), reduced serum uric acid (18.8%, 48.7%) and creatinine (17.4%, 41.1%). Moreover, Shenfu enhanced cell viability (17.2%, 59.9%) and inhibited cell apoptosis (63.0%) and p38/ERK phosphorylation in in vitro cultured epithelial cells with LPS stimulation. Mechanistically, Shenfu mediated the protective effect by upregulating claudin-4 expression. In addition, Shenfu could protect against both lung and intestinal epithelial damage in acute gastrointestinal injury-exacerbated ALI. DISCUSSION AND CONCLUSIONS: Taken together, the results revealed the therapeutic effect and the underlying mechanism of Shenfu injection in an ALI in mouse model, indicating its clinical potential to treat patients with ALI.

Adult patients with allied disorders of Hirschsprung's disease in emergency department: An 11-year retrospective study.

BACKGROUND: In the past years, only a few studies with a limited number of adult patients analyzed clinical features of allied disorders of Hirschsprung's disease (ADHD), most of which were individual case reports or lacked detailed clinical information. Although many studies have reported patients presenting to the emergency department (ED) with recurrent abdominal symptoms for a number of disorders, there are few data involving ADHD. However, owing to a lack of awareness of the disease, misdiagnoses and mistreatments are common. Severe complications such as perforation, bleeding, malabsorption, and even death in ADHD had been reported by many studies. AIM: To assist ED clinicians in having a more comprehensive understanding of this disease and making an early suspected diagnosis of ADHD more effectively. METHODS: We enrolled 53 patients who visited the ED and were eventually diagnosed with ADHD over the past 11 years in our hospital. Their basic information, clinical manifestations, and imaging findings were analyzed. Blood indices were compared between the ADHD and irritable bowel syndrome (IBS) groups. RESULTS: Adult patients with ADHD had a mean age of 48.8 ± 14.3 years, and 77.4% had been treated before admission. The transverse colon was the most common dilated part (73.6%), and constipation (67.9%) was the most common symptom. ADHD patients can present with uncommon symptoms and false-negative imaging findings. Logistic regression analysis indicated that body mass index (BMI) [odds ratio (OR) = 0.786, P = 0.013], cholinesterase (per 1000 units; OR = 0.693, P = 0.008), and blood chlorine (OR = 0.816, P = 0.022) were determined to be independent related factors between the ADHD and IBS groups. The area under the receiver operating characteristics curve of these three indices combined was 0.812 (P < 0.001). CONCLUSION: Emergency physicians should be vigilant regarding patients with chronic constipation, abdominal pain, or abdominal distension, and consider the possibility of ADHD despite its rarity. Abdominal computed tomography examination is recommended as a useful tool in the suspected diagnosis of ADHD. BMI, cholinesterase, and blood chlorine have good discriminative abilities between ADHD and IBS. The nutritional status of adult patients with ADHD is worthy of further attention. Surgical treatment for adult patients with ADHD is important and inevitable.

Cadmium induces ferroptosis mediated inflammation by activating Gpx4/Ager/p65 axis in pancreatic ß-cells.

Cadmium (Cd) is a widely distributed endocrine disruptor and has been reported to be closely correlated to the pathogenesis of diabetes. Since pancreatic ß-cells loss and dysfunction are central to pathogenesis of diabetes, studying Cd toxicity on pancreatic ß-cells and its molecular mechanism is an important scientific issue. However, less attention has been payed to study how Cd induces pancreatic ß-cells death and dysfunction in recent years. Thus, our study aims to explore the toxic mechanism of Cd treatment on pancreatic ß-cells using both cellular and animal models. Firstly, it was confirmed that Cd induced decreased cell viability and insulin secretion in a dose-and time-dependent manner in MIN6 cells. To explore the underlying mechanism, transcriptomic analysis was employed to screen the differentially expressed genes and disturbed metabolic pathways. Go and KEGG analysis showed that Cd exposure triggered ferroptosis process in MIN6 cells. We further validated that Cd led to GSH depletion, Gpx4 reduction, lipid peroxidation, mitochondrial membrane potential loss and ultrastructural damage at mitochondrial level. Since immune system process was also perturbed based on GO analysis, we found that Cd activated Ager/Pkc/p65 inflammatory process. Moreover, ferroptosis inhibitor Fer-1 could effectively antagonized the activation of Ager-mediated immune process. It was also revealed that Cd induced iron accumulation as well as decreased Gpx4 expression in mice islets. We also uncovered that Cd led to systemic and pancreatic inflammation as early as third week after Cd exposure. Our study emphasizes the importance of ferroptotic cell death on Cd-induced systemic chronic inflammation. A novel target is provided to prevent Cd-induced pancreatic ß-cells dysfunction and improve the chronic inflammatory state for prediabetes prevention.

Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells.

Ferroptosis is a form of programmed cell death that was only recognized in 2012. Until recently, numerous researchers have turned their attention to the mechanism and function of ferroptosis. A large number of studies have shown potential links between cell ferroptosis and infection, inflammation, and tumor. At the same time, immune cells are vital players in these above-mentioned processes. To date, there is no comprehensive literature review to summarize the relationship between ferroptosis and immune cells. Therefore, it is of great significance to explore the functional relationship between the two. This review will attempt to explain the link between ferroptosis and various immune cells, as well as determine the role ferroptosis plays in infection, inflammation, and malignancies. From this, we may find the potential therapeutic targets of these diseases.

Cadmium perturbed metabolomic signature in pancreatic beta cells correlates with disturbed metabolite profile in human urine.

Cd exposure has been demonstrated to induce a variety of metabolic disorders accompanied with imbalance of glucose and lipid homeostasis. The metabolic toxicity of Cd exposure at metabolome-wide level remains elusive. In our study, we demonstrated that Cd exposure via drinking water increased blood glucose levels, decreased serum insulin levels, led to glucose intolerance and suppressed insulin expression in the pancreas of C57/6J mice. Cd exposure significantly inhibited cell viability and suppressed insulin secretion in MIN6 cells in vitro. Since pancreatic ß-cells are the only source of insulin production in the body and play a pivotal role in modulating glucose and lipid metabolisms, we further delineated the metabolomic signatures of Cd exposure in insulin-secreting MIN6 cells by using non-target metabolomics. PCA and OPLS-DA analysis clearly suggested that Cd exposure led to a marked metabolic alteration in MIN6 cells. 76 perturbed metabolites were identified after Cd exposure. Classification of metabolites suggested that Cd perturbed metabolites belong to nucleosides, nucleotides and analogues, organic acids and derivatives, and lipids and lipid-like molecules. 28 perturbed metabolites existed in mitochondrion, suggesting mitochondrion as the major target organelle in metabolic toxicity of Cd exposure. KEGG pathway analysis revealed that 20 metabolic pathways were disturbed by Cd exposure. Mitochondrial TCA cycle and glycerophospholipid metabolism were remarkably disturbed. The mRNA expressions of genes in mitochondrial TCA cycle and fatty acid oxidation in pancreas and MIN6 cells were significantly dysregulated by Cd exposure. Disturbances in mitochondrial TCA cycle and glycerophospholipid metabolism result in producing perturbed metabolites in pancreatic ß-cells. Moreover, 14 perturbed metabolites identified in MIN6 cells co-existed in the urine of Cd exposed workers. 11 biomarkers of diabetes mellitus were also found to be significantly altered in the urine of Cd exposed workers. In conclusion, findings of this study greatly extend our understanding of metabolic toxicity of Cd exposure in pancreatic ß-cells at metabolome-wide level and offer some new clues for linking Cd exposure to development of diabetes mellitus. Results of this study also support the notion that Cd induced metabolic toxicity could be monitored by examining perturbed urinary metabolites in humans and highlight the significance of reducing Cd exposure via drinking water at population level.

Cadmium exposure suppresses insulin secretion through mtROS-mediated mitochondrial dysfunction and inflammatory response in pancreatic beta cells.

BACKGROUND: Cadmium (Cd) exposure is a worldwide environmental threat to the public health and participates in the pathogenesis of multiple diseases. Epidemiologic research have established a direct relation between Cd exposure and diabetes development in humans. Although pancreatic ß-cell dysfunction has been considered as the major culprit in the pathogenesis of diabetes, there is a paucity of studies to elucidate the molecular mechanism of Cd toxicity on ß-cells. METHODS: To unveil the toxic effect and its underlying mechanism of Cd exposure on ß-cells, we used an in vitro MIN6 cell model of environment-relevant Cd exposure to elucidate the crucial role of mtROS-mediated mitochondrial dysfunction and inflammatory response in suppression of pancreatic ß-cell insulin secretion. RESULTS: We uncovered that Cd treatment suppresses cell viability and induces insulin secretion dysfunction in a dose-dependent manner. Moreover, Cd exposure elicits the inflammatory response, as indicated by increased IL-1ß, IL-6 and TNF-α expressions. Significant elevations of intracellular ROS and mitochondrial ROS levels were detected as early as 3 h after Cd treatment. In mitochondrial function analysis, we demonstrated that Cd treatment induced mitochondrial dysfunction and disorder of mitochondrial fission indicated by the significant decline in ATP production, the marked depolarization of mitochondrial membrane potential, the decrease in mtDNA copy numbers, the suppressions of mitochondrial transcription factor A (Tfam) and mitochondrial fission-related gene Drp1 expressions. Pretreatment with TEMPO, a specific mitochondrial ROS (mtROS) scavenger, efficiently antagonizes Cd cytotoxicity, which is indicated by attenuating Cd-induced mitochondrial dysfunction, suppressing IL-1ß, IL-6 and TNF-α expressions, ameliorating insulin production dysfunction and preserving cell viability in MIN6 cells. CONCLUSION: Our study demonstrates that Cd exposure induces an inflammatory response through mtROS-mediated mitochondrial dysfunction. Antagonism of mtROS production might be an effective strategy to prevent pancreatic toxicity from environment-relevant Cd exposure.

Cadmium exposure impairs pancreatic ß-cell function and exaggerates diabetes by disrupting lipid metabolism.

Cadmium is known as an environmental pollutant that contributes to pancreatic damage and the pathogenesis of diabetes. However, less attention has been devoted to elucidating the mechanisms underlying Cd-induced pancreatic ß-cell dysfunction and the role of Cd toxicity in the development of diabetes. In this study, we demonstrated that exposure to Cd caused remarkable pancreatic ß-cell dysfunction and death, both in vitro and in vivo. Lipidomic analysis of Cd-exposed pancreatic ß-cells using high-resolution mass spectrometry revealed that Cd exposure altered the profile and abundance of lipids. Cd exposure induced intracellular lipid accumulation, promoted lipid biogenesis, elevated pro-inflammatory lipid contents and inhibited lipid degradation. Furthermore, Cd exposure upregulated the expression levels of TNF-α, IL-1ß and IL-6 in pancreatic ß-cells and elevated the TNF-α, IL1-ß and IL-6 levels in the serum and pancreas. Taken together, the results of our study demonstrated that environmental relevant Cd exposure causes pro-inflammatory lipids elevation and insulin secretion dysfunction in ß-cells and hence exaggerates diabetes development. Combined exposure to environmental hazardous chemicals might markedly increase the probability of developing diabetes in humans. This study provides new metabolic and pharmacological targets for antagonizing Cd toxicity.

Role of routine check-up in the prognosis of patients with pancreatic cancer: A puzzling phenomenon.

BACKGROUND: The high coverage of annual routine health check-up in China is a unique phenomenon throughout the world. However, its clinical value is controversial. In this cohort study, we chose pancreatic cancer as a disease model to explore the role of routine check-up in the prognosis of patients with pancreatic cancer. METHODS: Data from 157 patients who were diagnosed with pancreatic cancer between January 2010 and April 2014 were collected. Patients were divided into two groups depending on how their disease was detected. Group A (n = 85): Patients were diagnosed with pancreatic cancer in clinic visits. Group B (n = 72): Patients were diagnosed with pancreatic cancer in routine check-ups. We compared their prognosis. RESULTS: The tumor stage in group B was earlier than that in group A. The 1-year survival rate in group B was significantly higher than that in group A (74.6% vs. 42.4%, P < 0.001), while the 3- and 5-year survival rates of the two groups showed no significant difference (P > 0.05). The difference of overall survival time between the two groups was not significant (22.0 vs. 9.0 months, P = 0.078). CONCLUSIONS: The stage of pancreatic cancer diagnosed in routine check-ups was earlier and therefore, the intervention was earlier which improved short-term survival rate. However, early intervention did not improve overall survival in the long-term.

Early Activation of Myeloid-Derived Suppressor Cells Participate in Sepsis-Induced Immune Suppression via PD-L1/PD-1 Axis.

Background: Myeloid derived suppressor cells (MDSCs) have been reported to keep elevating during sepsis. The current study was performed to investigate the immunosuppressive effect of MDSCs and their subsets with the underlying mechanisms. Methods: The immunosuppressive status was manifested by the apoptosis of splenocytes, quantity of T cells and PD-1 expression. The dynamics of quantity and PD-L1 level of MDSCs and the subsets were determined over time. The subset of MDSCs with high PD-L1 level was co-cultured with T cells to observe the suppressive effect. Results: Abdominal abscess was observed after 7 days post-sepsis. Five biomarkers related to organ functions were all significantly higher in the CLP group. The survival rate was consistent with the middle grade severity of sepsis model. Apoptosis of splenocytes increased over time during sepsis; CD4 + T cell decreased from day 1 post-sepsis; CD8+ T cells significantly reduced at day 7. The PD-1 expression in spleen was upregulated from an early stage of sepsis, and negatively related with the quantity of T cells. MDSCs were low at day 1 post-sepsis, but increased to a high level later; the dynamics of PMN-MDSC was similar to MDSCs. PD-L1 on MDSCs was highest at day 1 post-sepsis; PMN-MDSC was the main subset expressing PD-L1. The PMN-MDSC with high PD-L1 expression level extracted on day 1 after surgery from CLP mice significantly inhibited the proliferation of T cells. Conclusions: Sepsis-induced immunosuppression is initiated from a very early stage, a high expression level of PD-L1 on MDSCs and the main subset, PMN-MDSC might play a critical role suppressive role on T cells through PD-L1/PD-1 axis.

The life-saving emergency thoracic endovascular aorta repair management on suspected aortoesophageal foreign body injury.

BACKGROUND: Fatal aortic rupture caused by esophageal foreign body (EFB), is associated with a high mortality, but can be prevented by thoracic endovascular aorta repair (TEVAR) that performed increasingly as technology improves. This study aims to investigate the cause, management and prognosis of suspected penetrating aortoesophageal foreign body injury. METHODS: Twelve cases who met the criteria were enrolled in this study. The demographic and clinical data were reviewed for evaluating the characteristics of EFB. RESULTS: Among 12 cases enrolled, 7 were males and 5 were females, with an age 27-86 years. The distance of EFB from aorta (DFA) of 7 cases were less than or equal to 0 mm, 5 cases were 0-2 mm. Eleven cases were managed with TEVAR, only one case was with open surgery standby but finally treated by flexible endoscopy (FE) successfully, without TEVAR. In group with TEVAR, EFB of 7 cases were successfully removed by rigid endoscopy (RE), and one of them was failed at the first RE treatment. EFB of 2 cases were successfully removed by open surgery with TEVAR, and other 9 cases were managed by endoscopies with TEVAR. The mean length of stay of hospitalization (LOS) and length of ICU stay of patients treated by open surgery with TEVAR (18.50±2.12 days and 5.50±0.71 days) was significantly longer than those of patients treated by endoscopy with TEVAR (7.00±2.74 days and 1.33±1.12 days, P<0.001 and P=0.001, respectively). Five cases had severe complications. CONCLUSION: Rational application of TEVAR can be a life-saving management for aortoesophageal foreign body injury, and jointed with endoscopy is safe and effective with a shorter length of ICU or total hospital stay.

Retrospective observational analysis of esophageal foreign bodies: a novel characterization based on shape.

This single-center retrospective study aims to investigate the clinical features of esophageal foreign bodies (EFBs) and determine the influence of EFB shapes on management and prognosis. A total of 427 patients aged 13 to 95 years with suspected EFB ingestion were enrolled between January 2013 and June 2018, 183 of whom were male. EFBs were divided into six shapes: pin (n = 161), sheet (n = 97), trident (n = 51), spindle (n = 66), irregular (n = 46), and sphere (n = 6). Spindle-shaped EFBs correlated with a significantly higher rate of perforation and severe complications (P < 0.001 and P = 0.021, respectively) than any other EFB shape, while sheet-shaped EFBs were linked to less severe complications (P = 0.006). The number of pressure points was provided to stratify the risk of poor prognosis for each shape. EFBs with only two pressure points (pin and spindle EFBs) required more advanced management strategies and were correlated with a higher number of patients suffering esophageal perforation (27.11%) and severe complications (12.44%) when compared with other shapes (χ2 = 11.149 and P = 0.001; χ2 = 5.901 and P = 0.015, respectively). Spindle shape was an independent risk factor for poor prognosis, and contributed a more clinical risk than the pin shape. In conclusion, clinical features, management, perforation rate, and severe complications differed based on EFB shape. The EFBs with two pressure points, especially the spindle-shaped EFBs, were more dangerous compared with those with more pressure points.

Multiorgan Drug Action of Levosimendan in Critical Illnesses.

Cardiotonic drugs mainly include digitalis, catecholamines, phosphodiesterase inhibitors, and calcium sensitizers, which have been successively discovered and applied in clinical practice. However, there are only a few new drugs available in this field, and the selection is very limited. Digitalis, catecholamines, and phosphodiesterase inhibitors increase myocardial contractility by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP) and Ca2+, and this increase in intracellular calcium ion concentration enhances myocardial oxygen consumption and causes arrhythmia. For these reasons, the research focus on positive inotropic agents has shifted from calcium mobilization to calcium sensitization. Intracellular calcium sensitizers are more effective and safer drugs because they do not increase the intracellular concentration of calcium ions. However, only three calcium sensitizers have been fully developed and used in the past three decades. One of these drugs, levosimendan, has multiple molecular targets and exerts its pharmacological effects by not only increasing myocardial contractility, but also enhancing respiratory muscle function and liver and kidney protection, and it is useful for patients with severe sepsis and septic shock. Recently, more than 60 randomized controlled clinical trials of levosimendan have been reported; however, these clinical trials have occasionally shown different findings. This article reviews the research progress of levosimendan in critical illnesses in recent years.

VEGF levels in plasma in relation to metabolic control, inflammation, and microvascular complications in type-2 diabetes: A cohort study.

The vascular endothelial growth factor (VEGF) level in human circulation may reflect the severity of endothelial dysfunction in patients with diabetes mellitus, which leads to diabetic microvascular complications.We determined plasma VEGF levels as well as metabolic control and inflammatory factors in 26 healthy subjects and 52 type-2 diabetes mellitus (T2DM) patients with or without diabetic microvascular complications. Pearson correlation coefficient was used to evaluate the associations among those indices.The results showed that VEGF levels in plasma were positively correlated with fasting blood glucose level, glycosylated hemoglobin (HbA1c) level, type 1 helper T cell (Th1) percentage, and Th1/Th2 ratio, while they were negatively correlated with regulatory T cell percentage. Multiple linear regression analysis showed that HbA1c and Th1/Th2 ratio were the independent predictors of VEGF levels in T2DM patients.Thus, in T2DM patients with poor glycemic control as well as an elevated Th1/Th2 cell ratio, more VEGF might be released.

Association between the vascular endothelial growth factor single nucleotide polymorphisms and diabetic retinopathy risk: A meta-analysis.

BACKGROUND: The aim of the present study was to reveal the relationship between vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) and susceptibility to diabetic retinopathy (DR). METHODS: A literature review was conducted (PubMed, Web of Science, Embase) to identify papers about VEGF SNPs and DR published up to 23 September 2015. The VEGF gene SNPs analyzed with regard to DR susceptibility were rs2010963 (G > C), rs833061 (T > C), rs699947 (C > A), rs3025039 (C > T) and rs1570360 (G > A). Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated, and meta-analyses were performed using fixed or random effects models. RESULTS: Sixteen studies were included in the meta-analysis. Significant associations between the rs3025039 (C > T) polymorphism and increased DR risk were found in the allele model (T/C; pooled OR 1.60, 95% CI 1.07-2.41, P = 0.02), homozygote model (TT/CC; pooled OR 2.08, 95% CI 1.29-3.35, P = 0.003), heterozygote model (TC/CC; pooled OR 1.68, 95% CI 1.04-2.72, P = 0.04), dominant model (TT+TC/CC; pooled OR 1.72, 95% CI 1.06-2.80, P = 0.03), and recessive model (TT/TC+CC; pooled OR 1.80, 95% CI 1.12-2.90, P = 0.02). For rs833061, a significant association between VEGF SNPs and DR was found only in the allele model (C/T; pooled OR 6.34, 95% CI 2.10-19.14, P = 0.001). CONCLUSIONS: The rs3025039 and rs833061 SNPs are most likely associated with an increased risk of DR. The T allele in rs3025039 and the C allele in rs833061 are associated with increased DR susceptibility.

Curcumin targets the TFEB-lysosome pathway for induction of autophagy.

Curcumin is a hydrophobic polyphenol derived from the herb Curcumalonga and its wide spectrum of pharmacological activities has been widely studied. It has been reported that Curcumin can induce autophagy through inhibition of the Akt-mTOR pathway. However, the effect of Curcumin on lysosome remains largely elusive. In this study, we first found that Curcumin treatment enhances autophagic flux in both human colon cancer HCT116 cells and mouse embryonic fibroblasts (MEFs). Moreover, Curcumin treatment promotes lysosomal function, evidenced by the increased lysosomal acidification and enzyme activity. Second, Curcumin is capable of suppressing the mammalian target of rapamycin (mTOR). Interestingly, Curcumin fails to inhibit mTOR and to activate lysosomal function in Tsc2-/-MEFs with constitutive activation of mTOR, indicating that Curcumin-mediated lysosomal activation is achieved via suppression of mTOR. Third, Curcumin treatment activates transcription factor EB (TFEB), a key nuclear transcription factor in control of autophagy and lysosome biogenesis and function, based on the following observations: (i) Curcumin directly binds to TFEB, (ii) Curcumin promotes TFEB nuclear translocation; and (iii) Curcumin increases transcriptional activity of TFEB. Finally, inhibition of autophagy and lysosome leads to more cell death in Curcumin-treated HCT116 cells, suggesting that autophagy and lysosomal activation serves as a cell survival mechanism to protect against Curcumin-mediated cell death. Taken together, data from our study provide a novel insight into the regulatory mechanisms of Curcumin on autophagy and lysosome, which may facilitate the development of Curcumin as a potential cancer therapeutic agent.