Brazilin Actuates Ferroptosis in Breast Cancer Cells via p53/SLC7A11/GPX4 Signaling Pathway.

OBJECTIVE: To investigate the mechanism of induction of ferroptosis by brazilin in breast cancer cells. METHODS: Breast cancer 4T1 cells were divided into 6 groups: control, brazilin 1/2 half maximal inhibitory concentration (IC50), IC50, 2×IC50, erastin (10 µg/mL) and capecitabine (10 µg/mL) groups. The effect of brazilin on the proliferation of 4T1 cells was detected by cell counting kit-8 assay, and the treatment dose of brazilin was screened. The effect of brazilin on the mitochondrial morphology of 4T1 cells, and the mitochondrial damage was evaluated under electron microscopy. The levels of Fe2+, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and glutathione peroxidase 4 (GPX4) were estimated using various detection kits. The invasion and migration abilities of 4T1 cells were detected by scratch assay and transwell assay. The expressions levels of tumor protein p53, solute carrier family 7 member 11 (SLC7A11), GPX4 and acyl-CoA synthetase long-chain family member 4 (ACSL4) proteins were quantified by Western blot assay. RESULTS: Compared to the control group, the 10 (1/2 IC50), 20 (IC50) and 40 (2×IC50) µg/mL brazilin, erastin, and capecitabine groups showed a significant decrease in the cell survival rate, invasion and migration abilities, GSH, SLC7A11 and GPX4 protein expression levels, and mitochondrial volume and ridge (P<0.05), and a significant increase in the mitochondria membrane density, Fe2+, ROS and MDA levels, and p53 and ACSL4 protein expression levels (P<0.05). CONCLUSIONS: Brazilin actuated ferroptosis in breast cancer cells, and the underlying mechanism is mainly associated with the p53/SLC7A11/GPX4 signaling pathway.

Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies.

Amidst the global healthcare landscape, the menace of snakebite envenoming (SBE) has persisted, silently afflicting millions and annually claiming tens of thousands of lives [...].

Type 2 diabetes mellitus in metabolic-associated fatty liver disease vs. type 2 diabetes mellitus non-alcoholic fatty liver disease: a longitudinal cohort analysis.

INTRODUCTION AND OBJECTIVES: Type 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of "metabolic associated fatty liver disease" (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM. MATERIALS AND METHODS: The current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events. RESULTS: 6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p < 0.001) and all-cause mortality (HR: 1.75, CI: 1.29 to 2.40, p < 0.001). CONCLUSIONS: The identification and treatment of NAFLD in patients with T2DM is a major concern and the premature change to MAFLD results in an over-diagnosis of fatty liver, exaggerated mortality, and morbidity in patients with T2DM. The definition of MAFLD causes further heterogeneity in fatty liver disease/NAFLD.

Differential proteomic analysis of children infected with respiratory syncytial virus.

Respiratory syncytial virus (RSV) infection is the main cause of lower respiratory tract infection in children. However, there is no effective treatment for RSV infection. Here, we aimed to identify potential biomarkers to aid in the treatment of RSV infection. Children in the acute and convalescence phases of RSV infection were recruited and proteomic analysis was performed to identify differentially expressed proteins (DEPs). Subsequently, promising candidate proteins were determined by functional enrichment and protein-protein interaction network analysis, and underwent further validation by western blot both in clinical and mouse model samples. Among the 79 DEPs identified in RSV patient samples, 4 proteins (BPGM, TPI1, PRDX2, and CFL1) were confirmed to be significantly upregulated during RSV infection. Functional analysis showed that BPGM and TPI1 were mainly involved in glycolysis, indicating an association between RSV infection and the glycolysis metabolic pathway. Our findings provide insights into the proteomic profile during RSV infection and indicated that BPGM, TPI1, PRDX2, and CFL1 may be potential therapeutic biomarkers or targets for the treatment of RSV infection.

Differential proteomic analysis of children infected with respiratory syncytial virus

Respiratory syncytial virus (RSV) infection is the main cause of lower respiratory tract infection in children. However, there is no effective treatment for RSV infection. Here, we aimed to identify potential biomarkers to aid in the treatment of RSV infection. Children in the acute and convalescence phases of RSV infection were recruited and proteomic analysis was performed to identify differentially expressed proteins (DEPs). Subsequently, promising candidate proteins were determined by functional enrichment and protein-protein interaction network analysis, and underwent further validation by western blot both in clinical and mouse model samples. Among the 79 DEPs identified in RSV patient samples, 4 proteins (BPGM, TPI1, PRDX2, and CFL1) were confirmed to be significantly upregulated during RSV infection. Functional analysis showed that BPGM and TPI1 were mainly involved in glycolysis, indicating an association between RSV infection and the glycolysis metabolic pathway. Our findings provide insights into the proteomic profile during RSV infection and indicated that BPGM, TPI1, PRDX2, and CFL1 may be potential therapeutic biomarkers or targets for the treatment of RSV infection.

Henoch-Schönlein purpura nephritis associated with monoclonal gammopathy of renal significance: a case report.

Monoclonal gammopathy of renal significance (MGRS) can present with different morphologic features and lead to kidney failure. The Henoch-Schönlein purpura nephritis (HSPN) that cannot be relieved by treatment with glucocorticoid and immunosuppressive agents suggests the presence of monoclonal gammopathy in adult patients. The present study reports on a single case of HSPN associated with IgA-κMGRS. The patient who suffered from recurrent skin purpura for 6 months and nephrotic syndrome for 2 months was admitted to our hospital. Bone marrow biopsy showed monoclonal gammopathy of undetermined significance. Kidney biopsy indicated a Henoch-Schönlein purpura nephritis (HSPN, ISKDC classified as type III) with positive staining with κ-light chain in the glomeruli and renal tubular epithelial cells. Furthermore, skin biopsy showed leukocytoclastic vasculitis and negative staining for Congo red and light chain. Given both the renal and cutaneous involvement, the patient was considered to have HSPN associated with IgA-κMGRS. The patient experienced an exacerbation in his purpura-like lesions and clinical status after treatment with glucocorticoid and immunosuppressive agents. Consequently, the patient was put on a regimen that included dexamethasone (20 mg on the 1st, 4th, 8th, and 11th days of each month, iv) and bortezomib (2.4 mg on the 1st, 4th, 8th, and 11th days of each month, iv). Eight weeks after treatment, he had complete resolution of his cutaneous purpura and his biochemical parameters improved. The latent presence of MGRS in cases of HSPN should be considered in adult patients. Increased cognizance and correct treatment options could improve patient outcomes.

Henoch-Schönlein purpura nephritis associated with monoclonal gammopathy of renal significance: a case report

Monoclonal gammopathy of renal significance (MGRS) can present with different morphologic features and lead to kidney failure. The Henoch-Schönlein purpura nephritis (HSPN) that cannot be relieved by treatment with glucocorticoid and immunosuppressive agents suggests the presence of monoclonal gammopathy in adult patients. The present study reports on a single case of HSPN associated with IgA-κMGRS. The patient who suffered from recurrent skin purpura for 6 months and nephrotic syndrome for 2 months was admitted to our hospital. Bone marrow biopsy showed monoclonal gammopathy of undetermined significance. Kidney biopsy indicated a Henoch-Schönlein purpura nephritis (HSPN, ISKDC classified as type III) with positive staining with κ-light chain in the glomeruli and renal tubular epithelial cells. Furthermore, skin biopsy showed leukocytoclastic vasculitis and negative staining for Congo red and light chain. Given both the renal and cutaneous involvement, the patient was considered to have HSPN associated with IgA-κMGRS. The patient experienced an exacerbation in his purpura-like lesions and clinical status after treatment with glucocorticoid and immunosuppressive agents. Consequently, the patient was put on a regimen that included dexamethasone (20 mg on the 1st, 4th, 8th, and 11th days of each month, iv) and bortezomib (2.4 mg on the 1st, 4th, 8th, and 11th days of each month, iv). Eight weeks after treatment, he had complete resolution of his cutaneous purpura and his biochemical parameters improved. The latent presence of MGRS in cases of HSPN should be considered in adult patients. Increased cognizance and correct treatment options could improve patient outcomes.

Changes in antimicrobial susceptibility of commonly clinically significant isolates before and after the interventions on surgical prophylactic antibiotics (SPAs) in Shanghai

Abstract Surveillances and interventions on antibiotics use have been suggested to improve serious drug-resistance worldwide. Since 2007, our hospital have proposed many measures for regulating surgical prophylactic antibiotics (carbapenems, third gen. cephalosporins, vancomycin, etc.) prescribing practices, like formulary restriction or replacement for surgical prophylactic antibiotics and timely feedback. To assess the impacts on drug-resistance after interventions, we enrolled infected patients in 2006 (pre-intervention period) and 2014 (post-intervention period) in a tertiary hospital in Shanghai. Proportions of targeted pathogens were analyzed: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), imipenem-resistant Escherichia coli (IREC), imipenem-resistant Klebsiella pneumoniae (IRKP), imipenem-resistant Acinetobacter baumannii (IRAB) and imipenem-resistant Pseudomonas aeruginosa (IRPA) isolates. Rates of them were estimated and compared between Surgical Department, ICU and Internal Department during two periods. The total proportions of targeted isolates in Surgical Department (62.44%, 2006; 64.09%, 2014) were more than those in ICU (46.13%, 2006; 50.99%, 2014) and in Internal Department (44.54%, 2006; 51.20%, 2014). Only MRSA has decreased significantly (80.48%, 2006; 55.97%, 2014) (p < 0.0001). The percentages of VRE and IREC in 3 departments were all <15%, and the slightest change were also both observed in Surgical Department (VRE: 0.76%, 2006; 2.03%, 2014) (IREC: 2.69%, 2006; 2.63%, 2014). The interventions on surgical prophylactic antibiotics can be effective for improving resistance; antimicrobial stewardship must be combined with infection control practices.

Changes in antimicrobial susceptibility of commonly clinically significant isolates before and after the interventions on surgical prophylactic antibiotics (SPAs) in Shanghai

Surveillances and interventions on antibiotics use have been suggested to improve serious drug-resistance worldwide. Since 2007, our hospital have proposed many measures for regulating surgical prophylactic antibiotics (carbapenems, third gen. cephalosporins, vancomycin, etc.) prescribing practices, like formulary restriction or replacement for surgical prophylactic antibiotics and timely feedback. To assess the impacts on drug-resistance after interventions, we enrolled infected patients in 2006 (pre-intervention period) and 2014 (post-intervention period) in a tertiary hospital in Shanghai. Proportions of targeted pathogens were analyzed: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), imipenem-resistant Escherichia coli (IREC), imipenem-resistant Klebsiella pneumoniae (IRKP), imipenem-resistant Acinetobacter baumannii (IRAB) and imipenem-resistant Pseudomonas aeruginosa (IRPA) isolates. Rates of them were estimated and compared between Surgical Department, ICU and Internal Department during two periods. The total proportions of targeted isolates in Surgical Department (62.44%, 2006; 64.09%, 2014) were more than those in ICU (46.13%, 2006; 50.99%, 2014) and in Internal Department (44.54%, 2006; 51.20%, 2014). Only MRSA has decreased significantly (80.48%, 2006; 55.97%, 2014) (p < 0.0001). The percentages of VRE and IREC in 3 departments were all <15%, and the slightest change were also both observed in Surgical Department (VRE: 0.76%, 2006; 2.03%, 2014) (IREC: 2.69%, 2006; 2.63%, 2014). The interventions on surgical prophylactic antibiotics can be effective for improving resistance; antimicrobial stewardship must be combined with infection control practices.(AU)

Changes in antimicrobial susceptibility of commonly clinically significant isolates before and after the interventions on surgical prophylactic antibiotics (SPAs) in Shanghai.

Surveillances and interventions on antibiotics use have been suggested to improve serious drug-resistance worldwide. Since 2007, our hospital have proposed many measures for regulating surgical prophylactic antibiotics (carbapenems, third gen. cephalosporins, vancomycin, etc.) prescribing practices, like formulary restriction or replacement for surgical prophylactic antibiotics and timely feedback. To assess the impacts on drug-resistance after interventions, we enrolled infected patients in 2006 (pre-intervention period) and 2014 (post-intervention period) in a tertiary hospital in Shanghai. Proportions of targeted pathogens were analyzed: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), imipenem-resistant Escherichia coli (IREC), imipenem-resistant Klebsiella pneumoniae (IRKP), imipenem-resistant Acinetobacter baumannii (IRAB) and imipenem-resistant Pseudomonas aeruginosa (IRPA) isolates. Rates of them were estimated and compared between Surgical Department, ICU and Internal Department during two periods. The total proportions of targeted isolates in Surgical Department (62.44%, 2006; 64.09%, 2014) were more than those in ICU (46.13%, 2006; 50.99%, 2014) and in Internal Department (44.54%, 2006; 51.20%, 2014). Only MRSA has decreased significantly (80.48%, 2006; 55.97%, 2014) (p<0.0001). The percentages of VRE and IREC in 3 departments were all <15%, and the slightest change were also both observed in Surgical Department (VRE: 0.76%, 2006; 2.03%, 2014) (IREC: 2.69%, 2006; 2.63%, 2014). The interventions on surgical prophylactic antibiotics can be effective for improving resistance; antimicrobial stewardship must be combined with infection control practices.

Electroconvulsive Therapy Under General Anesthesia With Cisatracurium, Laryngeal Mask Airways, and Bispectral Index.

OBJECTIVES: Electroconvulsive therapy (ECT) has dramatically reduced musculoskeletal complications when carried out with muscle relaxants under general anesthesia. However, seizure quality can be affected by the depth of anesthesia and choice of anesthetic agent. The purpose of this study was to describe a general anesthetic technique for ECT by using laryngeal mask, bispectral index (BIS), and muscle relaxant monitoring. METHODS: Twenty-one patients, between ages 18 and 70 years (American Society of Anesthesiologists physical status I-III), who underwent a total of 89 sessions of ECT were examined in a retrospective study. Anesthesia was induced by use of propofol (1.0 mg/kg) followed by cisatracurium (0.2 mg/kg). The BIS, train-of-four, and end-tidal carbon dioxide were all monitored continuously. A laryngeal mask airway was used to maintain and protect the airway during the procedure. Electroconvulsive therapy stimuli were applied bilaterally when the train-of-four was assessed as being zero and BIS scores were 70. All patients then received 5 µg sufentanil and 2 mg midazolam, while titrated to maintain the BIS value at 40 to 50, before the muscle relaxation exhibited complete recovery. RESULTS: The mean duration of treatment process takes approximately 82.5 minutes. Mean (SD) seizure length was 58.8 (28.3) seconds, with 4.5% incidence of restimulation per treatment. Incidence of awareness was 0%. No patients exhibited delirium, nausea, vomiting, or myalgia in the postseizure phase. CONCLUSIONS: Bispectral index monitoring of the depth of anesthesia may have improved seizure quality, and awareness did not occur.

Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth.

OBJECTIVE: To determine the benefit of newborn screening for the long-term prognosis of patients with classic infantile-onset Pompe disease (IOPD). STUDY DESIGN: A cohort of patients with classic IOPD were diagnosed by newborn screening, treated with recombinant human acid α-glucosidase (rhGAA), and followed prospectively. Outcome measurements included survival, left ventricular mass, serum creatinine kinase, motor function, mental development, and systemic manifestations. RESULTS: Ten patients who presented with left ventricular hypertrophy at diagnosis received rhGAA infusions starting at a median age of 16 days (6-34 days). All patients were cross-reactive immunologic material-positive. After a median treatment time of 63 months (range 28-90 months), all could walk independently, and none required mechanical ventilation. All patients had motor capability sufficient for participating in daily activities, but muscle weakness over the pelvic girdle appeared gradually after 2 years of age. Ptosis was present in one-half of the patients, and speech disorders were common. Anti-rhGAA antibody titers were low (median maximal titer value 1:1600, range: undetectable ∼ 1:12,800). CONCLUSION: By studying patients treated since birth who have no significant anti-rhGAA antibody interference, this prospective study demonstrates that the efficacy of rhGAA therapy is high and consistent for the treatment of classic IOPD. This study also exposes limitations of rhGAA treatment. The etiology of the manifestations in these early-treated patients will require further study.

Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

Higher dose dexamethasone increases early postoperative cognitive dysfunction.

OBJECTIVE: To investigate the effects of intravenous administration of dexamethasone on early postoperative cognitive dysfunction (POCD). METHODS: In this prospective randomized trial, 1000 patients with facial spasm undergoing microvascular decompression (MVD) were randomly assigned to receive normal sodium (Dex-0 group, n=333), dexamethasone 0.1 mg/kg (Dex-1 group, n=333), or dexamethasone 0.2 mg/kg (Dex-2 group, n=334). Exclusion criteria included: a history of neurologic or mental disease, renal failure, active liver disease, cardiac or pulmonary dysfunction, endocrine, metabolic, or peptic ulcer disease, a history of past surgery, <6 years of schooling, inability to complete neuropsychological testing, visual dysfunction, and auditory dysfunction. Patients were also excluded at any point if additional steroid was required. Propofol and sufentanil were administered for anesthetic induction, whereas propofol and remifentanil were given for maintenance of anesthesia. A battery of 9 neuropsychological tests was administered preoperatively and the on day 5 postoperatively. A postoperative deficit was defined as a postoperative decrement to preoperative score of >1SD on any test. Patients who experienced >2 deficits were considered to have experienced early POCD. RESULTS: Nine hundred and fifty-four patients completed both preoperative and postoperative neuropsychological testing. Within the 3 groups: Dex-0 group, n=319; Dex-1 group, n=320 and Dex-2, n=315. POCD occurred in 71 patients (22.3%) in the Dex-0 group, in 66 patients (20.6%) in the Dex-1 group, and 99 patients (31.4%) in the Dex-2 group. POCD was significant among the 3 groups (P=0.003). Partitions of χ method was applied for multiple comparisons showing that Dex-2 group was significantly different from Dex-1 and Dex-0 groups. CONCLUSIONS: Administration of higher dose of dexamethasone (0.2 mg/kg) increases the incidence of POCD in the early postoperative period after microvascular decompression under general anesthesia.

Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation.

OBJECTIVE: The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF). METHODS: A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system. RESULTS: Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart. CONCLUSION: These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia.

Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

OBJECTIVE: The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF). METHODS: A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system. RESULTS: Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart. CONCLUSION: These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia. .