Combination of plant metabolites hinders starch digestion and glucose absorption while facilitating insulin sensitivity to diabetes.

Introduction: Diabetes mellitus (DM) is a common endocrine disease resulting from interactions between genetic and environmental factors. Type II DM (T2DM) accounts for approximately 90% of all DM cases. Current medicines used in the treatment of DM have some adverse or undesirable effects on patients, necessitating the use of alternative medications. Methods: To overcome the low bioavailability of plant metabolites, all entities were first screened through pharmacokinetic, network pharmacology, and molecular docking predictions. Experiments were further conducted on a combination of antidiabetic phytoactive molecules (rosmarinic acid, RA; luteolin, Lut; resveratrol, RS), along with in vitro evaluation (α-amylase inhibition assay) and diabetic mice tests (oral glucose tolerance test, OGTT; oral starch tolerance test, OSTT) for maximal responses to validate starch digestion and glucose absorption while facilitating insulin sensitivity. Results: The results revealed that the combination of metabolites achieved all required criteria, including ADMET, drug likeness, and Lipinski rule. To determine the mechanisms underlying diabetic hyperglycemia and T2DM treatments, network pharmacology was used for regulatory network, PPI network, GO, and KEGG enrichment analyses. Furthermore, the combined metabolites showed adequate in silico predictions (α-amylase, α-glucosidase, and pancreatic lipase for improving starch digestion; SGLT-2, AMPK, glucokinase, aldose reductase, acetylcholinesterase, and acetylcholine M2 receptor for mediating glucose absorption; GLP-1R, DPP-IV, and PPAR-γ for regulating insulin sensitivity), in vitro α-amylase inhibition, and in vivo efficacy (OSTT versus acarbose; OGTT versus metformin and insulin) as nutraceuticals against T2DM. Discussion: The results demonstrate that the combination of RA, Lut, and RS could be exploited for multitarget therapy as prospective antihyperglycemic phytopharmaceuticals that hinder starch digestion and glucose absorption while facilitating insulin sensitivity.

A narrative review: The pharmaceutical evolution of phenolic syringaldehyde.

To better understand the pharmacological characters of syringaldehyde (SA), which is a key-odorant compound of whisky and brandy, this review article is the first to compile the published literature for molecular docking that were subsequently validated by in vitro and in vivo assays to predict and develop insights into the medicinal properties of SA in terms of anti-oxidation, anti-inflammation, and anti-diabetes. The molecular docking displayed significantly binding affinity for SA towards tumor necrosis factor-α, interleukin-6, and antioxidant enzymes when inflammation from myocardial infarction and spinal cord ischemia. Moreover, SA nicely docked with dipeptidyl peptidase-IV, glucagon-like peptide 1 receptor, peroxisome proliferator-activated receptor, acetylcholine M2 receptor, and acetylcholinesterase in anti-diabetes investigations. These are associated with (1) an increase glucose utilization and insulin sensitivity to an anti-hyperglycemic effect; and (2) to potentiate intestinal contractility to abolish the α-amylase reaction when concurrently reducing retention time and glucose absorption of the intestinal tract to achieve a glucose-lowering effect. In silico screening of multi-targets concomitantly with preclinical tests could provide a potential exploration for new indications for drug discovery and development.

Accuracy of calculating mechanical power of ventilation by one commonly used equation.

Gattinoni's equation, [Formula: see text], now commonly used to calculate the mechanical power (MP) of ventilation. However, it calculates only inspiratory MP. In addition, the inclusion of PEEP in Gattinoni's equation raises debate because PEEP does not produce net displacement or contribute to MP. Measuring the area within the pressure-volume loop accurately reflects the MP received in a whole ventilation cycle and the MP thus obtained is not influenced by PEEP. The MP of 25 invasively ventilated patients were calculated by Gattinoni's equation and measured by integration of the areas within the pressure-volume loops of the ventilation cycles. The MP obtained from both methods were compared. The effects of PEEPs on MP were also evaluated. We found that the MP obtained from both methods were correlated by R2 = 0.75 and 0.66 at PEEP 5 and 10 cmH2O, respectively. The biases of the two methods were 3.13 (2.03 to 4.23) J/min (P < 0.0001) and - 1.23 (- 2.22 to - 0.24) J/min (P = 0.02) at PEEP 5 and 10 cmH2O, respectively. These P values suggested that both methods were significantly incongruent. When the tidal volume used was 6 ml/Kg, the MP by Gattinoni's equation at PEEP 5 and 10 cmH2O were significantly different (4.51 vs 7.21 J/min, P < 0.001), but the MP by PV loop area was not influenced by PEEPs (6.46 vs 6.47 J/min, P = 0.331). Similar results were observed across all tidal volumes. We conclude that the Gattinoni's equation is not accurate in calculating the MP of a whole ventilatory cycle and is significantly influenced by PEEP, which theoretically does not contribute to MP.

Ventilator Parameters in the Diagnosis and Prognosis of Acute Respiratory Distress Syndrome in Postoperative Patients: A Preliminary Study.

This study investigated the usefulness of ventilator parameters in the prediction of development and outcome of acute respiratory distress syndrome (ARDS) in postoperative patients with esophageal or lung cancer on admission to the surgical intensive care unit (SICU). A total of 32 post-operative patients with lung or esophageal cancer from SICU in a tertiary medical center were retrospectively analyzed. The study patients were divided into an ARDS group (n = 21) and a non-ARDS group (n = 11). The ARDS group contained the postoperative patients who developed ARDS after lung or esophageal cancer surgery. The ventilator variables were analyzed in this study. Principal component analysis (PCA) was performed to reduce the correlated ventilator variables to a small set of variables. The top three ventilator variables with large coefficients, as determined by PCA, were considered as sensitive variables and included in the analysis model based on the rule of 10 events per variable. Firth logistic regression with selective stepwise elimination procedure was performed to identify the most important predictors of morbidity and mortality in patients with ARDS. Ventilator parameters, including rapid shallow breath index during mechanical ventilation (RSBIv), rate pressure product of ventilation (RPPv), rate pressure volume index (RPVI), mechanical work (MW), and inspiration to expiration time ratio (IER), were analyzed in this study. It was found that the ARDS patients had significantly greater respiratory rate (RR), airway resistance (Raw), RSBIv, RPPv, RPVI, positive end-expiratory pressure (PEEP), and IER and significantly lower respiratory interval (RI), expiration time (Te), flow rate (V˙), tidal volume (VT), dynamic compliance (Cdyn), mechanical work of ventilation (MW), and MW/IER ratio than the non-ARDS patients. The non-survivors of ARDS had significantly greater peak inspiratory pressure above PEEP (PIP), RSBIv, RPPv, and RPVI than the survivors of ARDS. By using PCA, the MW/IER was found to be the most important predictor of the development of ARDS, and both RPPv and RPVI were significant predictors of mortality in patients with ARDS. In conclusion, some ventilator parameters, such as RPPv, RPVI, and MW/IER defined in this study, can be derived from ventilator readings and used to predict the development and outcome of ARDS in mechanically ventilated patients on admission to the SICU.

Efficacy of induction regimens for cryptococcal meningitis in HIV-infected adults: a systematic review and network meta-analysis.

Cryptococcal meningitis (CM) is the most fatal adult meningitis in patients with human immunodeficiency virus (HIV). There is no conclusive evidence for the superiority of 1-week amphotericin B deoxycholate (AmphB) + flucytosine (5-FC) regimen over other antifungals in the management of HIV patients with CM (HIV-CM patients). We aimed to evaluate the differences in efficacy and tolerability of different antifungal agents in HIV-CM patients by conducting a current network meta-analysis NMA. Overall, 19 randomized controlled trials were included with 2642 participants. A regimen indicated a possibly lower early mortality rate, namely, AmphB + 5-FC + Azole (OR = 1.1E-12, 95% CIs = 1.3E-41 to 0.06) comparing to AmphB + 5-FC. The current NMA provides evidence that AmphB + 5-FC + Azole are superior to all the investigated treatments for induction regimen in HIV-CM patients.

Food intake and its effect on the species and abundance of intestinal flora in colorectal cancer and healthy individuals.

BACKGROUND/AIM: It is known that an imbalance in the intestinal f lora plays a crucial role in colorectal cancer (CRC), but the effect of food consumption patterns on the types of intestinal flora remains to be clarified. We aimed to analyze the associations between food intake and intestinal flora in healthy and CRC individuals. METHODS: Food intake data were recorded using the Food Frequency Questionnaire (FFQ). The composition and diversity of the intestinal flora detected by 16S rRNA gene sequencing, and the data were analyzed by R version 3.1.1 software. RESULTS: Higher intake of red meat or pickled foods, and lower intake of white meat, fruits, vegetables, beans, nuts were found in the CRC group compared with the healthy group. Higher levels of Fusobacteria and Proteobacteria, and lower levels of Firmicutes were observed in the CRC group. Partial correlation analysis revealed that the intake of fruits, beans, and nuts was negatively correlated with Proteobacteria and Fusobacteria, but pickled food was positively correlated with Fusobacteria (p < 0.05). Fish, beans, and nuts intake was negatively correlated with Escherichia (p = 0.01). Multiple regression analysis revealed that vegetable oil (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.13 to 0.82), vegetables (OR, 0.26; 95% CI, 0.10 to 0.64), eggs (OR, 0.26; 95% CI, 0.10 to 0.69), pickled foods (OR, 21.02; 95% CI, 6.02 to 73.45), and red meat (OR, 4.23; 95% CI, 1.68 to 10.60) had an impact on CRC risk. CONCLUSION: The species and abundance of intestinal flora varies between CRC and healthy individuals and may be affected by their food preference.

α-Glucosidase Inhibitor Can Effectively Inhibit the Risk of Tuberculosis in Patients with Diabetes: A Nested Case-Control Study.

Diabetes mellitus (DM) and tuberculosis (TB) are major public health and economic burdens. DM increases Mycobacterium tuberculosis (M.tb) infection rates and treatment durations. This study evaluated the relationship between five classes of oral DM medications and TB infection risk in DM patients. We used longitudinal records from the Taiwan Longitudinal Health Insurance Research Database. DM patients were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 250 and A code A181. TB patients were identified using ICD-9-CM code 010.x-017.x. Oral DM medications were divided into five classes: sulfonylureas, biguanides, meglitinides, α-glucosidase inhibitors (AGIs), and thiazolidinediones. Users were classified as nonusers, low-concentration users, and high-concentration users. The incidence rate ratio (IRR) was derived using multivariate Poisson regression to calculate the relative risk of TB infection. DM patients using low- and high-concentration AGIs had significantly lower TB infection risks compared with nonusers. The IRRs of the sulfonylureas and AGI users were [CI] 0.693-0.948) and (95% CI 0.651-0.995), respectively. The other four classes of medications exhibited no significant effect on TB infection risk in DM patients. Furthermore, DM patients using high-concentration AGIs had a significantly lower TB infection risk compared with those using low-concentration AGIs (IRR 0.918, 95% CI: 0.854-0.987). We noted a dose-response relationship in the effects of DM medications on TB risk. Accordingly, we suggest that DM patients use AGIs to benefit from their protective effect on TB infection risk.

Microbiome in Intestinal Lavage Fluid May Be A Better Indicator in Evaluating The Risk of Developing Colorectal Cancer Compared with Fecal Samples.

OBJECTIVE: Intestinal microbiota plays a vital role in the pathogenesis of colorectal cancer (CRC), which is crucial for assessing the risk and prognosis of CRC. Most studies regarding human gut microbiota mainly based on the feces, but the exact composition of microbiota vary significantly due to fecal composition is easily affected by many factors. We aim to evaluate whether intestinal lavage fluid (IVF) is a better substitution mirroring the gut microbiota. METHODS: We performed 16S rRNA gene analysis on fecal and IVF samples from 30 CRC patients and 25 healthy individuals, comparison in luminal (feces) / mucosal (IVF) adherent bacterial community profiles were analyzed. RESULTS: The difference between feces and IVF were observed, including the diversity and abundance of pathogenic bacteria (either in single strain or in co-occurrence pattern). IVF group shared 605 OTUs with the fecal group, but there was 94 OTUs only observed in fecal samples, while 247 OTUs were mainly existing in the IVF group. Among them, 27 vital bacterial species detected in IVF, while 10 critical species detected in fecal samples. The co-occurrence bacteria Fusobacteria Cluster and Proteobacteria Cluster 2 significantly increased in IVF than in control (P < .01), while Firmicutes Cluster 1, Firmicutes Cluster 2 and Proteobacteria Cluster 1 were markedly lower in IVF than in control (P < .001). In CRC feces, Fusobacteria Cluster was higher than in control (P < .05), but Firmicutes Cluster 1 was of substantially less abundance than in control (P < .001). Proteobacteria Cluster 2 was increased dramatically in IVF than in feces (P < .05), Firmicutes Cluster 1 were of substantially less abundance than in feces (P < .05). CONCLUSION: Pathogenic microbiota is more abundant in IVF than in feces. Microbiota of IVF may closely be related to the mucosal-associated microbial communities, which benefit from elucidating the relationship of the intestinal microbiota and CRC carcinogenesis.

miRNA-766 induces apoptosis of human colon cancer cells through the p53/Bax signaling pathway by MDM4.

miRNAs are closely associated with tumor genesis and development. The present study investigated the role of the expression of miRNA-766 in the survival of patients with colon cancer and the underlying molecular mechanisms. Reverse transcription-quantitative polymerase chain reaction analysis and microarray analysis were used to analyze the expression of miRNA-766. The results revealed that the expression of miRNA-766 was decreased in patients with colon cancer. The overall survival and disease-free survival rates of patients with colon cancer with a high expression of miRNA-766 were prolonged, compared with those with a low expression of miRNA-766. The overexpression of miRNA-766 reduced cell growth and induced apoptosis in colon cancer cells through suppression of the MDM4/p53 pathway. By contrast, the downregulation of miRNA-766 promoted cell growth and reduced apoptosis in colon cancer cells through activation of the MDM4/p53 pathway. The promotion of MDM4 attenuated the anticancer effect of miRNA-766 in colon cancer cells. These results demonstrated that miRNA-766 induced cell apoptosis in human colon cancer through MDM4/p53.

Better airway resistance reduction profile in intubated COPD patients by personalized bronchodilator dosing: A pilot randomized control trial.

INTRODUCTION: The optimal dose of inhaled metered-dose bronchodilators for intubated patients with chronic obstructive pulmonary disease (COPD) is unknown. In this study, we proposed a bronchodilator dosing schedule based on an individual's airway resistance (Raw) and tested its efficacy in reducing Raw. METHODS: A total of 51 newly admitted patients with invasively ventilated COPD were randomly assigned to receive personalized or fixed bronchodilator dosing. Personal target Raw was defined by measuring each individual's Raw after maximal pharmacologic bronchodilatation. Thereafter, Raw was measured every 8 h until the 28th day. Patients in the fixed-dosing group received only predetermined doses. Additional doses of bronchodilators were given to patients in the personalized-dosing group when the measured Raw exceeded their target Raw. RESULTS: The median daily doses of salmeterol/fluticasone were 9.2 (personalized-dosing) vs 7.6 (fixed-dosing) puffs (P < 0.001). The relative deviation of Raw from the personal target was expressed as (measured Raw - target Raw)/target Raw. The experimental group showed a smaller relative Raw deviation than the control group (0.09 ±â€¯0.10 vs 0.44 ±â€¯0.11, P = 0.02). There were no differences between the two groups in terms of ventilator-free days from day 1 to day 28, number of episodes of nosocomial pneumonia, total number of puffs of rescue bronchodilator, number of drug-related adverse effects or mortality rate at day 180. CONCLUSION: Personalized dosing of inhaled bronchodilator administered to invasively ventilated COPD patients can produce a better reduction in Raw. Further studies with larger sample size are required to verify the conclusion of this pilot study.

Spontaneous recovery of ventilator-associated pneumothorax.

BACKGROUND: The usual management of ventilator-associated pneumothorax (VPX) is tube thoracostomy. However, this recommendation is based on tradition rather than on solid evidence. Although it has been applied successfully to other types of pneumothoraces, observation has not been used in the management of VPX. OBJECTIVES: In this study, we investigated whether observation is a valid treatment strategy for VPX. METHODS: We retrospectively analyzed data of 471 patients with VPX (2003-2010) and found that 27 did not receive tube thoracostomy. Most of those patients (89%) had documented do-not-resuscitate orders and had refused tube thoracostomy. For comparison, 54 patients with tube thoracostomy, matched by age and do-not-resuscitate status, were chosen as controls. Among patients without tube thoracostomy, we compared attribute differences between those recovered and those not recovered. RESULTS: Thirteen patients (48%) without tube thoracostomy experienced spontaneous recovery of their pneumothoraces. This rate of chest tube-free recovery was higher than that of patients with tube thoracostomy (48 vs. 17%; p = 0.003). The patients did not differ in in-hospital mortality rate, time to ventilator discontinuation or survival. By univariate logistic regression, spontaneous recovery was associated with VPX caused by needle puncture, lack of respiratory distress, large tidal volume and low oxygen requirement following pneumothorax, as well as by physician recommendation against intubation. CONCLUSION: Observation under physician surveillance is an effective option of managing many VPXs, especially those caused by needle puncture, when patients are not in respiratory distress or when patients have acceptable tidal volumes and oxygen requirements following pneumothorax.

Simultaneous use of traditional Chinese medicine (si-ni-tang) to treat septic shock patients: study protocol for a randomized controlled trial.

BACKGROUND: Even though there are continually upgraded recommendations for managing sepsis, such as "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock", mortality is still high. Si-ni-tang, a remedy documented in Shanghan Lun, a medical collection from ancient China, is used for treating patients with sepsis and septic shock. Using a well-designed clinical trial, we are eager to survey the effectiveness of the concurrent use of this remedy in restoring these patients' hemodynamic status, or "Yang Qi". METHODS/DESIGN: Patients admitted to our medical intensive care units with the diagnosis of septic shock, defined as persistent hypotension induced by sepsis despite adequate fluid resuscitation, are eligible for participation. The inclusion criteria include: age from 20 to 85 years, conditions meeting the definition of septic shock, use of vasopressors within 24 hours of entering the study, and use of a nasogastric tube for feeding. The enrolled patients are randomly allocated either to the si-ni-tang group or the placebo group. The prescription of the trial drugs (si-ni-tang/placebo) is 2.25 grams 4 times a day for 7 days or till shock reversal (if shock reversal occurs in less than 7 days). Data, including duration of vasopressor infusion, gender, age, co-morbidities, APACHE II score, predicted mortality, ICU mortality, ICU length of stay, hospital mortality, hospital length of stay, source of sepsis, and culture results, are collected for the following analysis. DISCUSSION: Si-ni-tang is composed of processed Zingiber officinale, Glycyrrhiza uralensis, and Aconitum carmichaeli. Zingiber officinale and Glycyrrhiza uralensis are found to have the ability to reduce pro-inflammatory cytokine production, to inhibit lipopolisaccharide-induced macrophage activation and function, and to lessen the bacterial load and suppress acute and chronic inflammation. Aconitum carmichaeli is known to have vasopressor activity, and positive chronotropic and inotropic effects. As this remedy has a potential benefit in treating septic shock patients, we designed a double-blind, prospective, randomized controlled trial and would like to publish the results and conclusions later. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01223430.

Active lymphangiogenesis is a major risk factor for anastomotic leakage following sphincter-sparing resection of rectal cancer.

OBJECTIVE: Anastomotic leakage is a major complication of rectal surgery and controversy about its risk factors still exists. The aim of present study was to identify risk factors for anastomotic leakage following sphincter-sparing resection of rectal cancer, focusing on the role of tissular lymphatic vessel density (LVD) in tumorous margin and distal clearance margin. METHODS: In a 9-year period, from September 1999 to September 2009, 750 consecutive patients who underwent anterior resection with restoration of the bowel continuity were included. Univariate and multivariate analysis were applied to identify risk factors for anastomotic leakage. RESULTS: The rate of anastomotic leakage was 7.6% (57 of 750 patients). In a multivariate analysis, high LVD in tumorous margin [P=0.0017; odds ratio (OR)=5.93; 95% confidence interval (CI)=2.61-8.514], high LVD in distal clearance margin (P=0.0011; OR=6.05; 95% CI=2.72-10.108) and lower tumor location (P=0.006; OR=4.620; 95% CI=1.76-6.97) were identified as independent factors for anastomotic leakage. A significant LVD correlation was shown by Spearman's rank test between the tumorous and distal clearance margin (r=0.796). CONCLUSIONS: Tissular LVD in tumorous or distal clearance margin and lower tumor location are important risk factors for anastomotic leakage.

Soluble Fas ligand is another good diagnostic marker for tuberculous pleurisy.

Soluble Fas ligand (sFasL) is abundant in effusions of tuberculous (TB) pleurisy; however, its diagnostic value has not been scrutinized. We collected pleural effusions from 79 patients, including 23 with TB pleurisy and 56 without TB, and measured sFasL, adenosine deaminase (ADA), and interferon-γ (IFN-γ) concentrations of each specimen. The median of the sFasL concentration of the TB group was 57.3 pg/mL, which was significantly higher than that of the non-TB group (27.4 pg/mL) (P < 0.001). When cutoff value was 39.85 pg/mL, the sensitivity and specificity of sFasL were 95.7% and 80.4%, respectively. The area under the receiver operating characteristic curve for sFasL was not significantly different from those of ADA and IFN-γ. Soluble FasL concentrations of TB patients were significantly higher than those of parapneumonic effusion subgroup (P = 0.039). In conclusion, pleural effusion sFasL is another good diagnostic marker for TB pleurisy.

Toona sinensis extracts induced cell cycle arrest and apoptosis in the human lung large cell carcinoma.

Toona sinensis extracts have been shown to exhibit anti-cancer effects in human ovarian cancer cell lines, human promyelocytic leukemia cells and human lung adenocarcinoma. Its safety has also been confirmed in animal studies. However, its anti-cancer properties in human lung large cell carcinoma have not been studied. Here, we used a powder obtained by freeze-drying the supernatant of centrifuged crude extract from Toona sinensis leaves (TSL-1) to treat the human lung carcinoma cell line H661. Cell viability was evaluated by the 3-(4-,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay. Flow cytometry analysis revealed that TSL-1 blocked H661 cell cycle progression. Western blot analysis showed decreased expression of cell cycle proteins that promote cell cycle progression, including cyclin-dependent kinase 4 and cyclin D1, and increased the expression of proteins that inhibit cell cycle progression, including p27. Furthermore, flow cytometry analysis showed that TSL-1 induced H661 cell apoptosis. Western blot analysis showed that TSL-1 reduced the expression of the anti-apoptotic protein B-cell lymphoma 2, and degraded the DNA repair protein, poly(ADP-ribose) polymerase. TSL-1 shows potential as a novel therapeutic agent or for use as an adjuvant for treating human lung large cell carcinoma.