Stereodivergent Synthesis of Alkaloid (±)-223A and (±)-6-epi-223A via Rh-Catalyzed Hydroformylation Double Cyclization.

A stereodivergent approach toward total syntheses of Dendrobatid alkaloids 223A and 6-epi-223A is described. The approach features a concise construction of an indolizidine skeleton by Rh-catalyzed domino hydroformylation double cyclization and sequential stereocontrolled transformations such as reductive alkylation or anti-selective α-alkylation of the 5-oxoindolizidine. These stereoselective reactions afford the desired stereochemistry in the targets.

Hybrid-Pattern Recognition Modeling with Arrhythmia Signal Processing for Ubiquitous Health Management.

We established a web-based ubiquitous health management (UHM) system, "ECG4UHM", for processing ECG signals with AI-enabled models to recognize hybrid arrhythmia patterns, including atrial premature atrial complex (APC), atrial fibrillation (AFib), ventricular premature complex (VPC), and ventricular tachycardia (VT), versus normal sinus rhythm (NSR). The analytical model coupled machine learning methods, such as multiple layer perceptron (MLP), random forest (RF), support vector machine (SVM), and naive Bayes (NB), to process the hybrid patterns of four arrhythmia symptoms for AI computation. The data pre-processing used Hilbert-Huang transform (HHT) with empirical mode decomposition to calculate ECGs' intrinsic mode functions (IMFs). The area centroids of the IMFs' marginal Hilbert spectrum were suggested as the HHT-based features. We engaged the MATLABTM compiler and runtime server in the ECG4UHM to build the recognition modules for driving AI computation to identify the arrhythmia symptoms. The modeling extracted the crucial data sets from the MIT-BIH arrhythmia open database. The validated models, including the premature pattern (i.e., APC-VPC) and the fibril-rapid pattern (i.e., AFib-VT) against NSR, could reach the best area under the curve (AUC) of the receiver operating characteristic (ROC) of approximately 0.99. The models for all hybrid patterns, without VPC versus AFib and VT, achieved an average accuracy of approximately 90%. With the prediction test, the respective AUCs of the NSR and APC versus the AFib, VPC, and VT were 0.94 and 0.93 for the RF and SVM on average. The average accuracy and the AUC of the MLP, RF, and SVM models for APC-VT reached the value of 0.98. The self-developed system with AI computation modeling can be the backend of the intelligent social-health system that can recognize hybrid arrhythmia patterns in the UHM and home-isolated cares.

Mesenchymal stromal cell-based therapies reduce obesity and metabolic syndromes induced by a high-fat diet.

Obesity is an alarming global health problem that results in multiaspect metabolic syndromes in both genders and most age groups. The lack of effective therapies for obesity and its associated metabolic syndrome is an urgent societal issue. To elucidate whether mesenchymal stromal cell (MSC)-based therapies can ameliorate high-fat diet-induced obesity and compare the effectiveness of several methodological approaches, we transplanted human MSCs, MSC-derived brown adipocytes (M-BA), and MSC lysateinto obese mice. All 3 MSC-based treatments improved obesity-associated metabolic syndromes including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, glucose intolerance, and inflammation in obese mice after repeated administration for 10 weeks. MSC-based treatments altered the ratio of adiponectin to leptin and regulated the expression of Pparα and Pparγ, which are involved in maintaining energy homeostasis, in major metabolic tissues. Among treatments, M-BA showed the strongest beneficial effect. Importantly, M-BA administration not only reduced obesity-associated metabolic syndromes but also reduced body weight and hyperlipidemia, indicating that it is an effective therapy for obesity. Together, our findings revealed the therapeutic potential of MSCs for the treatment of metabolic syndrome.

Involvement of Smac, p53, and caspase pathways in induction of apoptosis by gossypol in human retinoblastoma cells.

PURPOSE: Retinoblastoma is a malignant tumor of the retina usually occurring in young children. To date, the conventional treatments for retinoblastoma have been enucleation, cryotherapy, external beam radiotherapy, or chemotherapy. Most of these treatments, however, have possible side effects, including blindness, infections, fever, gastrointestinal toxicity, and neurotoxicity. More effective treatments are therefore imperative. Gossypol has been reported as a potential inhibitor of cell proliferation in various types of cancers, such as prostate cancer, breast cancer, leukemia, and lung cancer. This study investigates the possible antiproliferative effect of gossypol on retinoblastoma. METHODS: Human retinoblastoma cells were cultured with various concentrations of gossypol and checked for cell viability with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Nuclear condensation caused by cell apoptosis was detected by staining retinoblastoma cells with 4',6-diamidino-2-phenylindole (DAPI), counting those with condensed nuclei, and determining the percentage of apoptotic cells. In addition, the stages of apoptosis and phases in cell cycles were examined with flow cytometry. The possible signal transduction pathways involved were examined with a protein array assay and western blot analysis. RESULTS: After incubation, the cell survival rate was significantly lower after treatment with 5, 10, and 20 µM of gossypol. The maximum antisurvival effect of gossypol was observed at 20 µM, and the number of apoptotic cells was higher in the preparations cultured with 10 and 20 µM of gossypol. The results in flow cytometry indicated that at concentrations of 10 and 20 µM, gossypol increased the proportion of early- and late-apoptotic retinoblastoma cells and induced cell arrest of retinoblastoma cells at the same concentrations. This antiproliferative effect was later confirmed by upregulating the expression of death receptor 5 (DR5), caspase 8, caspase 9, caspase 3, cytochrome C, tumor protein 53 (p53), and second mitochondria-derived activator of caspases (Smac) in the signal transduction pathways. CONCLUSIONS: We concluded that gossypol has an antiproliferative effect on retinoblastoma cells.

Upregulated claudin-1 expression confers resistance to cell death of nasopharyngeal carcinoma cells.

Accumulating evidence reveals that aberrant expression of claudins manifests in various tumors; however, their biological functions are poorly understood. Here, we report on the elevated expression of claudin-1 in nasopharyngeal carcinoma (NPC) cell lines under serum deprivation or fluorouracil (5-FU) treatment. Interestingly, an increase in expression of claudin-1 considerably reduced apoptosis rather than enhancing cell proliferation. However, claudin-1 expression and activity were unaffected by external stimuli or Akt and NF-kappaB activation. Notably, predominant cytoplasmic and nuclear localization of claudin-1 in NPC cells reflected the aforementioned feature. On the other hand, loss of epithelial morphology and E-cadherin expression was associated with serum withdrawal in NPC cells. Interestingly, restoration of E-cadherin inhibited the protein elevation and antiapoptotic activity of claudin-1. In conclusion, our data demonstrate the regulation and novel biological function of claudin-1 and indicate the important role of claudin-1 in NPC tumorigenesis.

Widespread expression of prostate apoptosis response-4 in nasopharyngeal carcinoma.

BACKGROUND: Prostate apoptosis response-4 (Par-4) augments apoptosis in various tumors, either during apoptotic insult or by ectopic overexpression. However, investigation of Par-4 expression in nasopharyngeal carcinoma (NPC) is lacking. METHODS: Specimens from patients with NPC, hypopharyngeal carcinoma (HPC), or oral cavity cancer were examined for Par-4 expression using immunohistochemistry. NPC cell proliferation and apoptosis were analyzed using immunohistochemical staining for Ki67, B-cell lymphoma 2 (Bcl-2), and in situ terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick end-labeling (TUNEL) assay, respectively. RESULTS: Par-4 was ubiquitously expressed in NPC biopsies (96.2%, 25/26) and was significantly higher than in HPC (47.6%, 50/105, p < .0001) and oral cavity cancers (38.7%, 12/31, p < .0001). Remarkably, apoptosis of NPC cells was absent and Par-4 expression was associated with obvious expression of Bcl-2 and Ki67 in all patients tested with NPC. CONCLUSIONS: Immunohistochemistry results showed widespread expression of Par-4 in NPC and revealed sustainable proliferation of NPC cells regardless of Par-4 expression.

Protein expression and intracellular localization of prostate apoptosis response-4 (Par-4) are associated with apoptosis induction in nasopharyngeal carcinoma cell lines.

Prostate apoptosis response-4 (Par-4) is a proapoptotic gene that selectively induces cell death in most cancer cells. In addition to the increased percentage of apoptotic cells, caspase-3 activity, and poly (ADP-ribose) polymerase (PARP) cleavage, we demonstrate that elevated expression of Par-4 and nuclear entry resulted in apoptosis of nasopharyngeal carcinoma (NPC) cell lines either in serum deprivation or by ectopic overexpression of Par-4. Moreover, disassociation from the Par-4/Akt complex was correlated with the induced proapoptotic ability of Par-4. Therefore, our data suggest that the cytoplasmic localization and expression level of endogenous Par-4 in NPC cells are not sufficient to augment apoptosis.

Does a new videolaryngoscope (glidescope) provide better glottic exposure?

BACKGROUND: The GlideScope (Saturn Biomedical Systems Inc, Burnaby, British Columbia, Canada) is a new videolaryngoscope designed as an alternative to the conventional laryngoscope. It was designed to facilitate glottic exposure during tracheal intubation. This study assessed the effectiveness of the GlideScope in providing glottic exposure. METHODS: One hundred and three patients requiring general anesthesia for elective surgery were enrolled in this study. Under full monitoring, all patients were given fentanyl, propofol or thiopentone and muscle relaxant for induction. In each patient laryngoscopy was performed first with a Macintosh blade (size 3), then with the GlideScope. The optimal view of the larynx that could be achieved with each instrument was recorded and assessed using the grading scale of Cormack and Lehane (C&L grade). Intubation was performed with the GlideScope. RESULTS: The grading decreased in the majority (93.6%, 44/47) of patients with C&L grade > 1 when using the GlideScope. Of the 22 patients who were considered as subjects of difficult intubation, 20 had an improved laryngoscopic grade with GlideScope. One hundred and one patients were intubated successfully at the first attempt. CONCLUSIONS: The laryngeal view was better in the GildeScope group using this grading system. The GlideScope provided a better view of the glottis and is a useful alternative in airway management.