Tetrahydrobiopterin: Beyond Its Traditional Role as a Cofactor.

Tetrahydrobiopterin (BH4) is an endogenous cofactor for some enzymatic conversions of essential biomolecules, including nitric oxide, and monoamine neurotransmitters, and for the metabolism of phenylalanine and lipid esters. Over the last decade, BH4 metabolism has emerged as a promising metabolic target for negatively modulating toxic pathways that may result in cell death. Strong preclinical evidence has shown that BH4 metabolism has multiple biological roles beyond its traditional cofactor activity. We have shown that BH4 supports essential pathways, e.g., to generate energy, to enhance the antioxidant resistance of cells against stressful conditions, and to protect from sustained inflammation, among others. Therefore, BH4 should not be understood solely as an enzyme cofactor, but should instead be depicted as a cytoprotective pathway that is finely regulated by the interaction of three different metabolic pathways, thus assuring specific intracellular concentrations. Here, we bring state-of-the-art information about the dependency of mitochondrial activity upon the availability of BH4, as well as the cytoprotective pathways that are enhanced after BH4 exposure. We also bring evidence about the potential use of BH4 as a new pharmacological option for diseases in which mitochondrial disfunction has been implicated, including chronic metabolic disorders, neurodegenerative diseases, and primary mitochondriopathies.

Organic Electrochemical Transistors for In Vivo Bioelectronics.

Organic electrochemical transistors (OECTs) are presently a focus of intense research and hold great potential in expanding the horizons of the bioelectronics industry. The notable characteristics of OECTs, including their electrolyte-gating, which offers intimate interfacing with biological environments, and aqueous stability, make them particularly suitable to be operated within a living organism (in vivo). Unlike the existing in vivo bioelectronic devices, mostly based on rigid metal electrodes, OECTs form a soft mechanical contact with the biological milieu and ensure a high signal-to-noise ratio because of their powerful amplification capability. Such features make OECTs particularly desirable for a wide range of in vivo applications, including electrophysiological recordings, neuron stimulation, and neurotransmitter detection, and regulation of plant processes in vivo. In this review, a systematic compilation of the in vivo applications is presented that are addressed by the OECT technology. First, the operating mechanisms, and the device design and materials design principles of OECTs are examined, and then multiple examples are provided from the literature while identifying the unique device properties that enable the application progress. Finally, one critically looks at the future of the OECT technology for in vivo bioelectronic applications.

Automating the Clinical Assessment of Independent Wheelchair Sitting Pivot Transfer Techniques.

BACKGROUND: Using proper transfer technique can help to reduce forces and prevent secondary injuries. However, current assessment tools rely on the ability to subjectively identify harmful movement patterns. OBJECTIVES: The purpose of the study was to determine the accuracy of using a low-cost markerless motion capture camera and machine learning methods to evaluate the quality of independent wheelchair sitting pivot transfers. We hypothesized that the algorithms would be able to discern proper (low risk) and improper (high risk) wheelchair transfer techniques in accordance with component items on the Transfer Assessment Instrument (TAI). METHODS: Transfer motions of 91 full-time wheelchair users were recorded and used to develop machine learning classifiers that could be used to discern proper from improper technique. The data were labeled using the TAI item scores. Eleven out of 18 TAI items were evaluated by the classifiers. Motion variables from the Kinect were inputted as the features. Random forests and k-nearest neighbors algorithms were chosen as the classifiers. Eighty percent of the data were used for model training and hyperparameter turning. The validation process was performed using 20% of the data as the test set. RESULTS: The area under the receiver operating characteristic curve of the test set for each item was over 0.79. After adjusting the decision threshold, the precisions of the models were over 0.87, and the model accuracies were over 71%. CONCLUSION: The results show promise for the objective assessment of the transfer technique using a low cost camera and machine learning classifiers.

Protective effect of CD73 inhibitor α, ß-methylene ADP against amyloid-ß-induced cognitive impairment by inhibiting adenosine production in hippocampus

BACKGROUND: Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease. Recent studies have reported the close association between cognitive function in AD and purinergic receptors in the central nervous system. In the current study, we investigated the effect of CD73 inhibitor α, ß-methylene ADP (APCP) on cognitive impairment of AD in mice, and to explore the potential underlying mechanisms. RESULTS: We found that acute administration of Aß1­42 (i.c.v.) resulted in a significant increase in adenosine release by using microdialysis study. Chronic administration of APCP (10, 30 mg/kg) for 20 d obviously mitigated the spatial working memory impairment of Aß1­42-treated mice in both Morris water maze (MWM) test and Y-maze test. In addition, the extracellular adenosine production in the hippocampus was inhibited by APCP in Aß-treated mice. Further analyses indicated expression of acetyltransferase (ChAT) in hippocampus of mice of was significantly reduced, while acetylcholinesterase (AChE) expression increased, which compared to model group. We observed that APCP did not significantly alter the NLRP3 inflammasome activity in hippocampus, indicating that anti-central inflammation seems not to be involved in APCP effect. CONCLUSIONS: In conclusion, we report for the first time that inhibition of CD73 by APCP was able to protect against memory loss induced by Aß1­42 in mice, which may be due to the decrease of CD73-driven adenosine production in hippocampus. Enhancement of central cholinergic function of the central nervous system may also be involved in the effects of APCP.

Antidiabetic effect of Momordica charantia saponins in rats induced by high-fat diet combined with STZ

Background: The harmful effects of type 2 diabetes mellitus and its complications have become a major global public health problem. In this study, the effects of Momordica charantia saponins (MCS) on lipid metabolism, oxidative stress, and insulin signaling pathway in type 2 diabetic rats were investigated. Results: MCS could attenuate the tendency of weight loss of the model rats. It could also improve glucose tolerance; reduce fasting blood glucose, nonesterified fatty acid, triglyceride, and total cholesterol; and increase the insulin content and insulin sensitivity index of the rats. The activity of superoxide dismutase and catalase increased, and the content of malondialdehyde decreased in the liver and pancreas tissues of rats in MCS-treated groups significantly. In addition, the expression of p-IRS-1 (Y612) and p-Akt (S473) increased, and the expression of p-IRS-1 (S307) decreased in the liver tissues and pancreas tissues of rats in MCS-treated groups significantly. Conclusion: MCS has an antidiabetic effect, which may be related to its improving the lipid metabolism disorder, reducing oxidative stress level, and regulating the insulin signaling pathway.

Trapa natans pericarp extract ameliorates hyperglycemia and hyperlipidemia in type 2 diabetic mice

Abstract The pericarp of Trapa natans L., an annual aquatic floating herb belonging to Lythraceae family, is used as a folk medicine in China. In this study, extracts of Trapa natans pericarp were tested both in vitro and in vivo through a high-fat diet with a single medium dosage streptozotocin injection induced type 2 diabetic mice. Different solvent extracts of Trapa natans pericarp showed α-amylase and α-glucosidase inhibitory activity. After four weeks administration, the ethyl acetate extract of Trapa natans pericarp (50 and 100 mg/kg b.w.) reduced fasting blood glucose level, ameliorated oral glucose tolerance and insulin resistance, improved serum lipids alterations in type 2 diabetic mice as well. Additionally, ethyl acetate extract significantly elevated the insulin receptor substrate 1 and Akt serine/threonine kinase phosphorylation compared to diabetic group. HPLC-MS and HPLC-DAD analysis showed that the ethyl acetate extract was rich in hydrolysable tannins. Results support the notion that Trapa natans pericarp extract has a potential hypoglycemic activity.

Antitussive and expectorant properties of growing and fallen leaves of loquat (Eriobotrya japonica)

ABSTRACT Folium Eriobotryae, the dried leaves of loquat (Eriobotrya japonica, (Thunb.) Lindl., Rosaceae), is a traditional Chinese medicine used to treat cough with phlegm in China. Fallen and growing loquat leaves were tested for their effect on coughing and expectoration in mice. HPLC-ELSD and HPLC-MS analyses of aqueous and ethanol extracts of fallen or growing leaves were used to identify the chemical components responsible for this effect. Both the aqueous and ethanol extracts of growing and fallen leaves of loquat contained antitussive and expectorant activities. Moreover, an aqueous extract of growing loquat leaves with a higher flavonoid content displayed a stronger expectorant activity while the ethanol extract of fallen loquat leaves that contained a higher content of triterpenoid acids induced a stronger antitussive activity.

Brazilin isolated from Caesalpinia sappan L. acts as a novel collagen receptor agonist in human platelets.

BACKGROUND: Brazilin, isolated from the heartwood of Caesalpinia sappan L., has been shown to possess multiple pharmacological properties. METHODS: In this study, platelet aggregation, flow cytometry, immunoblotting analysis, and electron spin resonance (ESR) spectrometry were used to investigate the effects of brazilin on platelet activation ex vivo. Moreover, fluorescein sodium-induced platelet thrombi of mesenteric microvessels was also used in in vivo study. RESULTS: We demonstrated that relatively low concentrations of brazilin (1 to 10 µM) potentiated platelet aggregation induced by collagen (0.1 µg/ml) in washed human platelets. Higher concentrations of brazilin (20 to 50 µM) directly triggered platelet aggregation. Brazilin-mediated platelet aggregation was slightly inhibited by ATP (an antagonist of ADP). It was not inhibited by yohimbine (an antagonist of epinephrine), by SCH79797 (an antagonist of thrombin protease-activated receptor [PAR] 1), or by tcY-NH2 (an antagonist of PAR 4). Brazilin did not significantly affect FITC-triflavin binding to the integrin αIIbß(3) in platelet suspensions. Pretreatment of the platelets with caffeic acid phenethyl ester (an antagonist of collagen receptors) or JAQ1 and Sam.G4 monoclonal antibodies raised against collagen receptor glycoprotein VI and integrin α2ß(1), respectively, abolished platelet aggregation stimulated by collagen or brazilin. The immunoblotting analysis showed that brazilin stimulated the phosphorylation of phospholipase C (PLC)γ2 and Lyn, which were significantly attenuated in the presence of JAQ1 and Sam.G4. In addition, brazilin did not significantly trigger hydroxyl radical formation in ESR analysis. An in vivo mouse study showed that brazilin treatment (2 and 4 mg/kg) significantly shortened the occlusion time for platelet plug formation in mesenteric venules. CONCLUSION: To the best of our knowledge, this study provides the first evidence that brazilin acts a novel collagen receptor agonist. Brazilin is a plant-based natural product, may offer therapeutic potential as intended anti-thrombotic agents for targeting of collagen receptors or to be used a useful tool for the study of detailed mechanisms in collagen receptors-mediated platelet activation.