Identifying patient-specific behaviors to understand illness trajectories and predict relapses in bipolar disorder using passive sensing and deep anomaly detection: protocol for a contactless cohort study.

BACKGROUND: Predictive models for mental disorders or behaviors (e.g., suicide) have been successfully developed at the level of populations, yet current demographic and clinical variables are neither sensitive nor specific enough for making individual clinical predictions. Forecasting episodes of illness is particularly relevant in bipolar disorder (BD), a mood disorder with high recurrence, disability, and suicide rates. Thus, to understand the dynamic changes involved in episode generation in BD, we propose to extract and interpret individual illness trajectories and patterns suggestive of relapse using passive sensing, nonlinear techniques, and deep anomaly detection. Here we describe the study we have designed to test this hypothesis and the rationale for its design. METHOD: This is a protocol for a contactless cohort study in 200 adult BD patients. Participants will be followed for up to 2 years during which they will be monitored continuously using passive sensing, a wearable that collects multimodal physiological (heart rate variability) and objective (sleep, activity) data. Participants will complete (i) a comprehensive baseline assessment; (ii) weekly assessments; (iii) daily assessments using electronic rating scales. Data will be analyzed using nonlinear techniques and deep anomaly detection to forecast episodes of illness. DISCUSSION: This proposed contactless, large cohort study aims to obtain and combine high-dimensional, multimodal physiological, objective, and subjective data. Our work, by conceptualizing mood as a dynamic property of biological systems, will demonstrate the feasibility of incorporating individual variability in a model informing clinical trajectories and predicting relapse in BD.

The anti-inflammatory activities of Ainsliaea fragrans Champ. extract and its components in lipopolysaccharide-stimulated RAW264.7 macrophages through inhibition of NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ainsliaea fragrans Champ. (A. fragrans) is a traditional Chinese herbal that contains components like 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid. It exhibits anti-inflammatory activities which has been used for the treatment of gynecological diseases for many years in China. The aims of the present study were to investigate the anti-inflammatory activities of A. fragrans and elucidate the underlying mechanisms with regard to its molecular basis of action for the best component. MATERIALS AND METHODS: The anti-inflammatory effects of A. fragrans were studied by using lipopolysaccharide (LPS)-stimulated activation of nitric oxide (NO) in mouse RAW264.7 macrophages. Expression of inducible NO synthase (iNOS) and pro-inflammatory cytokines, inhibitory κBα (IκBα) degradation and nuclear translocation of NF-κB p65 were further investigated. RESULTS: The present study demonstrated that A. fragrans could suppress the production of NO in LPS-stimulated RAW264.7 macrophages. Further investigations showed A. fragrans could suppress iNOS expression. A. fragrans also inhibited the expression of tumor necrosis factor-alpha and interleukin-6. A. fragrans significantly decreased the degradation of IκBα, reduced the level of nuclear translocation of p65. All these results suggested the inhibitory effects of A. fragrans on the production of inflammatory mediators through the inhibition of the NF-κB activation pathway. CONCLUSION: Our results indicated that A. fragrans inhibited inflammatory events and iNOS expression in LPS-stimulated RAW264.7 cells through the inactivation of NF-κB pathway. This study gives scientific evidence that validate the use of A. fragrans in treatment of patients with gynecological diseases in clinical practice in traditional Chinese medicine.

Hypoglycemic effect of catalpol on high-fat diet/streptozotocin-induced diabetic mice by increasing skeletal muscle mitochondrial biogenesis.

Catalpol, an iridoid glycoside, exists in the root of Radix Rehmanniae. Some studies have shown that catalpol has a remarkable hypoglycemic effect in the streptozotocin-induced diabetic model, but the underlying mechanism for this effect has not been fully elucidated. Because mitochondrial dysfunction plays a vital role in the pathology of diabetes and because improving mitochondrial function may offer a new approach for the treatment of diabetes, this study was designed. Catalpol was orally administered together with metformin to high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice daily for 4 weeks. Body weight (BW), fasting blood glucose (FBG) level, and glucose disposal (IPGTT) were measured during or after the treatment. The results showed a dose-dependent reduction of FBG level with no apparent changes in BW through four successive weeks of catalpol administration. Catalpol treatment substantially reduced serum total cholesterol and triglyceride levels in the diabetic mice. In addition, catalpol efficiently increased mitochondrial ATP production and reversed the decrease of mitochondrial membrane potential and mtDNA copy number in skeletal muscle tissue. Furthermore, catalpol (200 mg/kg) rescued mitochondrial ultrastructure in skeletal muscle, as detected with transmission electron microscopy. The relative mRNA level of peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) α was significantly decreased in muscle tissue of diabetic mice, while this effect was reversed by catalpol, resulting in a dose-dependent up-regulation. Taken together, we found that catalpol was capable of lowering FBG level via improving mitochondrial function in skeletal muscle of HFD/STZ-induced diabetic mice.

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay.

AIM: Aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). METHODS: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. RESULTS: The Z' value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 µmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 µmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein. CONCLUSION: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.

Synthesis and biological evaluation of 2,3-diaryl isoquinolinone derivatives as anti-breast cancer agents targeting ERα and VEGFR-2.

The estrogen receptor α is recognized as important pharmaceutical target for breast cancer therapy, and vascular endothelial growth factor receptors (VEGFRs) play important roles in tumor angiogenesis including breast cancer. A series of 2,3-diaryl isoquinolinone derivatives were designed and synthesized targeting both estrogen receptor α (ERα) and VEGFR-2. Bioactivity evaluation showed that compounds 7c, 7d and 7f exhibited significant anti-proliferative and anti-angiogenesis activities via ERα and VEGFR-2 dependent mechanisms.

Deoxypodophyllotoxin exerts both anti-angiogenic and vascular disrupting effects.

A functioning vascular supply is essential for solid tumor growth and metastases, which means that blood vessels are an ideal target for antitumor drug discovery. Targeting tumor vasculature involves two main approaches, anti-angiogenesis and vascular disruption. The anti-angiogenic and vascular disrupting activities of deoxypodophyllotoxin (DPT), a natural microtubule destabilizer, were examined with several in vitro, ex vivo and/or in vivo models. First, we demonstrated that DPT significantly inhibits the proliferation, migration and tube formation of endothelial cells and inhibits angiogenesis in rat aortic ring and chick chorioallantoic membrane assays. In further studies, DPT induced cytoskeleton reorganization in endothelial cells, which likely contributed to the anti-angiogenic effect at non-cytotoxic concentrations. DPT treatment at higher concentrations for longer time induced the cell cycle arrest, which may contributes to its anti-proliferation effect and anti-angiogenic activity. And DPT dramatically inducted the expression of cyclin B1 and p21 (WAF1/CIP1). Meanwhile, DPT disrupted capillary-like networks in vitro and newly formed vessels from rat aortic rings. Endothelial cell contraction associated with an increase in F-actin via the Rho/Rho kinase pathway likely contributed to the vascular disrupting activity. Taken together, our results provided the initial evidence that DPT exerts potent anti-angiogenic and vascular disrupting effects. This study also provides important insight into the mechanism of action of promising new anticancer drugs with both anti-angiogenic and vascular disrupting activities.