The G‐protein‐coupled receptor 40 agonist (GPR40) TAK‐875 is being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pharmacometric approaches such as model‐based exposure‐response and meta‐analyses were applied to (i) characterize exposure/dose–efficacy responses of TAK‐875, (ii) characterize the time course of glycosylated hemoglobin A1c (HbA1c) response with TAK‐875 6.25 to 200 mg q.d. doses for 12 weeks, (iii) project and compare HbA1c response with dipeptidyl peptidase 4 (DPP‐4) inhibitors and TAK‐875 up to 24 weeks, and (iv) provide a quantitative rationale for dose selection in phase 3. On the basis of phase 2 data, relationships between TAK‐875 concentrations and HbA1c were well characterized by exposure–response models. EC₅₀ and E_max of TAK‐875 were estimated to be 3.16 µg/ml and 0.366, respectively. Model‐based simulations over 24 weeks indicated that the 25‐ and 50‐mg q.d. doses of TAK‐875 achieve efficacy as comparable with or better than that of commonly used antidiabetic agents. CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e22; doi:10.1038/psp.2012.23; advance online publication 9 January 2013

This study sought to determine the relationship among broiler performance, organ development, and indicators of microbiota colonization. A total of 1,200 two-day-old male Ross 308 broiler chicks, divided among 3 cohorts of equal size, were housed in battery cages, and allotted based on body weight. On study d 11, birds were weighed, and birds with BW gain within the 10th and 90th percentiles were assigned to the Slow and Fast groups, respectively. Birds (n = 30 for each group) selected on d 11 were provided water and a corn-soybean meal-based diet ad libitum while maintained individually through study d 25 (i.e., a 14-d growth period). Parameters regarding growth performance, organ and intestine weights and lengths, and intestinal volatile fatty acid concentrations were measured. All data were analyzed by one-way ANOVA using the Mixed procedure of SAS. Fast birds exhibited greater (P < 0.001) BW gain and feed intake than slow birds, but feed conversion ratio (FCR) did not differ (P = 0.19). Additionally, Slow birds had higher (P < 0.05) relative weights (% of BW) for nearly all organs on d 11 and 25, most notably the gizzard, proventriculus, pancreas, and liver. Conversely, intestinal sections were longer (P < 0.05) in the Fast birds. Measurement of gut histomorphology did not show any notable differences between growth rate groups in terms of villi height, crypt depth, or their ratio for either time-point (P > 0.05). In terms of volatile fatty acid concentrations of luminal contents, acetate concentrations were 10.2% higher (P < 0.001) in the ileum of the Slow birds compared with Fast birds on d 25. Overall, the findings suggest that total BW gain is influenced by the development of metabolically active organs, as supported by lower weight gain in Slow birds with relatively larger organ weights and shorter intestinal lengths than their Fast counterparts. The general lack of differences in fermentation end-product concentrations in luminal contents does not rule out influence of the microbiota on growth rate of broilers, which warrants further investigation.

Objective: To develop a novel multi-TE MR spectroscopic imaging (MRSI) approach to enable label-free, simultaneous, high-resolution mapping of several molecules and their biophysical parameters in the brain. Methods: The proposed method uniquely integrated an augmented molecular-component-specific subspace model for multi-TE $^{1}$H-MRSI signals, an estimation-theoretic experiment optimization (nonuniform TE selection) for molecule separation and parameter estimation, a physics-driven subspace learning strategy for spatiospectral reconstruction and molecular quantification, and a new accelerated multi-TE MRSI acquisition for generating high-resolution data in clinically relevant times. Numerical studies, phantom and in vivo experiments were conducted to validate the optimized experiment design and demonstrate the imaging capability offered by the proposed method. Results: The proposed TE optimization improved estimation of metabolites, neurotransmitters and their $T_{2}$’s over conventional TE choices, e.g., reducing variances of neurotransmitter concentration by $\sim\! 40\%$ and metabolite $T_{2}$ by $\sim\! 60\%$. Simultaneous metabolite and neurotransmitter mapping of the brain can be achieved at a nominal resolution of 3.4 × 3.4 × 6.4 mm$^{3}$. High-resolution, 3D metabolite $T_{2}$ mapping was made possible for the first time. The translational potential of the proposed method was demonstrated by mapping biochemical abnormality in a post-traumatic epilepsy (PTE) patient. Conclusion: The feasibility for high-resolution mapping of metabolites/neurotransmitters and metabolite $T_{2}$’s within clinically relevant time was demonstrated. We expect our method to offer richer information for revealing and understanding metabolic alterations in neurological diseases. Significance: A novel multi-TE MRSI approach was presented that enhanced the technological capability of multi-parametric molecular imaging of the brain. The proposed method presents new technology development and application opportunities for providing richer molecular level information to uncover and comprehend metabolic changes relevant in various neurological applications.

Objectives: This work aimed to quantitatively evaluate circulating interleukin concentration data available for patients with Type 2 diabetes. Methods: We performed a systematic review using PubMed, Web of Science, and the Cochrane Library. Original studies reporting data on circulating interleukin concentrations in at least one group of patients with Type 2 diabetes (obese Type 2 diabetes [OBD], overweight Type 2 diabetes [OWD], or lean Type 2 diabetes [LD]) and healthy weight controls (HWCs) were included. Data were extracted from 43 included studies uniquely encompassing 2646 patients with Type 2 diabetes and 6605 HWCs by independent investigators. We used a random‐effects model to pool data in the Comprehensive Meta‐Analysis Version 2 software. Effect sizes (ESs) were calculated as the standardized mean difference in interleukin concentrations between groups and then transformed into Hedge's g statistic. Results: Our results revealed higher circulating concentrations in patients with Type 2 diabetes compared with HWCs, including IL‐4, IL‐6, IL‐17, and IL‐18. When stratified by BMI subgroups, all patients with Type 2 diabetes displayed elevated IL‐6 concentrations compared with HWCs, with OBD patients having the highest ES, followed by OWD and LD. Similar to the overall results, higher interleukin concentrations in different BMI subgroups of patients with Type 2 diabetes were observed compared with HWCs in IL‐4 (OWD), IL‐17 (LD), and IL‐18 (OBD, but not OWD). Conclusion: Meta‐analysis outcomes demonstrated higher circulating concentrations of IL‐4, IL‐6, IL‐17, and IL‐18 in patients with Type 2 diabetes, strengthening the clinical evidence that Type 2 diabetes is accompanied by a systemic inflammatory response.

Polygonum multiflorum is a traditional Chinese medicinal herb used to nourish the blood, promote hair growth, and support neurological health. Its key bioactive component, 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), has shown potent antioxidant and anti-aging properties, making it a representative marker compound in modern pharmacological studies. We aimed to investigate the neuroprotective effects of THSG against cadmium (Cd)-induced neurotoxicity and to elucidate its underlying molecular mechanisms using both in vitro cellular models and an in vivo murine model. Male mice, 8 weeks of age, were randomly assigned to four groups: control, Cd-exposed, THSG-treated, and Cd+THSG co-treated. After 30 days of Cd exposure with or without THSG, behavioral tests, histological analysis, and assays for oxidative stress and inflammatory markers were conducted. In vitro, SH-SY5Y, BV2, and GL261 cells were used to investigate the cytoprotective and mechanistic effects of THSG against Cd-induced neurotoxicity via WST-1, RT-qPCR, Western blotting, LDH release, and immunofluorescence assays. THSG treatment significantly improved spatial learning and memory performance in Cd-exposed mice, while also effectively suppressing microglial and astrocyte activation and alleviating neuronal damage. In vitro, THSG alleviated Cd-induced cytotoxicity and morphological damage in neurons and glial cells. Western blot and immunofluorescence analyses revealed that THSG activated the BDNF/TrkB and PI3K/Akt signaling pathways, contributing to its neuroprotective effects. THSG confers robust neuroprotection against Cd-induced toxicity through multi-target mechanisms involving BDNF/TrkB and PI3K/Akt pathway activation, supporting its potential as a promising therapeutic agent for heavy metal-induced neurodegeneration.