Synthesis and Evaluation of 4-Cycloheptylphenols as Selective Estrogen Receptor-β Agonists (SERBAs)

A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the β over α isoform and with EC50 of 30–50 nM in cell-based and direct binding assays

The effects of supervised exercise training on weight control and other metabolic outcomes in patients with type 2 diabetes: a meta-analysis

Few studies have investigated the dose–response relationship between exercise and weight control. This study aimed to assess the effects of different types of supervised exercise training on weight control and other metabolic outcomes in patients with type 2 diabetes mellitus and explore the dose–response relationship between exercise volume/duration and these outcomes. PubMed/MEDLINE, Embase, and Cochrane databases were searched for studies between January 1980 and June 2019. Randomized control trials in type 2 diabetes mellitus patients with supervised exercise training versus control treatment were included. The primary outcome was changes in body weight (kg). The secondary outcomes included changes in waist circumference (cm) and total body fat percentage (%). Forty-two randomized control trials, including 3,625 patients with type 2 diabetes mellitus were included. Overall, exercise treatment was associated with significant reduction in body weight (weighted mean differences, −1.10 kg; 95% CI [−1.58, −0.62], p

A–C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions

Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A–C estrogens, lacking the B and D estrogen rings. The most potent and selective A–C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC50s of 20–30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound’s ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A–C estrogen is selective, brain penetrant, and facilitates memory consolidation

Stomatal responses of terrestrial plants to global change

Quantifying the stomatal responses of plants to global change factors is crucial for modeling terrestrial carbon and water cycles. Here we synthesize worldwide experimental data to show that stomatal conductance (gs) decreases with elevated carbon dioxide (CO2), warming, decreased precipitation, and tropospheric ozone pollution, but increases with increased precipitation and nitrogen (N) deposition. These responses vary with treatment magnitude, plant attributes (ambient gs, vegetation biomes, and plant functional types), and climate. All two-factor combinations (except warming + N deposition) significantly reduce gs, and their individual effects are commonly additive but tend to be antagonistic as the effect sizes increased. We further show that rising CO2 and warming would dominate the future change of plant gs across biomes. The results of our meta-analysis provide a foundation for understanding and predicting plant gs across biomes and guiding manipulative experiment designs in a real world where global change factors do not occur in isolation

Evaluation of the Agricultural Non-point Source Pollution in Chongqing Based on PSR Model

Through a series of exploration based on PSR framework model, for the purpose of building a suitable Chongqing agricultural non-point source pollution evaluation index system model framework, combined with the presence of Chongqing specific agro-environmental issues, we build a agricultural non-point source pollution assessment index system, and then study the agricultural system pressure, agro-environmental status and human response in total 3 major categories, develope an agricultural non-point source pollution evaluation index consisting of 3 criteria indicators and 19 indicators. As can be seen from the analysis, pressures and responses tend to increase and decrease linearly, state and complex have large fluctuations, and their fluctuations are similar mainly due to the elimination of pressures and impact, increasing the impact for agricultural non-point source pollution

iRoot SP Promotes Osteo/Odontogenesis of Bone Marrow Mesenchymal Stem Cells via Activation of NF-κB and MAPK Signaling Pathways

The regeneration of bone and tooth tissues, and related cellular therapies, has attracted widespread attention. Bone marrow mesenchymal stem cells (BMSCs) are potential candidates for such regeneration. iRoot SP is a premixed bioceramic root canal sealer widely used in clinical settings. However, the effect of iRoot SP on the biological features of BMSCs has not been elucidated. In the present study, we found that 0.2 mg/ml iRoot SP conditioned medium promoted osteo/odontogenic differentiation and enhanced mineralization of BMSCs without affecting the proliferative ability. Mechanistically, the NF-κB and MAPK signaling pathways were activated in SP-treated BMSCs, and differentiation was inhibited when cultured with the specific inhibitor. Taken together, these findings demonstrate that iRoot SP promotes osteo/odontogenic differentiation of BMSCs via the NF-κB and MAPK signaling pathways, which could provide a new theoretical basis for clinical applications of iRoot SP and a new therapeutic target for the regeneration of bone and tooth tissue in the future

Data from: Modulation of functional activity and connectivity by acupuncture in patients with Alzheimer disease as measured by resting-state fMRI

Acupuncture has been used in the therapy of Alzheimer disease (AD); however, its neural mechanisms are still unclear. The aim of this study is to examine the effect of acupuncture on the functional connectivity in AD by using resting-state functional magnetic resonance imaging (rs-fMRI). Twenty-eight subjects (14 AD and 14 normal controls) participated in this study. The rs-fMRI data were acquired before and after acupuncture stimulation at the acupoints of Tai chong (Liv3) and Hegu (LI4). During the baseline resting state, by using the amplitude of low-frequency fluctuations (ALFF), we found a significantly decreased or increased ALFF in the AD patients relative to the controls. These regions were located in the right superior frontal gyrus (SFG), left postcentral gyrus, subgenual cingulate cortex (SCC), right middle cingulate cortex (MCC), right inferior frontal gyrus (IFG), right hippocampus and the right inferior temporal gyrus (ITG). Then, we selected these brain regions as seeds to investigate whether regional activity and functional connectivity could be modulated by acupuncture in the AD patients. When compared to the pre-acupuncture stage, several of the above regions showed an increased or decreased ALFF after acupuncture in the AD patients. In addition, the functional connectivity between the hippocampus and the precentral gyrus showed enhancement after acupuncture in the AD patients. Finally, there were close correlations between the functional activity, connectivity and clinical performance in the AD patients. The current study confirmed that acupuncture at Tai chong (Liv3) and He gu (LI4) can modulate functional activity and connectivity of specific cognition-related regions in AD patients

Dentin-Derived Inorganic Minerals Promote the Osteogenesis of Bone Marrow-Derived Mesenchymal Stem Cells: Potential Applications for Bone Regeneration

Background. Oral and maxillofacial bone loss is highly prevalent among populations, and nowadays, increased attention has been focused on dentin derivatives serving as desirable graft materials for bone regeneration. In this study, dentin-derived inorganic mineral (DIM) was fabricated with a high-temperature calcination technique and the effects of DIM on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) and the bone formation were elucidated. Methods. The effects of DIM on BMMSC proliferation and apoptosis capacity were evaluated by CCK-8, flow cytometry, and EdU assays. Alkaline phosphatase (ALP) activity detection, ALP staining, alizarin red staining, and osteogenic marker expression analysis were performed to investigate the influence of DIM on the osteogenic differentiation of BMMSCs, as well as the relevant signal mechanisms. The model of critical-sized defects in the calvarium of rats was constructed for exploring the in vivo efficiency of DIM on bone regeneration. Results. Cell viability assays indicated that DIM had no cytotoxicity. BMMSCs cultured with DIM presented a higher level of osteogenic differentiation ability than those in the control group. The activation in ERK and p38 signals was detected in DIM-treated BMMSCs, and both pathways and osteogenic process were suppressed while using ERK inhibitor U0126 and p38 inhibitor SB203580, respectively. Furthermore, the animal experiments revealed that DIM could dramatically enhance new bone formation compared to the control group. Conclusion. DIM could promote BMMSC osteogenic differentiation via triggering the ERK and p38 MAPK signaling pathways and might be a novel predictable material for facilitating bone formation