.

Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes.

Body conformation traits in early-lactation associated with clinical mastitis and lameness in lactating Chinese holstein cows.

Background: Comprehending the correlation between body conformation traits of cows at the early stages of lactation and prevalent lactation diseases might facilitate the execution of selection and feeding strategies that prioritize cow health. This study aimed to evaluate the impact of body conformation traits on the incidence of clinical mastitis and lameness in Chinese Holstein cows. From a pasture herd of 1472 early lactating Chinese Holstein cows, we evaluated 20 body conformation traits.

Construction of a Dual-Mode Immune Platform Based on the Photothermal Effect of AgCo@NC NPs for the Detection of α-Fetoprotein.

Compared with the accuracy of a single signal and the limitation of environmental applicability, the application value of dual-mode detection is gradually increasing. To this end, based on the photothermal effect of Ag/Co embedded N-rich mesoporous carbon nanomaterials (AgCo@NC NPs), we designed a dual-mode signal response system for the detection of α-fetoprotein (AFP). First, AgCo@NC NPs act as a photothermal immunoprobe that converts light energy into heat driven by a near-infrared (NIR) laser and obtains temperature changes corresponding to the analyte concentration on a hand-held thermal imager.

Characterization of T-cell subsets in response to foot-and-mouth disease bivalent inactivated vaccine in Chinese Holstein cows.

Vaccination plays a crucial role in the prevention and control of FMD; however, outbreaks persist occurring worldwide. Assessing the immune response to FMD vaccines is essential for effective prevention of FMD. In this study, a seven-color flow cytometry protocol was developed to systematically evaluate the T-cell response of Chinese Holstein cows vaccinated with FMD bivalent inactivated vaccine.

Mantuoluosides A-H, new steroids isolated from the leaves of Datura stramonium L.

Eight new steroids, designated mantuoluosides A-H (1-8), were obtained from the enrichment of steroids of the Datura stramonium L. using HPD-BJQH macroporous resin. Their respective structures were elucidated based on spectroscopic methods and comparison data with literature.

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic.

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential for treating diseases such as cancer and infectious, inflammatory, and neurodegenerative diseases, especially for those with "undruggable" pathogenic protein targets. With the recent rise of the "molecular glue" type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed.

Exogenous Aβ monomers improve synaptic and cognitive function in Alzheimer's disease model mice.

Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer's disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-β peptide (Aβ) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aβ monomers could improve the impaired memory not only in cDKO mice without Aβ deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aβ deposition, which were mediated by α7-nAChR.

αCaMKII in the lateral amygdala mediates PTSD-Like behaviors and NMDAR-Dependent LTD.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals. However, its molecular and cellular mechanisms remain largely unexplored. Here, we found PTSD susceptible mice exhibited significant up-regulation of alpha-Ca/calmodulin-dependent kinase II (αCaMKII) in the lateral amygdala (LA).

Structure-Activity Relationship of -Carborane Selective Estrogen Receptor β Agonists.

Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored.

Oxyberberine Prevented Lipopolysaccharide-Induced Acute Lung Injury through Inhibition of Mitophagy.

Acute lung injury (ALI) is a serious respiratory syndrome characterized with uncontrolled inflammatory response. Oxyberberine has strong potential for clinical usage since it showed strong anti-inflammatory, antifungal, and antiarrhythmic effects in various diseases. In the present study, we evaluated whether oxyberberine can inhibit lipopolysaccharide- (LPS-) induced ALI and further evaluated the possible involvement of mitophagy by using A549 cells, a human lung epithelial cell line.

Pharmacokinetics and Tolerability of the Novel Non-immunosuppressive Fingolimod Derivative, OSU-2S, in Dogs and Comparisons with Data in Mice and Rats.

In this study, we characterized the pharmacokinetics of OSU-2S, a fingolimod-derived, non-immunosuppressive phosphatase activator, in mice, rats, and dogs, as well as tolerability and food effects in dogs. Across all species tested, plasma protein binding for OSU-2S was > 99.5%, and metabolic stability and hepatic intrinsic clearance were in the moderate range.

[Xuebijing injection attenuates hydrogen sulfide-induced endothelial barrier dysfunction by upregulating claudin-5 expression].

Objective: To study the new mechanism of Xuebijing injection improving the function of pulmonary vascular barrier from the perspective of claudin-5 protein.

Methods: Acute lung injury (ALI) model was induced by hydrogen sulfide (HS) exposure. (1) In vivo study: Sprague-Dawley (SD) rats were divided into control group, HS exposure group (exposure to 300×10 HS for 3 hours), Xuebijing control group (Xuebijing injection 4 mL/kg , twice a day, for 3 days), and Xuebijing intervention group (HS exposure after pretreatment of Xuebijing injection) according to random number method, with 6 rats in each group.

Improvement of intellectual outcomes in 20 children with refractory epilepsy after individualized surgery.

Background: Refractory epilepsy is a common and troublesome neurosurgical disease. This study is designed to compare seizure control and degrees in intellectual outcome in children with refractory epilepsy after surgical treatment.

Methods: 20 children with refractory epilepsy were treated with tailored epilepsy surgery or vagus nerve stimulation (VNS).

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats.

Multi-kinase inhibitors can associate with heat shock proteins through their NH2-termini by which they suppress chaperone function.

We performed proteomic studies using the GRP78 chaperone-inhibitor drug AR-12 (OSU-03012) as bait. Multiple additional chaperone and chaperone-associated proteins were shown to interact with AR-12, including: GRP75, HSP75, BAG2; HSP27; ULK-1; and thioredoxin. AR-12 down-regulated in situ immuno-fluorescence detection of ATP binding chaperones using antibodies directed against the NH2-termini of the proteins but only weakly reduced detection using antibodies directed against the central and COOH portions of the proteins.

AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis.

In cancer cells, the epithelial-mesenchymal transition (EMT) confers the ability to invade basement membranes and metastasize to distant sites, establishing it as an appealing target for therapeutic intervention. Here, we report a novel function of the master metabolic kinase AMPK in suppressing EMT by modulating the Akt-MDM2-Foxo3 signaling axis. This mechanistic link was supported by the effects of siRNA-mediated knockdown and pharmacologic activation of AMPK on epithelial and mesenchymal markers in established breast and prostate cancer cells.

G15, a GPR30 antagonist, induces apoptosis and autophagy in human oral squamous carcinoma cells.

As GPR30 has been implicated in mediating cancer cell proliferation, this study aimed to examine the antitumor effect of the GPR30 antagonist G15 in human oral squamous cell carcinoma (OSCC). G15 induced dose-dependent cytotoxicity, apoptosis and G2/M cell cycle arrest in a panel of OSCC cells. The results showed that G15 could inhibit the growth of the oral cancer cells with IC50 value 11.

Vitamin E facilitates the inactivation of the kinase Akt by the phosphatase PHLPP1.

Vitamin E is a fat-soluble vitamin with antioxidant properties. Tocopherols are the predominant form of vitamin E found in the diet and in supplements and have garnered interest for their potential cancer therapeutic and preventive effects, such as the dephosphorylation of Akt, a serine/threonine kinase with a pivotal role in cell growth, survival, and metabolism. Dephosphorylation of Akt at Ser473 substantially reduces its catalytic activity and inhibits downstream signaling.

Suppression of prostate epithelial proliferation and intraprostatic progrowth signaling in transgenic mice by a new energy restriction-mimetic agent.

Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition.

Development of novel antibacterial agents against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to public health because of its resistance to multiple antibiotics most commonly used to treat infection. In this study, we report the unique ability of the cyclooxygenase-2 (COX-2) inhibitor celecoxib to kill Staphylococcus aureus and MRSA with modest potency. We hypothesize that the anti-Staphylococcus activity of celecoxib could be pharmacologically exploited to develop novel anti-MRSA agents with a distinct mechanism.

Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals.

Tetraspanins are commonly believed to act only as "molecular facilitators," with no direct role in signal transduction. We herein demonstrate that upon ligation, CD37, a tetraspanin molecule expressed on mature normal and transformed B cells, becomes tyrosine phosphorylated, associates with proximal signaling molecules, and initiates a cascade of events leading to apoptosis. Moreover, we have identified two tyrosine residues with opposing regulatory functions: one lies in the N-terminal domain of CD37 in a predicted "ITIM-like" motif and mediates SHP1-dependent death, whereas the second lies in a predicted "ITAM motif" in the C-terminal domain of CD37 and counteracts death signals by mediating phosphatidylinositol 3-kinase-dependent survival.