BCI Improves Alcohol-Induced Cognitive and Emotional Impairments by Restoring pERK-BDNF.

Binge drinking causes a range of problems especially damage to the nervous system, and the specific neural mechanism of brain loss and behavioral abnormalities caused by which is still unclear. Extracellular regulated protein kinases (ERK) maintain neuronal survival, growth, and regulation of synaptic plasticity by phosphorylating specific transcription factors to regulate expression of brain-derived neurotrophic factor (BDNF). Dual-specific phosphatase 1 (DUSP1) and DUSP6 dephosphorylate tyrosine and serine/threonine residues in ERK1/2 to inactivate them. To investigate the molecular mechanism by which alcohol affects memory and emotion, a chronic intermittent alcohol exposure (CIAE) model was established. The results demonstrated that mice in the CIAE group developed short-term recognition memory impairment and anxiety-like behavior; meanwhile, the expression of DUSP1 and DUSP66 in the mPFC was increased, while the levels of p-ERK and BDNF were decreased. Micro-injection of DUSP1/6 inhibitor BCI into the medial prefrontal cortex (mPFC) restored the dendritic morphology by reversing the activity of ERK-BDNF and ultimately improved cognitive and emotional impairment caused by CIAE. These findings indicate that CIAE inhibits ERK-BDNF by increasing DUSP1/6 in the mPFC that may be associated with cognitive and emotional deficits. Consequently, DUSP1 and DUSP6 appear to be potential targets for the treatment of alcoholic brain disorders.

Low acyl gellan gum immobilized Lactobacillus bulgaricus T15 produce D-lactic acid from non-detoxified corn stover hydrolysate.

Straw biorefinery offers economical and sustainable production of chemicals. The merits of cell immobilization technology have become the key technology to meet D-lactic acid production from non- detoxified corn stover. In this paper, Low acyl gellan gum (LA-GAGR) was employed first time for Lactobacillus bulgaricus T15 immobilization and applied in D-lactic acid (D-LA) production from non-detoxified corn stover hydrolysate. Compared with the conventional calcium alginate (E404), LA-GAGR has a hencky stress of 82.09 kPa and excellent tolerance to 5-hydroxymethylfurfural (5-HMF), ferulic acid (FA), and vanillin. These features make LA-GAGR immobilized T15 work for 50 days via cell-recycle fermentation with D-LA yield of 2.77 ± 0.27 g/L h, while E404 immobilized T15 can only work for 30 days. The production of D-LA from non-detoxified corn stover hydrolysate with LA-GAGR immobilized T15 was also higher than that of free T15 fermentation and E404 immobilized T15 fermentation. In conclusion, LA-GAGR is an excellent cell immobilization material with great potential for industrial application in straw biorefinery industry.

In Silico and In Vivo Pharmacokinetic Evaluation of 84-B10, a Novel Drug Candidate against Acute Kidney Injury and Chronic Kidney Disease.

Acute kidney injury (AKI) and chronic kidney disease (CKD) have become public health problems due to high morbidity and mortality. Currently, drugs recommended for patients with AKI or CKD are extremely limited, and candidates based on a new mechanism need to be explored. 84-B10 is a novel 3-phenylglutaric acid derivative that can activate the mitochondrial protease, Lon protease 1 (LONP1), and may protect against cisplatin-induced AKI and unilateral ureteral obstruction- or 5/6 nephrectomy [5/6Nx]-induced CKD model. Preclinical studies have shown that 84-B10 has a good therapeutic effect, low toxicity, and is a good prospect for further development. In the present study, the UHPLC-MS/MS method was first validated then applied to the pharmacokinetic study and tissue distribution of 84-B10 in rats. Physicochemical properties of 84-B10 were then acquired in silico. Based on these physicochemical and integral physiological parameters, a physiological based pharmacokinetic (PBPK) model was developed using the PK-Sim platform. The fitting accuracy was estimated with the obtained experimental data. Subsequently, the validated model was employed to predict the pharmacokinetic profiles in healthy and chronic kidney injury patients to evaluate potential clinical outcomes. Cmax in CKD patients was about 3250 ng/mL after a single dose of 84-B10 (0.41 mg/kg), and Cmax,ss was 1360 ng/mL after multiple doses. This study may serve in clinical dosage setting in the future.

Non-Benzoquinone Geldanamycin Analog, WK-88-1, Induces Apoptosis in Human Breast Cancer Cell Lines.

Heat shock protein 90 (Hsp90) is treated as a molecular therapeutic target for the prevention and treatment of cancer. Geldanamycin (GA) was the first identified natural Hsp90 inhibitor, but hepatotoxicity has limited its clinical application. Nevertheless, a new GA analog (WK-88- 1) with the non-benzoquinone skeleton, obtained from genetically engineered Streptomyces hygroscopicus, was found to have anticancer activity against two human breast cancer cell lines. WK-88-1 produced concentration-dependent inhibition of cell proliferation, cell cycle arrest, and apoptosis in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cell lines. Detailed analysis showed that WK-88-1 downregulated some key cell cycle molecules (CDK1 and cyclin B1) and lead to G2/M cell cycle arrest. Further studies also showed that WK-88-1 could induce human breast cancer cell apoptosis by downregulating Hsp90 client proteins (Akt, p-Akt, IKK, c-Raf, and Bcl-2), decreasing the ATP level, increasing reactive oxygen species production, and lowering the mitochondrial membrane potential. Meanwhile, we discovered that WK-88-1 significantly decreased the levels of Her-2 and ER-α in MCF-7 cells but not in MDA-MB-231 cells. In addition, WK-88-1 significantly increased caspase-3, -8, and -9 activities and the cleavage of PARP in a concentration-dependent manner (with the exception of caspase-3 and PARP in MCF-7 cells). Taken together, our preliminary results suggest that WK-88-1 has the potential to play a role in breast cancer therapy.

Enzymatic synthesis of novel corylifol A glucosides via a UDP-glycosyltransferase.

Corylifol A, a member of the isoflavone subclass of isoflavonoids, has long been considered to have various biological activities. Here, we sought to synthesize corylifol A glucosides by the in vitro glucosylation reaction using the UDP-glycosyltransferase YjiC from Bacillus licheniformis DSM 13, and obtained two novel glucosides: corylifol A-4',7-di-O-beta-d-glucopyranoside (1) and corylifol A-4'-O-beta-d-glucopyranoside (2). To improve the yield of the products, the reaction time, concentration of UDP-glucose, and pH of the buffer were optimized. The Michaelis constant (Km) was calculated to be 2.88 mM, and the maximal velocity (Vmax) was calculated to be 77.32 nmol/min/mg for UDP-glycosyltransferase. Meanwhile, the water-solubility of compounds 1 and 2 was approximately 27.03 and 15.13 times higher, respectively, than that of their parent compound corylifol A. Additionally, the corylifol A glycosylated products exhibited the highest stability at pH 9.6 and better temperature stability than corylifol A at 40, 60, 80 and 100 °C. In addition, cytotoxicity activity assays against three human tumor cell lines, only corylifol A showed moderate anti-proliferative activity. Overall, this work demonstrates that glycosylation can enhance the water solubility and stability of promising compounds, with potential for further development and application.

[Biosynthesis of a new psoralidin glucoside by enzymatic glycosylation].

OBJECTIVE: To modify the structure of psoralidin using in vitro enzymatic glycosylation to improve its water solubility and stability. METHODS: A new psoralidin glucoside (1) was obtained by enzymatic glycosylation using a UDP- glycosyltransferase. The chemical structure of compound 1 was elucidated by HR-ESI-MS and nuclear magnetic resonance (NMR) analysis. The high-performance liquid chromatography (HPLC) peaks were integrated and sample solution concentrations were calculated. MTT assay was used to detect the cytotoxicity of the compounds against 3 cancer cell lines in vitro. Results Based on the spectroscopic data, the new psoralidin glucoside was identified as psoralidin-6',7-di-O-ß-D- glucopyranoside (1), whose water solubility was 32.6-fold higher than that of the substrate. Analyses of pH and temperature stability demonstrated that compound 1 was more stable than psoralidin at pH 8.8 and at high temperatures. Only psoralidin exhibited a moderate cytotoxicity against 3 human cancer cell lines. Conclusion In vitro enzymatic glycosylation is a powerful approach for structural modification and improving water solubility and stability of compounds.