Rational drug design of CB2 receptor ligands: from 2012 to 2021.

Cannabinoid receptors belong to the large family of G-protein-coupled receptors, which can be divided into two receptor types, cannabinoid receptor type-1 (CB1) and cannabinoid receptor type-2 (CB2). Marinol, Cesamet and Sativex are marketed CB1 drugs which are still in use and work well, but the central nervous system side effects caused by activation CB1, which limited the development of CB1 ligands. So far, no selective CB2 ligand has been approved for marketing, but lots of its ligands in the clinical stage and pre-clinical stage have positive effects on the treatment of some disease models and have great potential for development. Most selective CB2 agonists are designed and synthesized based on non-selective CB2 agonists through the classical med-chem strategies, e.g. molecular hybridization, scaffold hopping, bioisosterism, etc. During these processes, the balance between selectivity, activity, and pharmacokinetic properties needs to be achieved. Hence, we summarized some reported ligands on the basis of the optimization strategies in recent 10 years, and the limitations and future directions.

100 Gb/s NRZ OOK signal regeneration using four-wave mixing in a silicon waveguide with reverse-biased p-i-n junction.

A silicon waveguide with reverse-biased p-i-n junction is used to experimentally demonstrate all-optical regeneration of non-return-to-zero (NRZ) on-off keying (OOK) signal based on four-wave mixing. The silicon waveguide allows a high conversion efficiency of -12 dB. The 0.22 dB (1.1 dB) quality (Q) factor and 0.74 dB (6.3 dB) extinction ratio (ER) improvements on average are achieved for 100 Gb/s (50 Gb/s) NRZ OOK signal regeneration at different receiving powers via the optimal match between the input signal optical power and input-output transfer curve. To the best of our knowledge, this silicon-based all-optical regenerator exhibits superior regeneration performance, including large ER and Q factor improvements, and the highest regeneration speed of NRZ OOK signal, and it has wide applications in 5 G/6 G networks.

DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output.

A DNA-encoded library is a collection of small molecules covalently linked to DNA that has unique information about the identity and the structure of each library member. A DNA-encoded chemical library (DEL) is broadly adopted by major pharmaceutical companies and used in numerous drug discovery programs. The application of the DEL technology is advantageous at the initial period of drug discovery because of reduced cost, time, and storage space for the identification of target compounds. The key points for the construction of DELs comprise the development and the selection of the encoding methods, transfer of routine chemical reaction from off-DNA to on-DNA, and exploration of new chemical reactions on DNA. The limitations in the chemical space and the diversity of DEL were reduced gradually by using novel DNA-compatible reactions based on the formation and the cleavage of various bonds. Here, we summarized a series of novel DNA-compatible chemistry reactions for DEL building blocks and analysed the druggability of screened hit molecules via DELs in the past five years.

Effect of Quyu Chencuo Formula () on Renal Fibrosis in Obstructive Nephropathy Rats.

OBJECTIVE: To observe the effect of Quyu Chencuo Formula (, QCF) on renal fibrosis in rats with obstructive nephropathy. METHODS: Twenty-four rats were randomly divided into three groups, 4 for sham operation as the control group, 10 for unilateral ureteral obstruction (UUO) model group, and the rest 10 for QCF treating UUO model group. All rats were sacrificed under 3% pentobarbital (50 mg/kg) anesthesia on the 14th day after surgery, then the right kidney samples of rats were harvested for hematoxylin eosin (HE) staining and Masson staining to observe the renal pathological changes. Immunohistochemistry and Western blotting were used to examine the expression of transforming growth factor ß1 (TGF-ß1), and real-time polymerase chain reaction (RT-PCR) was employed to examine the expressions of TGF-ß1, α-smooth muscle actin (α-SMA) and E-cadherin mRNA. RESULTS: HE and Masson staining showed that the renal interstitial of the rats in the control group had no significant fibrotic lesion; in the model group, there were obvious interstitial fibrosis; for the QCF group, there were epithelial cell necrosis, infiltration of lymphocytes and mononuclear cells, aggravated interstitial fibrosis in varied degrees, but the pathological changes were less in the QCF group than in the model group. The immunohistochemistry and Western blotting results showed that the TGF-ß1 expression was increased significantly in the model group, while decreased significantly in the QCF group (P<0.05); RT-PCR showed that the mRNA expression of α-SMA and TGF-ß1 increased significantly in the model group, while both were significantly decreased in the QCF group compared with the model group (P<0.05). The mRNA expression of E-cadherin was decreased significantly in the model group, and it was significantly increased in the QCF group as compared with the model group (P<0.05). CONCLUSION: QCF may improve renal fibrosis by regulating the expressions of TGF-ß1, α-SMA and E-cadherin, and prevent the progress of kidney fibrosis.

Novel spirocyclic tranylcypromine derivatives as lysine-specific demethylase 1 (LSD1) inhibitors.

Herein we describe the design, synthesis, and biological evaluation of a novel series of tranylcypromine-based LSD1 inhibitors via conformational restriction using spiro ring systems. A simple, direct spirocyclic analog of tranylcypromine (compounds 8a and 8b) was shown to be a 28- to 129-fold more potent inhibitor of LSD1 enzyme compared to tranylcypromine. Further incorporation of various substituted benzyl groups to the amino group resulted in a suite of 2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-amines that are potent LSD1 inhibitors with excellent selectivity profiles (e.g.14a, 15b, 16a, 19a and 20b) against closely related enzymes such as MAO-A, MAO-B, and LSD2.

A systematic review and meta-analysis comparing the prognosis of multicentric occurrence and vs. intrahepatic metastasis in patients with recurrent hepatocellular carcinoma after hepatectomy.

BACKGROUND: The aim of this meta-analysis was to evaluate the prognosis of patients with different types of hepatocellular cancer (HCC) recurrence following hepatectomy. Specifically, it evaluated overall survival and disease-free survival in HCC patients with multicentric occurrence (MO) or intrahepatic metastasis (IM). METHODS: Medline, Cochrane, EMBASE, and Google Scholar were searched until August 22, 2016 using the following search terms: hepatocellular carcinoma, multicentric occurrence, intrahepatic metastasis, early recurrence, and late recurrence. Prospective, retrospective, and case control studies were included. RESULTS: The pooled results showed that patients in the MO group had lower risk of death than the IM group (pooled HR = 0.495, 95% CI = 0.378 to 0.648, P < 0.001). The MO group also had significantly longer disease-free survival than the IM group (pooled HR = 0.774, 95% CI = 0.663 to 0.903, P = 0.001). Sensitivity analysis indicated that no one study dominated the findings and that the data are robust. Overall the included studies were of good quality. CONCLUSION: This study found that MO patients have greater survival following surgery than IM patients, indicating the prognosis of MO patients is significantly better than that for IM patients.

Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis.

Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.

MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer.

Our study aimed to explore associations between microRNA-21 (miR-21) and PTEN/PI3K/AKT signaling pathway and, further, to elucidate the regulation of miR-21 on biological behaviors in human esophageal cancer cells. The expressions of miR-21, PTEN, PI3K, and AKT were detected in 89 esophageal cancer samples and 58 adjacent normal tissues respectively. The human esophageal cancer cells (TE11) were grouped as following: blank (TE11 cells without transfection), negative (TE11 cells with miR-21 negative inhibitor), and Inhibition-miR21 (TE11 cells with miR-21 inhibitor). Western blot was used for detection of PTEN, P13K, and AKT protein expressions, MTT method for cell proliferation, Transwell assay for cell migration and invasion, and flow cytometry for cell cycle and apoptosis. MiR-21, PI3K, and AKT have higher expressions, but PTEN has lower expression in esophageal cancer tissues compared with adjacent normal tissues. The esophageal cancer tissues with lymph node metastasis and poor differentiation showed significantly low positive rate of PTEN protein, but high positive rates of PI3K and AKT proteins. Compared with blank and negative groups, PTEN expression of TE11 cells in Inhibition-miR21 group was significantly up-regulated, but PI3K and AKT were down-regulated. Further, PTEN was a target gene of miR-21. Besides, compared with blank and negative groups, the proliferation, migration, and invasion of TE11 cells were less active in Inhibition-miR21 group. TE11 cells were significantly increased in the G0/G1 phase of cell cycles, but decreased in the S and G2/M phase in Inhibition-miR21 group. The TE11 cells exhibited significantly increased apoptosis rates. MiR-21 targets key proteins in PTEN/PI3K/AKT signal pathway, promoting proliferation, migration, invasion, and cell cycle, and inhibiting apoptosis of human esophageal cancer cells. It may serve as a novel therapeutic target in esophageal cancer.