Discovery and development of novel rhodanine derivatives targeting enoyl-acyl carrier protein reductase.

A series of rhodanine derivatives RB1-RB23 were synthesized through a two-round screening. Their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability were evaluated. The most potent hit compound RB23 indicated comparable InhA inhibiton (IC50 = 2.55 µM) with the positive control Triclosan (IC50 = 6.14 µM) and Isoniazid (IC50 = 8.29 µM). Its improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation revealed the possible binding pattern of this series and picked the key interacted residues as Ser20, Phe149, Lys165 and Thr196. The 3D-QSAR model visualized the SAR discussion and hinted new information. Modifying the surroundings near rhodanine moiety might be promising attempts in later investigations.

Discovery of novel oxoindolin derivatives as atypical dual inhibitors for DNA Gyrase and FabH.

The antibacterial agents and therapies today are facing serious problems such as drug resistance. Introducing dual inhibiting effect is a valid approach to solve this trouble and bring advantages including wide adaptability, favorable safety and superiority of combination. We started from potential DNA Gyrase inhibitory backbone isatin to develop oxoindolin derivatives as atypical dual Gyrase (major) and FabH (assistant) inhibitors via a two-round screening. Aiming at blocking both duplication (Gyrase) and survival (FabH), most of synthesized compounds indicated potency against Gyrase and some of them inferred favorable inhibitory effect on FabH. The top hit I18 suggested comparable Gyrase inhibitory activity (IC50 = 0.025 µM) and antibacterial effect with the positive control Novobiocin (IC50 = 0.040 µM). FabH inhibitory activity (IC50 = 5.20 µM) was also successfully introduced. Docking simulation hinted possible important interacted residues and binding patterns for both target proteins. Adequate Structure-Activity Relation discussions provide the future orientations of modification. With high potency, low initial toxicity and dual inhibiting strategy, advanced compounds with therapeutic methods will be developed for clinical application.

Introducing Broadened Antibacterial Activity to Rhodanine Derivatives Targeting Enoyl-Acyl Carrier Protein Reductase.

Broadened antibacterial activity was introduced to rhodanine derivatives targeting Mycobacterial tuberculosis enoyl-acyl carrier protein reductase (Mtb InhA) by recruiting feature of xacins to bring DNA Gyrase B inhibitory capability. This is significant for preventing further bacterial injections in the tuberculosis treatment. The most potent compound Cy14 suggested comparable bioactivity (IC50 = 3.18 µM for Mtb InhA; IC50 = 10 nM for DNA Gyrase B) with positive controls. Structure-activity relationship discussion and molecular docking model revealed the significance of rhodanine moiety and derived methoxyl on meta-position, pointing out orientations for future modification.

Pancreatic stellate cells increase pancreatic cancer cells invasion through the hepatocyte growth factor /c-Met/survivin regulated by P53/P21.

Pancreatic stellate cells (PSCs) are a key cellular component of the pancreatic tumor microenvironment and are considered to contribute to tumor invasion and metastasis. Multiple cytokines and growth factors derived from PSCs are involved in malignant cancer progression, including hepatocyte growth factor (HGF). However, the molecular mechanisms by which HGF regulates cancer invasion and metastasis have not been completely elucidated. Here, we report that two pancreatic cancer (PC) cell lines, Panc-1 and SW1990, displayed different invasive and migratory abilities after treatment with HGF secreted by PSCs. We found that HGF enhanced the invasive and migratory capacity of Panc-1 cells because of P53 deficiency, leading to overexpression of c-Met, which was regulated through P21. Additionally, our data showed that HGF/c-Met-mediated invasion and migration required the upregulation of survivin expression. In conclusion, PSCs promote PC cells invasion and migration via the HGF/c-Met/survivin pathway, which is negatively regulated by P53/P21.

Detection Methods and Research Progress of Human Serum Albumin.

Human serum albumin (HSA) is a biological macromolecule with important physiological functions; abnormal HSA levels are associated with coronary heart disease, multiple myeloma, diabetes, nephropathy, neurometabolic disorders, liver cirrhosis and other diseases. Therefore, accurate and quantitative detection of HAS have extremely important research and application value in biological science, molecular biology, clinical medicine and other fields. As for the detection method of HSA, dye-binding method and immune method are the first to be used, and have been applied in clinical detection. In recent years, many new detection technologies have emerged, such as fluorescent probe detection method, nano-materials for HSA detection, biosensor and so on. Although there are many methods developed recently to detect HSA, comprehensive reviews for HSA detection methods are still rare. Thus, writing this review to fill in the blank is in need. In order to highlight the recent progress in the field of HSA detection, in this review, the methods used to detect HSA are summarized and sorted, the advantages and disadvantages of these detection methods are also listed, then the research progress of small molecular fluorescence probe method is emphatically introduced in this paper. Then, we briefly discussed the challenges and future development directions in this field.

[A study of microPET for assessing regional cerebral glucose metabolism and the expression of dopamine receptor type 2 in a rat model of Parkinson's disease].

OBJECTIVE: To employ (18)F-fluoro-2-deoxyglucose ((18)F-FDG) and (3-N-[(11)C] methylspiperone)(11)C-NMSP microPET to assess the changes of regional cerebral glucose metabolism and the expression of dopamine receptor type 2 (DRD(2)) in a rat model of Parkinson's disease (PD). METHODS: A hemiparkinsonian model was established in rats by unilateral pretreatment with 6-hydroxydopamine (6-OHDA). At 2 weeks after 6-OHDA insult, (18)F-FDG and (11)C-NMSP microPET scan were performed to compare the differences of regional cerebral glucose metabolism and the expression of DRD(2) between the PD and control groups respectively. The immunohistochemical staining was used to detect the expression of tyrosine hydroxylase in two groups. RESULTS: In the PD model, the glucose metabolism rates were 88.2% ± 2.2%, 94.5% ± 4.5% and 96.2% ± 5.8% respectively, in right striatum, hippocampus and sensorimotor cortex. And they were significantly lower than those in the control group [92.7% ± 2.8% (P < 0.01), 98.9% ± 3.9% (P < 0.01) & 102.8% ± 2.1% (P < 0.01)]. The expression of DRD(2) in right striatum was significantly higher in the PD group than that in the control group (112.9% ± 9.0% vs 102.3% ± 1.4%, P < 0.01). CONCLUSION: In the PD rats, glucose metabolism decreases in injured side striatum, hippocampus and sensorimotor cortex while and the expression of DRD(2) increases in injured side striatum.(18)F-FDG and (11)C-NMSP microPET can effectively assess the regional cerebral glucose metabolism and the expression of DRD(2) in PD. They may serve as effective molecular imaging tools for an early diagnosis of PD.

Cloning and functional characterization of SAD genes in potato.

Stearoyl-acyl carrier protein desaturase (SAD), locating in the plastid stroma, is an important fatty acid biosynthetic enzyme in higher plants. SAD catalyzes desaturation of stearoyl-ACP to oleyl-ACP and plays a key role in determining the homeostasis between saturated fatty acids and unsaturated fatty acids, which is an important player in cold acclimation in plants. Here, four new full-length cDNA of SADs (ScoSAD, SaSAD, ScaSAD and StSAD) were cloned from four Solanum species, Solanum commersonii, S. acaule, S. cardiophyllum and S. tuberosum, respectively. The ORF of the four SADs were 1182 bp in length, encoding 393 amino acids. A sequence alignment indicated 13 amino acids varied among the SADs of three wild species. Further analysis showed that the freezing tolerance and cold acclimation capacity of S. commersonii are similar to S. acaule and their SAD amino acid sequences were identical but differed from that of S. cardiophyllum, which is sensitive to freezing. Furthermore, the sequence alignments between StSAD and ScoSAD indicated that only 7 different amino acids at residues were found in SAD of S. tuberosum (Zhongshu8) against the protein sequence of ScoSAD. A phylogenetic analysis showed the three wild potato species had the closest genetic relationship with the SAD of S. lycopersicum and Nicotiana tomentosiformis but not S. tuberosum. The SAD gene from S. commersonii (ScoSAD) was cloned into multiple sites of the pBI121 plant binary vector and transformed into the cultivated potato variety Zhongshu 8. A freeze tolerance analysis showed overexpression of the ScoSAD gene in transgenic plants significantly enhanced freeze tolerance in cv. Zhongshu 8 and increased their linoleic acid content, suggesting that linoleic acid likely plays a key role in improving freeze tolerance in potato plants. This study provided some new insights into how SAD regulates in the freezing tolerance and cold acclimation in potato.