Renal nerve stimulation identifies renal innervation and optimizes the strategy for renal denervation in canine.

BACKGROUND: Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. METHODS: The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. RESULTS: The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P < 0.001). In addition, ablation at BP-elevation sites can result in a significant decrease in BP and plasma norepinephrine (NE) after 4 weeks (P = 0.002; P = 0.008), while ablation at BP-reduction sites can lead to significant increases in BP and plasma NE (P = 0.016; P = 0.033). CONCLUSIONS: RNS is an effective method to identify renal autonomic innervation. It could not only help to identify optimal target sites, but also avoid ablation of sympathetic-inhibitory areas during RDN.

Improving Coverage Rate for Urban Link Travel Time Prediction Using Probe Data in the Low Penetration Rate Environment.

Short-term travel time prediction is an important consideration in modern traffic control and management systems. As probe data technology has developed, research interest has moved from highways to urban roads. Most research has only focused on improving the prediction accuracy on urban roads because it is the key index of evaluating a model. However, the low penetration rate of probe vehicles at urban networks may result in the low coverage rate which restricts prediction models from practical applications. This research proposed a non-parametric model based on Bayes' theorem and a resampling process to predict short-term urban link travel time, which can enhance the coverage rate while maintaining the prediction accuracy. The proposed model used data from vehicles in both the target link and its crossing direction, so its coverage rate can be expanded, especially when the data penetration rate is low. In addition, the utilization of relationships between vehicles in both directions can reflect the influence of signal timing. The proposed model was evaluated in a computer simulation to test its robustness and reliability under different data penetration rates. The results implied that the proposed model has a high coverage rate, demonstrating stable and acceptable performance at different penetration rates.

Identification of a pyrimidinetrione derivative as the potent DprE1 inhibitor by structure-based virtual ligand screening.

Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl-ß-d-ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy.

Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase.

Kidney-type glutaminase (KGA), catalyzing the hydrolysis of glutamine to glutamate for energy supply, is over-expressed in many cancers and has been regarded as a new therapeutic target for cancers. Physapubescin I was isolated from the fruits of the edible herb Physalis pubescens L., commonly named as "husk tomato or hairy groundcherry", and was predicted to be a potential KGA inhibitor through structure-based virtual ligand screening. Enzyme inhibition assays, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) experiments have demonstrated the high efficiency and specificity of physapubescin I targeting KGA. EdU proliferation, Hoechst 33258 staining and cytotoxicity assays indicated that physapubescin I could inhibit cancer cell proliferation and promote apoptosis more effectively than the known KGA inhibitor, BPTES. Knockdown of KGA by siRNA reduced the inhibition of physapubescin I to SW1990 cells. Meanwhile, physapubescin I impaired glutamine metabolism in SW1990 cells with increasing intracellular level of glutamine, and correspondingly decreasing glutamate and its downstream metabolites, which may account for its inhibition of cancer cell proliferation and proapoptosis. Physapubescin I also showed significant tumor growth inhibition and low toxicity in a SW1990 xenograft mouse model. Collectively, physapubescin I may serve as a potential drug candidate or lead compound for cancer therapy by targeting KGA.

Steroids from Ganoderma sinense as new natural inhibitors of cancer-associated mutant IDH1.

Isocitrate dehydrogenase (IDH) is one of the key enzymes in the tricarboxylic acid cycle, and IDH mutations have been associated with many cancers, including glioblastoma, sarcoma, acute myeloid leukemia, etc. Three natural steroids 1-3 from Ganoderma sinense, a unique and rare edible-medicinal fungi in China, were found as potential IDH1 inhibitors by virtual ligand screening method. Among the three compounds, 3 showed the highest binding affinity to IDH1 with significant calculated binding free energy. Enzymatic kinetics demonstrated that 3 inhibited mutant enzyme in a noncompetitive manner. The half effective concentration of 3 for reducing the concentration of D-2HG in HT1080 cells was 35.97 µM. The levels of histone H3K9me3 methylation in HT1080 cells were reduced by treating with 3. Furthermore, knockdown of mutant IDH1 in HT1080 cells decreased the anti-proliferative sensitivity to 3. In short, our findings highlight that compound 3 may have clinical potential in tumor therapies as an effective inhibitor of mutant IDH1.

8-Chrysoeriol, as a potential BCL-2 inhibitor triggers apoptosis of SW1990 pancreatic cancer cells.

8-Chrysoeriol, a bioactive flavanoid, was firstly identified to bind directly to BCL-2 as BH3 mimetics by structure-based virtual ligand screening. And 3D docking model revealed the molecular basis of 8-Chrysoeriol targeting to BCL-2. The interaction between 8-Chrysoeriol and BCL-2 was further confirmed using Microscale Thermophoresis (MST) technique. Meanwhile, high expression level of antiapoptotic protein BCL-2 was detected in SW1990 pancreatic cancer cells and 8-Chrysoeriol showed obvious proapoptosis effect against SW1990 in vitro. Collectively, the results showed that 8-Chrysoeriol as a natural dietary product potentially targeting to BCL-2 could serve as a lead compound for SW1990 pancreatic cancer therapy.

Synthesis of novel andrographolide beckmann rearrangement derivatives and evaluation of their HK2-related anti-inflammatory activities.

Two series of andrographolide derivatives with introduction of amide moiety into ring A by Beckmann rearrangement were synthesized. In series 1, the ring A was converted to caprolactam, and an amide moiety was linked to C-19 of ring A in series 2. Among them, compound 8h exhibited obvious inhibition on HK2 enzyme activity (IC50 = 9.36 ±â€¯0.08 µM) and LPS-induced NO production in RAW264.7 cells (IC50 = 22.38 ±â€¯3.57 µM), and potent binding affinity with HK2 (Kd = 5.12 ±â€¯0.82 µM). The preliminary structure-activity relationships (SARs) suggested that the formation of caprolactam of ring A and esterification of C-19-hydroxyl could improve the inhibitory effects on HK2 enzyme of andrographolide derivatives. Furthermore, compound 8h significantly reduced the levels of IL-1ß and IL-6, down-regulated the expressions of iNOS and COX-2. Its anti-inflammatory effect was related to the inhibition of both NF-κB pathway and glycolysis enzyme HK2. Since HK2 could be a novel and effective target for anti-inflammation, compound 8h might be a new anti-inflammatory agent targeting at HK2, or serve as a lead compound to design and synthesize more HK2 inhibitors with better inflammatory effects.

Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH.

3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first rate-limiting step for the synthesis of glucose-derived serine by converting 3-phosphoglycerate (3-PG) to phosphohydroxypyruvate (p-Pyr), which has been reported to associate with tumorigenesis in many cancers. Iox A, a natural withanolide obtained from dietary tomatillo (Physalis ixocarpa), showed significant PHGDH inhibitory activity with an IC50 value of 1.66 ± 0.28 µM, and it was further confirmed to bind directly to PHGDH by the MST assay. Molecular docking demonstrated that Iox A coordinated at the allosteric site of PHGDH, which was consistent with the non-competitive kinetics. Meanwhile, Iox A selectively inhibited the proliferation of high PHGDH-expressing cancer cell lines (SW1990, MCF-7 and HeLa) and showed no obvious cytotoxicities on normal human cells (LO2, L929 and HPDE6-C7). In particular, Iox A showed a dose-dependent proapoptotic activity against SW1990 cells in a micromolar concentration as detected by flow cytometry and western blot analysis. DARTS and siRNA assays further demonstrated that Iox A directly targets at PHGDH to inhibit the proliferation of SW1990 cells. Furthermore, Iox A significantly inhibited the tumor growth in a SW1990 xenograft mouse model with low toxicities, suggesting its potential therapeutic application in pancreatic cancer treatment. Therefore, Iox A was identified as a novel natural PHGDH inhibitor with high targeting and low toxicities for the treatment of pancreatic cancers.

Terpenoids from Vitex trifolia and their anti-inflammatory activities.

A new diterpenoid glucoside, (3S,5S,6S,8R,9R,10S)-3,6,9-trihydroxy-13(14)-labdean-16,15-olide 3-O-ß-D-glucopyranoside (1), and a new iridoid glucoside, (1S, 5S,6R,9R)-10-O-p-hydroxybenzoyl-5,6ß-dihydroxy iridoid 1-O-ß-D-glucopyranoside (2), along with six known compounds (3-8) were isolated from Vitex trifolia L.. Their structures were elucidated by extensive spectroscopic analysis. All these isolated compounds were evaluated for their inhibitory effects on nitric oxide production in LPS-induced RAW 264.7 macrophages. Compounds 2, 4, 5, and 7 showed moderate inhibitory activities with IC50 values of 90.05, 88.51, 87.26, and 76.06 µM, respectively.