Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors.

Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene, which is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been shown to contribute to the progression of various cancers and is emerging as an important target for anti-tumor drug research. However, past efforts to develop SHP2 inhibitors into drugs have been unsuccessful owing to the positively charged nature of the active site pocket tending to bind negatively charged groups that are usually non-drug-like. Here, a series of uncharged pyrazoline derivatives were designed and developed as new SHP2 inhibitors using a structure-based strategy. Compound 4o, which exhibited the strongest SHP2 inhibitory activity, bound directly to the catalytic domain of SHP2 in a competitive manner through multiple hydrogen bonds. Compound 4o affected the RAS/MAPK signaling pathway by inhibiting SHP2, and subsequently induced apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. Notably, the oral administration of compound 4o in large doses showed no obvious toxicity. In summary, our findings provide a basis for the further development of compound 4o as a safe, effective and anti-tumor SHP2 inhibitor.

New Polyketides from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus with a ubiquitous distribution in Antarctica. Meanwhile, the study of its secondary metabolites is infrequent. Systematic research of the metabolites of the fungus Pseudogymnoascus sp. HSX2#-11, guided by the method of molecular networking, led to the isolation of one novel polyketide, pseudophenone A (1), along with six known analogs (2-7). The structure of the new compound was elucidated by extensive spectroscopic investigation and single-crystal X-ray diffraction. Pseudophenone A (1) is a dimer of diphenyl ketone and diphenyl ether, and there is only one analog of 1 to the best of our knowledge. Compounds 1 and 2 exhibited antibacterial activities against a panel of strains. This is the first time to use molecular networking to study the metabolic profiles of Antarctica fungi.

Nitrogenous Compounds from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus which is ubiquitously distributed in Antarctica. While the studies of its secondary metabolites are infrequent. Systematic research of the metabolites of the Antarctic fungus Pseudogymnoascus sp. HSX2#-11 led to the isolation of one new pyridine derivative, 4-(2-methoxycarbonyl-ethyl)-pyridine-2-carboxylic acid methyl ester (1), together with one pyrimidine, thymine (2), and eight diketopiperazines, cyclo-(dehydroAla-l-Val) (3), cyclo-(dehydroAla-l-Ile) (4), cyclo-(dehydroAla-l-Leu) (5), cyclo-(dehydroAla-l-Phe) (6), cyclo-(l-Val-l-Phe) (7), cyclo-(l-Leu-l-Phe) (8), cyclo-(l-Trp-l-Ile) (9) and cyclo-(l-Trp-l-Phe) (10). The structures of these compounds were established by extensive spectroscopic investigation, as well as by detailed comparison with literature data. This is the first report to discover pyridine, pyrimidine and diketopiperazines from the genus of Pseudogymnoascus.

The Fluoro-Thiazolylhydrazone Compound TSC-3C Inhibits Triple Negative Breast Cancer (TNBC) Cell Line Activity by Promoting Apoptosis, Regulating the MAPK Pathway and Inducing Mitochondrial Dysfunction.

Triple negative breast cancer (TNBC) is the most aggressive cancer in women, and despite improved treatments, it remains a major cause of morbidity and mortality. We and others have demonstrated that different hybrid compounds targeting PARP/MAPK or other pathways to inhibit cancer progression may lead to promising therapeutic results. We introduced fluorine to alter the physical properties of the compounds. TSC-3C was one of the generated compounds. Upon treatment with TSC-3C, MDA-MB-231 cell proliferation, invasion, and migration were inhibited. TSC-3C induced MDA-MB-231 cell mitochondrial dysfunction and apoptosis, which may be caused by reducing the level of phosphorylated p44/42 MAPK (ERK1/2) and increasing the level of p-JNK. The present study may help to elucidate the role of the MAPK pathway in the development of breast cancer and may promote further research on halogenated heterocyclic compounds for the treatment of breast cancer.

The associations among self-criticism, hopelessness, rumination, and NSSI in adolescents: A moderated mediation model.

INTRODUCTION: Nonsuicidal self-injury (NSSI) is a pervasive public health problem among adolescents. Self-criticism has been identified as an important risk factor for NSSI. Potential mediators of the relationship between self-criticism and NSSI and potential moderators that may exacerbate or buffer this association, however, have seldom been explored. The current study tested the mediating effect of hopelessness and the moderating effect of rumination. METHODS: 915 Chinese participants (405 girls; mean age = 15.85, SD = 1.47) were recruited from junior and senior high schools. They completed questionnaires regarding self-criticism, hopelessness, rumination, and NSSI. RESULTS: Self-criticism was significantly associated with NSSI, and this association was mediated by hopelessness. Rumination strengthened the association between self-criticism and hopelessness, as well as the association between hopelessness and NSSI. CONCLUSIONS: Although this study is a cross-sectional design, these findings can help researchers and practitioners understand the relationship among self-criticism, hopelessness, rumination, and NSSI. Moreover, implications for preventions and interventions of NSSI were discussed.

Energy-Efficient UAV-Enabled MEC System: Bits Allocation Optimization and Trajectory Design.

The unmanned aerial vehicle (UAV) enabled mobile edge computing (MEC) system is attracting a lot of attentions for the potential of low latency and low transmission energy consumption, due to the advantages of high mobility and easy deployment. It has been widely applied to provide communication and computing services, especially in Internet of Things (IoT). However, there are still some challenges in the UAV-enabled MEC system. Firstly, the endurance of the UAV is limited and further impacts the performance of the system. Secondly, mobile devices are battery-powered and the batteries of some devices are hard to change. Therefore, in this paper, a UAV-enabled MEC system in which the UAV is empowered to have computing capability and provides tasks offloading service is studied. The total energy consumption of the UAV-enabled system, which includes the energy consumption of the UAV and the energy consumption of the ground users, is minimized under the constraints of the UAV's energy budget, the number of each task's bits, the causality of the data and the velocity of the UAV. The bits allocation of uploading data, computing data, downloading data and the trajectory of the UAV are jointly optimized with the goal of minimizing the total energy consumption. Moreover, a two-stage alternating algorithm is proposed to solve the non-convex formulated problem. Finally, the simulation results show the superiority of the proposed scheme compared with other benchmark schemes. Finally, the performance of the proposed scheme is demonstrated under different settings.

Self-developed NF-κB inhibitor 270 protects against LPS-induced acute kidney injury and lung injury through improving inflammation.

Sepsis-induced acute kidney injury (AKI) and acute lung injury (ALI) have high morbidity and mortality, with no effective clinically available drugs. Anti-inflammation is effective strategy in the therapy of AKI and ALI. NF-κB is a target for the development of anti­inflammatory agents. The purpose of the study is to evaluate the effect of 270, self-developed NF-κB inhibitor, in LPS-induced AKI and ALI. LPS-induced macrophages were used to examine the anti-inflammation activity of 270 in vitro. Sepsis-induced AKI and ALI mice models were established by intraperitoneal injection of LPS (10 mg/kg) for 24 h. Oral administration 270 for 14 days before LPS stimulation. Plasma, kidney and lung tissues were collected and used for histopathology, biochemical assay, ELISA, RT-PCR, and western blot analyses. In vitro, we showed that 270 suppressed the inflammation response in LPS-induced RAW 264.7 macrophages and bone marrow derived macrophages. In vivo, we found that 270 ameliorated LPS-induced AKI and ALI, as evidenced by improving various pathological changes, reducing the expression of pro-inflammation genes, blocking the activation of NF-κB and JNK pathways, attenuating the elevated myeloperoxidase (MPO) activity and malondialdehyde (MDA) content, ameliorating the activated ER stress, reversing the inhibition effect on autophagy in kidney and lung tissues, and alleviating the enhanced plasma level of creatinine (Crea), blood urea nitrogen (BUN) and pro-inflammation cytokines. Our investigations provides evidence that NF-κB inhibitor 270 is a potential drug that against LPS-induced AKI and ALI in the future.

Sesquiterpenoids From the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The fungal strains Pseudogymnoascus are a kind of psychrophilic pathogenic fungi that are ubiquitously distributed in Antarctica, while the studies of their secondary metabolites are infrequent. Systematic research of the metabolites of the fungus Pseudogymnoascus sp. HSX2#-11 led to the isolation of six new tremulane sesquiterpenoids pseudotremulanes A-F (1-6), combined with one known analog 11,12-epoxy-12ß-hydroxy-1-tremulen-5-one (7), and five known steroids (8-12). The absolute configurations of the new compounds (1-6) were elucidated by their ECD spectra and ECD calculations. Compounds 1-7 were proved to be isomeride structures with the same chemical formula. Compounds 1/2, 3/4, 1/4, and 2/3 were identified as four pairs of epimerides at the locations of C-3, C-3, C-9, and C-9, respectively. Compounds 8 and 9 exhibited cytotoxic activities against human breast cancer (MDA-MB-231), colorectal cancer (HCT116), and hepatoma (HepG2) cell lines. Compounds 9 and 10 also showed antibacterial activities against marine fouling bacteria Aeromonas salmonicida. This is the first time to find terpenoids and steroids in the fungal genus Pseudogymnoascus.