Histidinibacterium aquaticum sp. nov., Isolated from Salt-Field Sea Water.

A Gram stain-negative, aerobic, motile, and rod-shaped bacterium designated 176SS1-4T was isolated from the salt-field sea water. Strain 176SS1-4T grew well at 25 °C on marine agar. The taxonomic affiliation of the novel isolate was identified using the polyphasic approach. By comparative 16S rRNA gene sequence, it could be shown that strain 176SS1-4T branches within the family Rhodobacteraceae and class Alphaproteobacteria and is related to Histidinibacterium lentulum B17T (96.0% sequence similarity). The digital DNA-DNA hybridization and average nucleotide identity between strain 176SS1-4T and H. lentulum B17T was 19.2% and 77%. The genome comprises of 3,905,029 bp with a G + C content of 67.7 mol. Ubiquinone 10 (Q-10) was the major respiratory quinone. The major fatty acids were summed feature 8 (comprising C18:1 ω7c and/or C18:1 ω6c), C16:0, C19:0 cyclo ω8c, C18:0, and C18:1 ω6c 11-methyl and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylcholine. On the basis of the genotypic and phenotypic characteristics, strain 176SS1-4T can be placed as a novel species within the genus Histidinibacterium; the name Histidinibacterium aquaticum sp. nov. has been proposed, with type strain 176SS1-4T (= KACC 19891T = LMG 31032T).

Synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel FMS inhibitors.

Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50 = 2 nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells.

Pharmacological evaluation of HM41322, a novel SGLT1/2 dual inhibitor, in vitro and in vivo.

HM41322 is a novel oral sodium-glucose cotransporter (SGLT) 1/2 dual inhibitor. In this study, the in vitro and in vivo pharmacokinetic and pharmacologic profiles of HM41322 were compared to those of dapagliflozin. HM41322 showed a 10-fold selectivity for SGLT2 over SGLT1. HM41322 showed an inhibitory effect on SGLT2 similar to dapagliflozin, but showed a more potent inhibitory effect on SGLT1 than dapagliflozin. The maximum plasma HM41322 level after single oral doses at 0.1, 1, and 3 mg/kg were 142, 439, and 1830 ng/ml, respectively, and the T1/2 was 3.1 h. HM41322 was rapidly absorbed and reached the circulation within 15 min. HM41322 maximized urinary glucose excretion by inhibiting both SGLT1 and SGLT2 in the kidney. HM41322 3 mg/kg caused the maximum urinary glucose excretion in normoglycemic mice (19.32±1.16 mg/g) at 24 h. In normal and diabetic mice, HM41322 significantly reduced glucose excursion. Four-week administration of HM41322 in db/db mice reduced HbA1c in a dose dependent manner. Taken together, HM41322 showed a favorable preclinical profile of postprandial glucose control through dual inhibitory activities against SGLT1 and SGLT2.

Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models.

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781-36B. The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781-36B is the most potent pan-HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.

Purification and Nitrogen Doping of Nanothin Exfoliated Graphite Through RF Thermal Plasma Treatment.

A mixture of nanothin exfoliated (NTE) graphite and urea (CO(NH2)2) powder was treated with radio frequency (RF) thermal plasma to achieve in situ purification and nitrogen doping of NTE graphite using the high-temperature flame of the RF plasma. Reactive species such as NH3, NH2, and HCNO generated by the thermolysis of urea play an important role in the purification and nitrogen doping of NTE graphite. The nitrogen content of NTE graphite subjected to plasma treatment increased by 5 times compared with that of raw NTE graphite. Three types of nitrogen species, namely, quaternary N, pyridinic N, and pyrrolic N, were observed after N doping with plasma treatment. The sheet resistance of N-doped NTE graphite reduced to 12-21% compared to that of the untreated NTE graphite, with the corresponding resistivity being ~7 × 10-6 Ω m.

HM71224, a selective Bruton's tyrosine kinase inhibitor, attenuates the development of murine lupus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with B cell hyperactivity, and lupus nephritis (LN), in particular, is promoted by the production of autoantibodies and immune complex deposition. Bruton's tyrosine kinase (BTK) plays critical roles in B cell receptor-related and Fc receptor-related signaling. We aimed to investigate the impact of therapeutic intervention with HM71224 (LY3337641), a selective BTK inhibitor, on the development of murine SLE-like disease features. METHODS: We examined the therapeutic effects of HM71224 on SLE-like disease features in MRL/lpr and NZB/W F1 mice. The disease-related skin lesion was macroscopically observed in MRL/lpr mice, and the impact on splenomegaly and lymphadenopathy was determined by the weight of the spleen and cervical lymph node. The renal function was evaluated by measuring blood urea nitrogen, serum creatinine, and urine protein, and the renal damage was assessed by histopathological grading. Survival rate was observed during the administration period. The impact of B cell inhibition was investigated in splenocytes from both mice using flow cytometry. Autoantibody was measured in serum by ELISA. RESULTS: HM71224 effectively suppressed splenic B220+GL7+, B220+CD138+, and B220+CD69+ B cell counts, and anti-dsDNA IgG and reduced splenomegaly and lymph node enlargement. The compound also prevented skin lesions caused by lupus development, ameliorated renal inflammation and damage with increased blood urea nitrogen and creatinine, and decreased proteinuria. Furthermore, HM71224 also decreased mortality from lupus development in both mouse models. CONCLUSION: Our results indicate that inhibition of BTK by HM71224 effectively reduced B cell hyperactivity and significantly attenuated the development of SLE and LN in rodent SLE models.

Radio Frequency-Thermal Plasma Synthesis of Metal Nano-Thin Exfoliated Graphite Hybrid.

Nano-metal with nano-thin exfoliated (NTE) graphite hybrid material has been synthesized by radio frequency (RF) thermal plasma. A micro-sized nickel powder and the NTE graphite powder were fed into the RF plasma and nano sized nickel particles attached to the surface of the NTE graphite were found. In the high temperature of RF thermal plasma that is of higher than 10,000 K, the NTE graphite was not vaporized or damaged, while the metal powder was vaporized. The size of nickel nanoparticles on the NTE graphite was 40 80 nme. The size and number density of produced metal nanoparticle can be controlled by the process pressure in a reactor, the feeding ratio of raw materials, and the flow rate of working gas. X-ray diffraction results of the produced hybrid nano material indicate that there was a bonding between the nano metal and the NTE graphite. The inert nature of surface of the NTE graphite has been a barrier for the NTE graphite to be used a compounding additive. The nano metal covered NTE graphite will open up many potential applications of NTE graphite and polymer compound materials.