Synthesis,biological evaluation,and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors

Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC₅₀ values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15_a, 15_b, and 15_d showed IC₅₀ from 17.39 to 47.10 µM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15_d which came second with regard to antitumor assay with IC₅₀ = 24.10, 40.90, and 33.40 µM against aforementioned cell lines, respectively. Furthermore, Compound 15_d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15_d showed IC₅₀ of 253 and 381 nM against HER2 and FGFR, respectively.     

UCP3 Regulates Single-Channel Activity of the Cardiac mCa1

Mitochondrial Ca²⁺ uptake (mCa²⁺ uptake) is thought to be mediated by the mitochondrial Ca²⁺ uniporter (MCU). UCP2 and UCP3 belong to a superfamily of mitochondrial ion transporters. Both proteins are expressed in the inner mitochondrial membrane of the heart. Recently, UCP2 was reported to modulate the function of the cardiac MCU related channel mCa1. However, the possible role of UCP3 in modulating cardiac mCa²⁺ uptake via the MCU remains inconclusive. To understand the role of UCP3, we analyzed cardiac mCa1 single-channel activity in mitoplast-attached single-channel recordings from isolated murine cardiac mitoplasts, from adult wild-type controls (WT), and from UCP3 knockout mice (UCP3^–/–). Single-channel registrations in UCP3^?/? confirmed a murine voltage-gated Ca²⁺ channel, i.e., mCa1, which was inhibited by Ru360. Compared to WT, mCa1 in UCP3^?/? revealed similar single-channel characteristics. However, in UCP3^?/? the channel exhibited decreased single-channel activity, which was insensitive to adenosine triphosphate (ATP) inhibition. Our results suggest that beyond UCP2, UCP3 also exhibits regulatory effects on cardiac mCa1/MCU function. Furthermore, we speculate that UCP3 might modulate previously described inhibitory effects of ATP on mCa1/MCU activity as well.     

Efficient inhibition of some multi-drug resistant pathogenic bacteria by bioactive metabolites from <Emphasis Type="Italic">Bacillus amyloliquefaciens</Emphasis> S<Subscript>5</Subscript>I<Subscript>4</Subscript> isolated from archaeological soil in Egypt

Sixty-eight bacterial cultures were isolated from 5 archaeological soils in Egypt. It is necessary to characterize bacteria from ancient temples to develop protection programs for such archaeological places. Purified bacterial cultures were then tested for their capability to inhibit some multi-drug resistant (MDR) pathogenic bacteria including Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, Escherichia coli and Klebsiella pneumoniae. Among the most active 10 antibacterial isolates, only one isolate designated as S₅I₄ was selected, characterized and identified as belonging to Bacillus amyloliquefaciens. The strain identification was confirmed by amplification of its 16S rRNA gene. The partial nucleotide sequence of the amplified 16S rRNA gene of the tested strain was submitted in GenBank with accession number AB813716. The physical and nutritional parameters were optimized to improve the production of antimicrobial agents by the B. amyloliquefaciens S₅I₄. The maximum antagonistic effect of this strain against the tested MDR pathogenic bacteria was achieved in presence of 1% galactose and 0.5% yeast extract at 37°C and pH 7.0 after 48 h incubation. The antibacterial compounds of B. amyloliquefaciens S₅I₄ were extracted, purified and characterized using spectroscopic analysis (IR, UV, proton NMR and MS). The compound having inhibitory activity was identified as butanedioic acid, octadecyl,1(1carboxy1methylethyl) 4octyl ester.     

A modifiedAmaranthus betacyanin test for cytokinin bioassay

A modified procedure for the extraction of betacyanin fromAmaranthus seedlings is described. Application of this modification increased the absorbance of cytokinin-treatedAmaranthus explants in most cases. The modifiedAmaranthus test is compared with the soybean callus test in the bioassay of kinetin, 6-benzylaminopurine, and 6(δ,δ-dimethylallyl) aminopurine.     

Clinical significance of a cytologic diagnosis of atypical glandular cells, favor endometrial origin, in Pap smears

OBJECTIVE: To evaluate the significance of a diagnosis of atypical glandular cells, favor endometrial origin (AGC-EM), using cytohistologic correlation. STUDY DESIGN: A retrospective search identified 90 cervicovaginal smears (vaginal pool) with a diagnosis of AGC-EM, in 2 tertiary care medical centers between January 1998 and December 2002. RESULTS: Forty-six (51%) were conventional preparations and 44 (49%) were liquid-based monolayers (SurePath, TriPath Imaging Inc., Burlington, North Carolina, U.S.A.). Follow-up biopsies were available in 55 of 90 (61%) cases, 15 of 90 (17%) cases had cytology follow-up, and 20 of 90 (22%) were lost to follow-up. The patients ranged in age from 30 to 86 years (mean, 56); 56 of 90 (62%) were > 50 years. Among the patients who underwent biopsy, 22 (40%) had a clinically significant lesion, including 10 (18%) endometrial adenocarcinomas, 8 (15%) endometrial hyperplasias and 4 (7%) high grade squamous intraepithelial lesion/squamous cell carcinoma, nonkeratinizing type. The remaining 33 patients had benign histology, including benign endometrium, endometrial polyp, tubal metaplasia, cystic endometrial atrophy and cervical microglandular hyperplasia. Of the patients with cytologic follow-up, 2 had Pap smears showing atypical squamous cells of undetermined significance, while the remainder had negative results. CONCLUSION: In our study population, 40% (22 of 55) of women who underwent biopsy following a diagnosis of AGC-EM had significant uterine lesions, with the majority of the lesions endometrial in origin. Patients with a diagnosis of AGC-EM, especially those > 50, should be followed closely, and endometrial sampling should be included in their initial workup.     

Fine needle aspiration biopsy of vertebral lesions

OBJECTIVE: To evaluate the accuracy of fine needle aspiration biopsy (FNAB) in the diagnosis of vertebral lesions. STUDY DESIGN: Eighty-nine FNAB cases of vertebral lesions from January 1996 to December 2001 were retrieved from the Allegheny General Hospital laboratory information system. The cases were reviewed and correlated with clinical findings, including previous clinical history, primary site of malignancy and final pathologic diagnosis. RESULTS: ENAB diagnoses were malignant in 43 cases, benign in 35, suspicious in 1, unsatisfactory in 7 and false negative in 3. Previous clinical history included malignancy (37 patients), osteomyelitis and systemic disease (11), and nonspecific or no history (41). In 34 cases (38.2%) both aspirates and core biopsies were available, and the diagnoses correlated in 29/34 cases (85%). Surgical or core biopsies in the unsatisfactory/suspicious group showed malignancy in 4 cases (50%). The sensitivity of FNAB of vertebral lesions was 96%, specificity 100%, positive predictive value 100% and negative predictive value 92%, with no false positive cases. CONCLUSION: FNAB of vertebral lesions is an effective, sensitive and specific procedure in the diagnostic workup of a patient with or without a prior history of malignancy. Surgical pathology examination, including core biopsies of unsatisfactory or suspicious lesions, can further improve the diagnostic yield.     

Synthesis and Characterization of New Lutidinium Ionic Liquid-Supported Vanadylsalicylaldoxime Complex for Catalytic Application in Epoxidation Reaction

A new chelating task-specific ionic liquid (TSIL), lutidinium-based salicylaldoxime ( LSOH ), and its square pyramidal vanadyl(II) complex (VO(LSO)₂) have been successfully synthesized and structurally characterized using elemental (CHN), spectral, and thermal analyses. The catalytic activity of the lutidinium-salicylaldoxime complex (VO(LSO)₂) in the alkene epoxidation reactions was studied under various reaction conditions, such as solvent effect, alkene/oxidant molar ratio, pH, reaction temperature, reaction time, and the catalyst dose. The results demonstrated that the CHCl₃ solvent, 1 : 3 of the cyclohexene/H₂O₂ ratio, pH 8, temperature of 340 K, and catalyst dose of 0.012 mmol are assigned as the optimum conditions for achieving maximum catalytic activity for VO(LSO)₂. Moreover, the VO(LSO)₂ complex has the potential for application in the effective and selective epoxidation of alkenes. Notably, under optimal VO(LSO)₂ conditions, cyclic alkenes convert more efficiently to their corresponding epoxides than linear alkenes.     

Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system

An efficient regulation of fuel metabolism in response to internal and environmental stimuli is a vital task that requires an intact carnitine system. The carnitine system, comprehensive of carnitine, its derivatives, and proteins involved in its transformation and transport, is indispensable for glucose and lipid metabolism in cells. Two major functions have been identified for the carnitine system: (1) to facilitate entry of long-chain fatty acids into mitochondria for their utilization in energy-generating processes; (2) to facilitate removal from mitochondria of short-chain and medium-chain fatty acids that accumulate as a result of normal and abnormal metabolism. In cancer patients, abnormalities of tumor tissue as well as nontumor tissue metabolism have been observed. Such abnormalities are supposed to contribute to deterioration of clinical status of patients, or might induce cancerogenesis by themselves. The carnitine system appears abnormally expressed both in tumor tissue, in such a way as to greatly reduce fatty acid beta-oxidation, and in nontumor tissue. In this view, the study of the carnitine system represents a tool to understand the molecular basis underlying the metabolism in normal and cancer cells. Some important anticancer drugs contribute to dysfunction of the carnitine system in nontumor tissues, which is reversed by carnitine treatment, without affecting anticancer therapeutic efficacy. In conclusion, a more complex approach to mechanisms that underlie tumor growth, which takes into account the altered metabolic pathways in cancer disease, could represent a challenge for the future of cancer research.