Boesenberols, Pimarane Diterpenes with TRAIL-Resistance-Overcoming Activity from Boesenbergia pandurata.

TRAIL is a potent and selective inducer of apoptosis in most cancer cells while sparing normal cells, which makes it an attractive target for the development of new cancer therapies. In a screening program on natural resources with the ability to abrogate TRAIL resistance, the bioassay-guided fractionation of Boesenbergia pandurata rhizomes resulted in the isolation of 17 pimarane diterpenes and a monoterpene. Among these, compounds 1-8, named boesenberols A-H, are new pimarane diterpenes. All compounds exhibited TRAIL-resistance-overcoming activity in TRAIL-resistant AGS cells. Subtoxic doses of the major compound 9 sensitized AGS cells to TRAIL-induced apoptosis by up-regulating apoptosis-inducing proteins, such as DR4, DR5, p53, Fas, CHOP, Bak, and cleaved caspases-3, -8, and -9, and down-regulating the levels of cell survival proteins, such as Bcl-2, c-FLIP, and GSK-3ß, in TRAIL-resistant AGS cells. Furthermore, compound 9 did not decrease the viability of noncancerous (HEK293) cells at concentrations up to 30 µM.

Bioassay-Guided Isolation of Compounds from Datura stramonium with TRAIL-Resistance Overcoming Activity.

TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids--scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 µM, respectively in TRAIL-resistant AGS cells.

Sulfotanone, a new alkyl sulfonic acid derivative from Streptomyces sp. IFM 11694 with TRAIL resistance-overcoming activity.

One new alkyl sulfonic acid derivative, sulfotanone (1), and the known panosialin wA (2) were isolated from the methanolic extract of mycelium of Streptomyces sp. 11694. The structure of the new compound (1) was established by a combination of spectroscopic techniques, including HRESIMS, IR, 1D and 2D NMR measurements. Compound 1 (40 µM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistance in human gastric adenocarcinoma cell lines.

New phenazine analogues from Streptomyces sp. IFM 11694 with TRAIL resistance-overcoming activities.

Two new phenazine derivatives, aotaphenazine (1) and 5,10-dihydrophencomycin (2), were isolated from the ethyl acetate extract of Streptomyces sp. IFM 11694. In addition, the known 1-phenazinecarboxylic acid (3), phencomycin (4) and 1,6-phenazinedicarboxylic acid (5) were identified. The structures of the isolated compounds (1-5) were characterized by spectroscopic methods including NMR and mass spectrometry data. Compound 1 showed the ability to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance at concentration of 12.5 µM. Aotaphenazine (1) enhanced the levels of apoptosis inducing proteins DR4, DR5, p53 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant human gastric adenocarcinoma (AGS) cells in a dose-dependent manner.

Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium.

The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 µM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 µM.

Toxicokinetics and recovery studies of dicamba dimethyl amine salt in goats following single oral administration.

BACKGROUND: Toxicokinetics and recovery studies of dicamba dimethyl amine salt (DDAS) were conducted to obtain more information about its toxicity and tissue retention in farm animals. RESULTS: The minimum oral toxic dose level of DDAS was determined as 1400 mg kg(-1) body weight. In the toxicokinetic study, blood DDAS concentration of 55.6 +/- 0.59 microg mL(-1) (mean +/- standard error) was detected at 0.08 h, which peaked to 102.3 +/- 5.03 microg mL(-1) at 0.25 h, and declined to a minimum of 4.1 +/- 0.06 microg mL(-1) at 36 h. In recovery studies, DDAS concentration in urine began to increase significantly (P < 0.05) from 12 h, peaked at 24 h and declined from 48 h onwards. Maximum excretion through faeces was at 24 h and was complete by 144 h. The residual level in tissues decreased significantly (P < 0.05) on day 7 as compared to day 4. In histopathological studies, cellular alterations in lungs, liver, kidney, adrenal gland and spleen were found. CONCLUSION: DDAS persists in the body for a shorter period and its major excretory route is through urine. DDAS has lower affinity to accumulate in tissues, and intensity of cellular alterations is not severe after single-dose oral administration.

Prevalence of uropathogens in diabetic patients and their corresponding resistance pattern: results of a survey conducted at diagnostic centers in dhaka, bangladesh.

OBJECTIVES: Urinary tract infection is the second most common clinical indication for empirical antibiotic treatment in primary and secondary health care settings. The incidence of diabetes mellitus throughout the world is increasing strikingly and in the long run, it has some major effects on the genitourinary system which makes diabetic patients more liable to urinary tract infection. This study is designed to reveal the distribution of uropathogens in diabetic patients according to age and sex, and corresponding resistance patterns. METHODS: A six-month retrospective review of urine culture assay data from August 2009 to January 2010 from randomly selected 85 patients who suffered from both urinary tract infection and diabetes was conducted. Relevant information was retrieved and analyzed statistically using Microsoft® Excel 2002 software. RESULTS: The study showed that females are more vulnerable to pathogenic attack than males throughout a wide age distribution. In terms of pathogenic distribution, Escherichia coli was the highest followed by Streptococcus sp., Acinetobacter, Klebsiella pneumoniae and few others. Though Meropenem showed no resistance with E. coli, Acinetobacter and Klebsiella pneumoniae, in the case of Streptococcus sp. it exhibited resistance of 25%. Amikacin exhibited only 3% resistance with E. coli, whereas no resistance with Acinetobacter and Klebsiella pneumoniae, and most interestingly showed 75% resistance with Streptococcus sp. Gentamicin exhibited no resistance with Acinetobacter while 26.9%, 50% and 87.5% resistance with E. coli, Klebsiella pneumoniae and Streptococcus sp. respectively. Hence, Nitrofurantoin exhibited less resistance 11.9% compared to 12.5% resistance with E. coli and Streptococcus sp. Nitrofurantoin was highly prone to resistance with Acinetobacter and Klebsiella pneumoniae (100%, 50% respectively). Cephalosporins (cephradine, cefixime, ceftriaxone, cefepime etc.) showed moderate resistance (avg. 50%), whereas amoxicillin and ciprofloxacin showed the highest resistance in all these cases. CONCLUSION: Pathogens are mostly resistant to antibiotics including amoxicillin, ciprofloxacin, cephalosporins and nitrofurantoin, with few exceptions including gentamicin, amikacin and meropenem.