Synthesis and biological evaluation of Schizandrin derivatives as potential anti-cancer agents.

A new series of Schizandrin (1) derivatives were synthesized utilizing the C-9 position of the Schizandrin core and evaluated for their cytotoxic activities against HeLa (cervical cancer), A549 (lung cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer) cell lines. Among the synthesized series, 4e, 4f, 4g and 5 showed potent activities against tested cell lines. More significantly, compound 5 exhibited most potent cytotoxic activity against DU-145 with an IC50 value of 1.38 µM which is comparable to the standard agent, doxorubicin. Further, flow cytometry analysis indicated that 5 arrested cells in G2/M phase and consequently leading to apoptosis. Molecular docking analysis showed that 5 occupied the colchicine binding pocket of tubulin. Overall, the present study demonstrates that 5, as a mitotic-agent.

Ovarian markers and irregular menses among women with type 1 diabetes in the Epidemiology of Diabetes Interventions and Complications study.

OBJECTIVE: Women with type 1 diabetes have increased risk of infertility compared to women without diabetes even after adjustment for irregular menses, but aetiologies are incompletely understood. Our aim was to examine the prevalence of abnormalities in ovarian markers consistent with polycystic ovary syndrome in women with type 1 diabetes and associations with irregular menses and diabetes-specific variables. DESIGN, PATIENTS AND MEASUREMENTS: We conducted a secondary analysis of women in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), a randomized trial and observational follow-up of intensive insulin therapy for type 1 diabetes. We included women with anti-Müllerian hormone (AMH) measurements among women not using oral contraceptives (n = 187). Initial AMH and testosterone measures were performed between EDIC years 1 and 4. History of irregular menses was assessed annually. RESULTS: The median age of women was 35 (interquartile ratio 29, 40) years; 133 (35%) had elevated AMH and 62 (17%) reported irregular menses. Twelve per cent of women had relative elevations in total testosterone. In multivariable models, lower insulin dosages were associated with higher AMH concentrations (P = .0027), but not diabetes duration, glycemic control, body mass index or irregular menses. Neither irregular menses nor diabetes-specific variables were associated with testosterone concentrations. CONCLUSIONS: Among women with type 1 diabetes in their thirties, abnormalities in ovarian markers are common and not associated with irregular menses and thus may partially account for decreased fecundity in women with type 1 diabetes.

Synthesis of new cis-fused tetrahydrochromeno[4,3-b]quinolines and their antiproliferative activity studies against MDA-MB-231 and MCF-7 breast cancer cell lines.

New cis-fused tetrahydrochromeno[4,3-b]quinolines have been synthesized by intramolecular [4+2] imino-Diels-Alder reactions of 2-azadienes derived in situ from aromatic amines and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones in the presence of 20mol% Yb(OTf)(3) in acetonitrile under reflux conditions in good to excellent yields. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. These compounds were evaluated for their antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cells. The results showed that compounds 3e, 3f, and 3k exhibit significant antiproliferative activity against MCF-7 breast cancer cells and low inhibitory activity against MDA-MB-231 breast cancer cell lines. Compound 3h displayed activity as comparable to tamoxifen on both the cell lines.

Oleanane-type isomeric triterpenoids from Barringtonia racemosa.

Two new isomeric acylated oleanane-type triterpenoids along with three known compounds were isolated from the MeOH extract of the dried fruits of Barringtonia racemosa. On the basis of spectroscopic methods, with special emphasis on 1D and 2D NMR techniques as well as chemical methods, the structures were characterized as racemosol A (1) [22alpha-acetoxy-3beta,15alpha,16alpha,21beta-tetrahydroxy-28-(2-methylbutyryl)olean-12-ene] and isoracemosol A (2) [21beta-acetoxy-3beta,15alpha,16alpha,28-tetrahydroxy-22alpha-(2-methylbutyryl)olean-12-ene]. The isolated compounds (1-5) were not active against HeLa and P388 D1 carcinoma cell lines.

Polymorphisms in the prostate-specific antigen gene promoter do not predict serum prostate-specific antigen levels in African-American men.

A major problem with the use of serum prostate-specific antigen (PSA) in predicting prostate cancer risk is the considerable variability of such measurements. Cramer et al. identified a set of single-nucleotide polymorphisms (SNPs) in the upstream regulatory region of the PSA gene that were each associated with increased promoter activity and serum PSA, further suggesting that genotyping these SNPs could be useful in improving the predictive value of PSA screening. In order to replicate this finding, DNA samples from 475 African-American men were genotyped for the same SNPs and no association was observed with either serum PSA level or prostate cancer diagnosis.

A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain.

BACKGROUND: Celiac plexus neurolysis, a chemical splanchnicectomy of the celiac plexus, is used to treat pain caused by pancreatic cancer. Most commonly, celiac plexus neurolysis is performed percutaneously under CT or fluoroscopic guidance, but can also be performed with EUS. The aim of this study was to prospectively assess the efficacy of EUS celiac plexus neurolysis in the management of pain caused by pancreatic cancer. METHODS: In this prospective study conducted in a community-based referral hospital, 58 patients with painful and inoperable pancreatic cancer were evaluated at 8 observation points before and after EUS celiac plexus neurolysis for up to 6 months. The following data were collected: age, gender, tumor location, vascular invasion, adjuvant therapy, and laboratory tests including prothrombin time, and complete blood counts were obtained at baseline (before EUS celiac plexus neurolysis); pain scores, morphine use, and adjuvant therapy were assessed at each observation. RESULTS: Pain scores were lower (p = 0.0001) 2 weeks after EUS celiac plexus neurolysis, an effect that was sustained for 24 weeks when adjusted for morphine use and adjuvant therapy. Forty-five of the 58 patients (78%) experienced a decline in pain scores after EUS celiac plexus neurolysis. Chemotherapy with and without radiation also decreased pain after EUS celiac plexus neurolysis (p = 0.002). Procedure-related transient abdominal pain was noted in 5 patients; there were no major complications. CONCLUSIONS: EUS celiac plexus neurolysis is safe and controls pain caused by unresectable pancreatic cancer.

Norbornene-constrained cyclic peptides with hairpin architecture: design, synthesis, conformation, and membrane ion transport.

A novel family of hairpin cyclic peptides has been designed on the basis of the use of norbornene units as the bridging ligands. The design is flexible with respect to the choice of an amino acid, the ring size, and the nature of the second bridging ligand as illustrated here with the preparation of a large number of norborneno cyclic peptides containing a variety of amino acids in ring sizes varying from 12- to 29-membered, with the choice of the second bridging ligand being a rigid norbornene (11, 13a,b), an adamantane unit (7a,b and 8), or a flexible cystine residue (4a,b and 10). The presence of built-in handles (as protected COOH groups) permits the attachment of a variety of subunits as shown here with the ligation of Leu-Leu, Val-Val, or Aib-Aib pendants in 4b, 7b, and 13b, respectively. This novel class of constrained cyclic peptides are demonstrated to adopt beta-sheet- or hairpin-like conformation as shown by (1)H NMR and CD spectra. Membrane ion-transport studies have shown that the norborneno cyclic peptides 4b and 7b containing Leu-Leu or Val-Val pendants symmetrically placed on the exterior of the ring show high efficiency and selectivity in the transport of specifically monovalent cations. This property can be attributed to the hairpin-like architecture induced by the norbornene unit since the bis-adamantano peptide 15 containing two pairs of Leu-Leu pendants on the exterior is able to transport both monovalent (Na(+), K(+)) and divalent (Mg(2+)/Ca(2+)) cations.

Epidemiology of vulvar vestibulitis syndrome: an exploratory case-control study.

BACKGROUND: Vulvar vestibulitis syndrome (VVS) is a chronic, persistent syndrome characterised by vestibular pain, tenderness, and erythema. The aetiology of VVS is unknown and few of the hypothesised risk factors have been tested in controlled studies. METHODS: Using a matched case-control study design, medical, sexual, health behaviour, and diet history of 28 women with VVS were compared with 50 friend controls without VVS to identify possible causal factors. RESULTS: Cases were more likely than controls to report every vaginal and urinary symptom at the time of interview measured, particularly vaginal soreness or pain (60.7%) and pain during intercourse (64.3%). There were no significant differences between cases and controls with respect to sexual behaviour. Cases were more likely than controls to report self reported history of physician diagnosed bacterial vaginosis (OR = 22.2, 95% CI = 2.8, 177.2, p value = 0.0001), vaginal yeast infections (OR = 4.9, 95% CI = 1.4, 18.0, p value = 0.01), and human papillomavirus (OR = 7.1, 95% CI = 0.6, 81.2, p value = 0.08). There were no differences between cases and controls with respect to dietary intake of oxalate. Cases were more likely than controls to report poor health status (OR = 5.7, 95% CI = 1.1, 28.7, p value = 0.02) and history of depression for 2 weeks or more during the past year (OR = 4.4, 95% CI = 1.6, 12.3, p value = 0.002). CONCLUSION: Self reported history of bacterial vaginosis, yeast infections, and human papillomavirus were strongly associated with VVS. An infectious origin for VVS should be pursued in larger controlled studies, using questionnaire and laboratory measures.

NMR study of the peptide present in the principal neutralizing determinant (PND) of HIV-1 envelope glycoprotein gp120.

The peptide sequence Gly-Pro-Gly-Arg-Ala-Phe (GPGRAF) is present in many principal neutralizing determinants (PND) of the human immunodeficiency virus type-1 (HIV-1). It has been shown that peptides from the PND sequence contain a significant beta turn in the conserved Gly-Pro-Gly-Arg sequence. In order to find out whether or not the smaller subunits also contain this turn, we have studied the NMR of a hexapeptide [GPGPRAF, peptide (I)], a heptapeptide Gly-Pro-Gly-Arg-Ala-Phe-Cys [GPGRAFC, peptide (II)] and a dodecapeptide [GPGRAFGPGRAF, peptide (III)], retaining the side chain protecting groups. Although the majority of conformations for these peptides are disordered, there is a considerable propensity of structures with beta turn in the GPGR sequence. While peptide (I) and peptide (III) seem to have both type I and type II beta turn conformations, peptide (II) shows a propensity of only type II beta turn. The nascent structures obtained in these peptides may get stabilized as the receptor binding conformation in the presence of the receptors, thus playing a significant role in vaccine development against HIV.