Metabolic Abnormalities, Inflammatory Markers and Endothelial Dysfunction in Hyperprolactinemia due to Prolactinoma before and after Normalization of Serum Prolactin: A Prospective Case Control Study.

Background: Hyperprolactinemia is associated with obesity, dyslipidemia, insulin resistance, and low-grade inflammation which may promote endothelial dysfunction (EnD). Limited work has been done on EnD in prolactinomas and we, therefore, studied serum markers of inflammation and EnD in patients with prolactinomas before and after treatment with dopamine agonists. Methodology: Fifty-six treatment naïve patients with prolactinomas and fifty-three (apparently healthy age and sex-matched) controls were enrolled in the study and subjected to clinical assessment and laboratory investigations including blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, urea, creatinine, uric acid, erythrocyte sedimentation rate (ESR), highly sensitive C-reactive protein (hsCRP) and markers of EnD i.e., intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Patients were treated with a dopamine agonist (cabergoline) and parameters (like ESR, hsCRP, ICAM-1, and VCAM-1) were measured at 12 weeks. Results: The majority of the patients (84%) were female, more than half (52%) had metabolic syndrome and over a third (36%) were obese. Blood glucose fasting, HbA1c, lipid fractions, ESR, hsCRP, ICAM-1, and VCAM-1 were significantly higher in patients than in controls. Median ICAM-1 was 1331.95 ng/ml (IQR 803.43-1825.99) in patients vs 753.04 ng/ml (IQR 402.04-871.55) in controls, P < 0.001 and median VCAM-1in patients was 971.35 ng/ml (IQR 695.03-1285.23) as against 634.56 ng/ml (IQR 177.49-946.50) in controls, p0.001. Serum ICAM-1 and VCAM-1 correlated positively with hsCRP. On multivariate regression analysis, serum hsCRP was the only significant predictor of change in ICAM-1 and VCAM-1. Normalization of serum PRL with CAB resulted in a significant decrease in metabolic parameters, ESR, hsCRP, ICAM-1, and VCAM-1. Conclusion: Hyperprolactinemia because of prolactinoma is associated with EnD secondary to systemic inflammation and metabolic abnormalities which improve after treatment with DA.

Coordination-driven self-assembly of ruthenium(ii) architectures: synthesis, characterization and cytotoxicity studies.

Coordination-driven self-assembly of organometallic η6-arene ruthenium(ii) supramolecular architectures (MA1-MA4) was carried out by employing dinuclear ruthenium acceptors [Ru2(µ-η4-C2O4)(CH3OH)2(η6-p-cymene)2](CF3SO3)2 (Rua), [Ru2(µ-η4-C6H2O4)(CH3OH)2(η6-p-cymene)2](CF3SO3)2 (Rub), [Ru2(dhnq)(H2O)2(η6-p-cymene)2](CF3SO3)2 (Ruc) and [Ru2(dhtq)(H2O)2(η6-p-cymene)2](CF3SO3)2 (Rud) separately with a new tetratopic donor (TD) in methanol at room temperature [TD = N,N,N',N'-tetra(pyridin-4-yl)-[1,1'-biphenyl]-4,4'-diamine]. All the coordination architectures were characterized by using spectroscopic techniques. The potency of these self-assembled architectures against human cervical cancer HeLa and human lung adenocarcinoma A549 cell lines is explored in vitro using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), annexin V-FITC/PI and 2',7'-dichlorofluorescein-diacetate assays.

Role of the Functional Polymorphism of Survivin Gene (-31G/C) and Risk of Breast Cancer in a North Indian Population.

INTRODUCTION: Survivin is an apoptosis inhibitor and plays a primary role in cancer development and progression. One of the most common polymorphism of the survivin promoter -31G/C (rs9904341) influences its expression and is associated with the risk of cancer development. This study was conducted to explore survivin promoter gene -31G/C (rs9904341) polymorphism and the risk of breast cancer. PATIENTS AND METHODS: The study group included 190 pathologically confirmed breast cancer patients, in addition to 200 distinct cancer-free controls from Jammu and Kashmir region of India, where breast cancer is the most common cancer in women. Single nucleotide polymorphism genotyping for -31G/C polymorphism in the survivin promoter region was done using a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The variant genotype/allele was found in 54.1% of the cases compared with 46.5% of controls. The combined prevalence of genotype GC+CC was significantly higher in patients compared with the control group (P = .02). Analyses of odds ratios (ORs) in the patient and control groups indicated that the presence of homozygous CC genotype was associated with increased risk for development of breast cancer (OR, 2.04; 95% confidence interval [CI], 1.07-2.98). The gene frequencies for G and C alleles were statistically different between patient and control groups (OR, 1.37; 95% CI, 1.03-1.84). CONCLUSION: The results suggest the association of -31G/C survivin polymorphism at a genotypic and allelic level in breast cancer.

Water-Soluble Pd8L4 Self-assembled Molecular Barrel as an Aqueous Carrier for Hydrophobic Curcumin.

A tetrafacial water-soluble molecular barrel (1) was synthesized by coordination driven self-assembly of a symmetrical tetrapyridyl donor (L) with a cis-blocked 90° acceptor [cis-(en)Pd(NO3)2] (en = ethane-1,2-diamine). The open barrel structure of (1) was confirmed by single crystal X-ray diffraction. The presence of a hydrophobic cavity with large windows makes it an ideal candidate for encapsulation and carrying hydrophobic drug like curcumin in an aqueous medium. The barrel (1) encapsulates curcumin inside its molecular cavity and protects highly photosensitive curcumin from photodegradation. The photostability of encapsulated curcumin is due to the absorption of a high proportion of the incident photons by the aromatic walls of 1 with a high absorption cross-sectional area, which helps the walls to shield the guest even against sunlight/UV radiations. As compared to free curcumin in water, we noticed a significant increase in solubility as well as cellular uptake of curcumin upon encapsulation inside the water-soluble molecular barrel (1) in aqueous medium. Fluorescence imaging confirmed that curcumin was delivered into HeLa cancer cells by the aqueous barrel (1) with the retention of its potential anticancer activity. While free curcumin is inactive toward cancer cells in aqueous medium at room temperature due to negligible solubility, the determined IC50 value of ∼14 µM for curcumin in aqueous medium in the presence of the barrel (1) reflects the efficiency of the barrel as a potential curcumin carrier in aqueous medium without any other additives. Thus, two major challenges of increasing the bioavailability and stability of curcumin in aqueous medium even in the presence of UV light have been addressed by using a new supramolecular water-soluble barrel (1) as a drug carrier.

Self-Assembly of Discrete RuII8 Molecular Cages and Their in Vitro Anticancer Activity.

Four new octanuclear Ru(II) cages (OC-1-OC-4) were synthesized from dinuclear p-cymene ruthenium(II) acceptors [Ru2(µ-η4-C2O4)(CH3OH)2(η6-p-cymene)2](O3SCF3)2 (A1), [Ru2(µ-η4-C6H2O4)(CH3OH)2(η6-p-cymene)2](O3SCF3)2 (A2), [Ru2(dhnq)(H2O)2(η6-p-cymene)2](O3SCF3)2 (A3), and [Ru2(dhtq)(H2O)2(η6-p-cymene)2](O3SCF3)2 (A4) separately with a tetradentate pyridyl ligand (L1) in methanol using coordination-driven self-assembly [L1= N,N,N',N'-tetra(pyridin-4-yl)benzene-1,4-diamine]. The octanuclear cages are fully characterized by various spectroscopic techniques including single-crystal X-ray diffraction analysis of OC-4. The self-assembled cages show strong in vitro anticancer activity against human lung adenocarcinoma A549 and human cervical cancer HeLa cell lines as observed from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Of all the octanuclear cages, OC-3 exhibits remarkable anticancer activity against both cancer cell lines and is more active than that reported for cisplatin. The excellent anticancer activity of OC-3 and OC-4 highlights the importance of the synergistic effects of the spacer component of the dinuclear p-cymene Ru(II) acceptor clips.

In vitro disintegration of goat brain cystatin fibrils using conventional and gemini surfactants: Putative therapeutic intervention in amyloidoses.

Many protein misfolding diseases in mammalian system are characterised by the accumulation of protein aggregates in amyloid fibrillar forms. Several therapeutic approaches include reduction in the production of the amyloidogenic form of proteins, increase in the clearance rate of misfolded or aggregated proteins, and direct inhibition of the self-assembly process have been explained. One of the possible remedial treatments for such disorders may be to identify molecules which are capable of either preventing formation of fibrils or disintegrating the formed fibrils. In this work, we have studied the effect of conventional surfactants; sodium dodecylsulphate (SDS), cetyl trimethylammonium bromide (CTAB) and dicationic gemini (16-4-16) surfactant on the disintegration of the goat brain cystatin (GBC) fibrils above their critical micelle concentrations (CMC) using ThT fluorescence, CD, TEM, Congo red and turbidity approaches. The results obtained are significant and showing the best disintegrating potency on GBC fibrils with gemini surfactant. The outcome from this work will aid in the development and/or design of potential inhibitory agents against amyloid deposits associated with amyloid diseases.

Anti-fibrillation propensity of a flavonoid baicalein against the fibrils of hen egg white lysozyme: potential therapeutics for lysozyme amyloidosis.

More than 20 human diseases involve the fibrillation of a specific protein/peptide which forms pathological deposits at various sites. Hereditary lysozyme amyloidosis is a systemic disorder which mostly affects liver, spleen and kidney. This conformational disorder is featured by lysozyme fibril formation. In vivo lysozyme fibrillation was simulated under in vitro conditions using a strong denaturant GdHCl at 3 M concentration. Sharp decline in the ANS fluorescence intensity compared to the partially unfolded states, almost 20-fold increase in ThT fluorescence intensity, increase in absorbance at 450 nm suggesting turbidity, negative ellipticity peak in the far-UVCD at 217 nm, red shift of 50 nm compared to the native state in Congo red assay and appearance of a network of long rope-like fibrils in transmission electron microscope (TEM) analysis suggested HEWL fibrillation. Anti-fibrillation potency of baicalein against the preformed fibrils of HEWL was investigated following ThT assay in which there was a dose-dependent decrease in ThT fluorescence intensity compared to the fibrillar state of HEWL with the maximum effect observed at 150-µM baicalein concentration, loss of negative ellipticity peak in the far-UVCD region, dip in the Rayleigh scattering intensity and absorbance at 350 and 450 nm, respectively, together with a reduction in the density of fibrillar structure in TEM imaging. Thus, it could be suggested that baicalein could prove to be a positive therapeutics for hereditary human lysozyme amyloidosis.

Role of +405C>G and +936C>T polymorphisms of the vascular endothelial growth factor gene and risk of esophageal cancer in the Kashmiri population.

BACKGROUND: The gene for the vascular endothelial growth factor (VEGF), which promotes angiogenesis and permeability, is polymorphic. The aim of the present study was to evaluate the relationship between +936C>T and +404C>G polymorphism of VEGF with risk of esophageal cancer in the Kashmiri population in India. MATERIALS AND METHODS: 150 esophageal cancer patients and 150 unrelated healthy controls were genotyped for two VGEF SNPs (+405C/G, and +936C/T) using DNA extracted from prospectively collected blood samples by the PCR-RFLP method. RESULTS: For the VEGF +936C>T polymorphism a significant association of CT and combined CT+TT genotypes was observed with increased risk of esophageal cancer (p=0.021; 0.024). For the +405C>G polymorphism we observed significantly increased frequency of GG genotype in cases as compared to controls and also the +405 GG Genotype was observed to have a two fold risk(OR=2.7356; 95%CI=1.1409- 6.5593; p=0.020). The combined genotypes of GG-CC and GG-CT of +405C>G and +936C>T were found to be significantly associated with increased risk of esophageal cancer (p=0.0376; 0.0099). CONCLUSIONS: From the results of the present study a significant association of +936C>T and +405C>G polymorphisms with increased esophageal cancer risk exists in the Kashmiri population.

Lack of association of a common polymorphism in the 3' -UTR of interleukin 8 with non small cell lung cancer in Kashmir.

BACKGROUND: Chronic inflammation is considered as an important factor in the pathogenesis of lung cancer. The presence of inflammatory cells and higher levels of pro-inflammatory cytokines in the tumor microenvironment and their surrounding tissues is gaining much importance in research. MATERIALS AND METHODS: One hundred ninety NSCLC cases and 200 age, smoking and sex matched controls were evaluated for association of IL-8 -251 (rs4073) and IL-8 -845 (rs2227532) in our population. Restriction fragment length polymorphism (RFLP) was used followed by direct sequencing for the detection of SNPs. RESULTS: The IL-8 -845 polymorphism was not found in our population. No significant association was observed between the IL-8 -251 AT genotypes and IL-8 -25 AA genotypes and NSCLC (p=0.05) in our population. The IL-8 -251 A allele was also non-significant (p=0.05) in NSCLC patients. CONCLUSIONS: In conclusion, this report reveals lack of association between IL-8 - 251 A/T polymorphism and NSCLC in our Kashmir Valley population.

The XRCC1 Arg399Gln gene polymorphism and risk of colorectal cancer: a study in Kashmir.

BACKGROUND: The DNA repair gene XRCC1 Arg399Gln gene polymorphism has been found to be implicated in the development of various cancers, including colorectal cancer (CRC), in different populations. We aimed to determine any association of this polymorphism with the risk of CRC in Kashmir. MATERIALS AND METHODS: A total of 120 confirmed cases of CRC and 146 healthy cancer free controls from the Kashmiri population were included in this study. Genotyping was carried out by the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Genotype frequencies of XRCC1 Arg399Gln observed in controls were 34.2%, 42.5% and 23.3% for GG (Arg/Arg), GA (Arg/Gln), AA( Gln/Gln), respectively, and 28.3%, 66.7% and 5% in cases, with an odds ratio (OR)=5.7 and 95% confidence interval (CI) =2.3-14.1 (p=0.0001). No significant association of Arg399Gln SNP with any clinicopathological parameters of CRC was found. CONCLUSIONS: We found the protective role of 399Gln allele against risk to the development of CRC. The XRCC1 heterozygote status appears to be a strong risk factor for CRC development in the Kashmiri population.

CYP1A1 polymorphisms and risk of lung cancer in the ethnic Kashmiri population.

The CYP1A1 category of enzymes plays a central role in the metabolic activation of major tobacco carcinogens. Several polymorphisms within the CYP1A1 locus have been identified and have been shown to be associated with lung cancer risk, particularly in Asian populations. Here we focused on the influence of three polymorphisms on lung cancer in ethnic Kashmiris, genotyping 109 lung cancer cases and 163 healthy controls by PCR-RFLP methods. While no polymorphic alleles in CYP1A1m4 (exon 7 thr to asn) site were detected in our population, the allele frequency of CYP1A1m1 (Msp1) and CYP1A1m2 (exon 7 ile to val) were 30.1 and 26.6 in controls and 44.5 and 38.9 in cases. The CYP1A1m1 and CYP1A1m2 variants were significantly associated with lung cancer susceptibility (ORs; 2.65, CI 95% = 1.562-4.49 and 2.24,CI 95%= 1.35-3.73).This risk was prominent in case of SCC compared with AC or other types of lung cancer. Stratified analysis showed a multiplicative interaction between tobacco smoking and variant CYP1A1m1 genotype on the risk of SCC. The ORs of SCC for non-smokers were 2.08 and 3.15 for smokers. When stratified by pack years, effect was stronger in the heaviest smokers (ORs= 6.00,95% CI= 1.672-21.532).The interaction between tobacco smoking and variant CYP1A1m2 genotype followed similar pattern. Our findings thus support the conclusion that CYP1A1m1 and m2 polymorphisms are associated with the smoking related lung cancer risk in Kashmiri population.