Exploring the interaction of Valsartan and Valsartan-Zn(ll) complex with DNA by spectroscopic and in silico methods.

Belonging to the Sartan family, antihypertensive drug - Valsartan (Val) had been found to possess antioxidant properties. Also, the zinc complex of Valsartan (VZn) has been recently recognized as inducing agents of the reductive stress effects thus possessing anticancer activity. Hence, in this work an attempt has been made to understand the interaction of Val and VZn with DNA using spectroscopic and in silico methods as DNA has been identified as the target for many anticancer drugs. VZn has been prepared in 2:1 M ratio and characterised by absorbance, FTIR, HRMS, NMR and Job's continuous variation method. VZn has been tested against human lungs cancer cell line which exhibited good anticancer activity (IC50 = 89 µg/mL). Interaction of Val and VZn with ct-DNA under physiological conditions has been studied by spectroscopic techniques such as fluorescence, absorbance, FTIR, circular dichroism (CD) and in silico methods. Fluorescence quenching, DNA melting and viscometric studies confirmed that both ligand and complex bind to the grooves of the ct-DNA. The experimental results have revealed that VZn strongly bind with DNA compared to Val. Docking study suggested that, Val binds at major groove while VZn binds to both minor and major grooves of B-DNA.

Synthesis, characterization, spectroscopic studies and biological evaluation of Schiff bases derived from 1-hydroxy-2-acetonapthanone.

The four Schiff bases (I - IV) were synthesized by the condensation reaction of 1(1-hydroxynaphthalen-2-yl)ethanone, 1-(4-chloro-1hydroxynaphthalen-2-yl)ethanone and 1-(4-bromo-1-hydroxynaphthalen-2-yl)ethanone with propane-1,3-diamine and pentane-1,3-diamine. The structural analysis is done by UVvis., FT-IR, 1H NMR, 13C NMR, LCMS and elemental analyses. These compounds were assayed for antibacterial (Escherichia coli and Salmonella Typhi) activity and antioxidant (2,2-Diphenyl-1-Picryl Hydrazyl(DPPH) and Hydroxyl radical scavenging method) activity. The antibacterial and antioxidant activities of synthesized Schiff bases exhibited better degrees of inhibitory effects. Among these, Schiff base 2,2'-((propane-1,3-diylbis(azanylylidene))bis(ethan-1-yl-1-ylidene))bis(4-chloronaphthalen-1-ol) (II) exhibited excellent antibacterial activity with MICs of 0.12, 0.25, 0.5 and 1 mg/ml against E. coli and Salmonella Typhi. Furthermore, two Schiff bases such as, 2,2'-((propane-1,3-diylbis(azanylylidene))bis(ethan-1-yl-1-ylidene))bis(naphthalen-1-ol) (I) and 2,2'-((pentane-1,3-diylbis(azanylylidene))bis(ethan-1-yl-1-ylidene))bis(4-bromonaphthalen-1-ol) (IV) exhibited promising antioxidant activity.

High Pressure Phases and Amorphization of a Negative Thermal Expansion Compound TaVO5.

Negative thermal expansion material TaVO5 is recently reported to have pressure induced structural phase transition and irreversible amorphization at 0.2 and above 8 GPa, respectively. Here, we have investigated the high pressure phase of TaVO5 using in situ neutron diffraction studies. The first high pressure phase is identified to be monoclinic P21/ c phase, same as the low temperature phase of TaVO5. On heating, amorphous TaVO5 transformed to a new crystalline phase, which showed signatures of higher coordination of vanadium indicating pressure induced amorphization (PIA). PIA observed in TaVO5 might be due to the kinetic hindrance of pressure induced decomposition (PID) into a compound with higher coordination of vanadium. Mechanism of PIA observed in TaVO5 is investigated by carrying out ex situ Raman, XRD, XPS, and XAS measurements. We have also proposed a pressure-temperature phase diagram of TaVO5 qualitatively delineating the phase boundaries between the ambient orthorhombic, monoclinic, and amorphous phases.

Pressure and Temperature Dependent Structural Studies on Hollandite Type Ferrotitanate and Crystal Structure of a High Pressure Phase.

The structural stability and phase transition behavior of tetragonal (I4/m) hollandite type K2Fe2Ti6O16 have been investigated by in situ high pressure X-ray diffraction using synchrotron radiation and a diamond anvil cell as well as by variable temperature powder neutron and X-ray diffraction. The tetragonal phase is found to be stable in a wider range of temperatures, while it reversibly transforms to a monoclinic (I2/m) structure at a moderate pressure, viz. 3.6 GPa. The pressure induced phase transition occurs with only a marginal change in structural arrangements. The unit cell parameters of ambient (t) and high pressure (m) phases can be related as am ∼ at, bm ∼ ct, and cm ∼ bt. The pressure evolution of the unit cell parameters indicates anisotropic compression with ßa = ßb ≥ ßc in the tetragonal phase and becomes more anisotropic with ßa ≪ ßb < ßc in the monoclinic phase. The pressure-volume equations of state of both phases have been obtained by second order Birch-Murnaghan equations of state, and the bulk moduli are 122 and 127 GPa for tetragonal and monoclinic phases, respectively. The temperature dependent unit cell parameters show nearly isotropic expansion, with marginally higher expansion along the c-axis compared to the a- and b-axes. The tetragonal to monoclinic phase transition occurs with a reduction of unit cell volume of about 1.1% while the reduction of unit cell volume up to 6 K is only about 0.6%. The fitting of temperature dependent unit cell volume by using the Einstein model of phonons indicates the Einstein temperature is about 266(18) K.

Structural manipulation and tailoring of dielectric properties in SrTi1-xFexTaxO3 perovskites: Design of new lead free relaxors.

We report composition dependent structure evolution from SrTiO3 to SrFe0.5Ta0.5O3 by powder X-ray and neutron diffraction studies of SrTi1-2xFexTaxO3 (0.00 ≤ × ≤ 0.50) compositions. Structural studies reveal cubic (Pm3m) perovskite-type structure of the parent SrTiO3 for x up to 0.075 and cation disordered orthorhombic (Pbnm) perovskite-type structure for x ≥ 0.33. A biphasic region consisting of a mixture of cubic and orthorhombic structures is found in the range for 0.10 ≤ × ≤ 0.25. Dielectric studies reveal transformation from a normal dielectric to relaxor like properties with increasing Fe(3+) and Ta(5+) concentration. Dielectric response is maximum at x = 0.33 in the series. The results establish a protocol for designing new lead-free relaxor materials based on the co-substitution of Fe(3+) and Ta(5+) for Ti(4+) in SrTiO3. A complex interplay of strain effects arising from distribution of cations at the octahedral sites of the perovskite structure controls the dielectric properties.

Development of a credible 3D-QSAR CoMSIA model and docking studies for a series of triazoles and tetrazoles containing 11ß-HSD1 inhibitors.

Type 2 diabetes mellitus is described by insulin resistance and high fasting blood glucose. Increased levels of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme result in insulin resistance and metabolic syndrome. Inhibition of 11ß-HSD1 decreases glucose production and increases hepatic insulin sensitivity. Use of selective 11ß-HSD1 inhibitors could prove to be an effective strategy for the treatment of the disease. It was decided to identify the essential structural features required by any compound to possess 11ß-HSD1 inhibitory activity. A dataset of 139 triazoles and tetrazoles having 11ß-HSD1 inhibitory activity was used for the development of a 3D-QSAR model. The best comparative molecular field analysis (CoMFA) model was generated with databased alignment, which was further used for comparative molecular similarity indices analysis (CoMSIA). The optimal CoMSIA model showed [Formula: see text] = 0.809 with five components, [Formula: see text] = 0.931, SEE = 0.323 and F-value = 249.126. The CoMSIA model offered better prediction than the CoMFA model with [Formula: see text] = 0.522 and 0.439, respectively, indicating that the CoMSIA model appeared to be a better one for the prediction of activity for the newly designed 11ß-HSD1 inhibitors. The selectivity aspect of 11ß-HSD1 over 11ß-HSD2 was studied with the help of docking studies.

Similar glucose control with basal-bolus regimen of insulin detemir plus insulin aspart and thrice-daily biphasic insulin aspart 30 in insulin-naive patients with type 2 diabetes: Results of a 50-week randomized clinical trial of stepwise insulin intensification.

OBJECTIVE: This study aimed to demonstrate the non-inferiority of 50-week treatment with stepwise insulin intensification of basal-bolus insulin analogues [insulin detemir (IDet) and aspart (IAsp)] versus biphasic insulin aspart 30 (BIAsp30) in insulin-naive type 2 diabetes mellitus (T2DM) patients not controlled by oral glucose-lowering drugs (OGLDs). RESEARCH DESIGN AND METHODS: In this open-label multicentre, multinational, randomized, parallel-arm treat-to-target trial, 403 insulin-naive patients with T2DM in four African countries were randomized to either an IDet+IAsp (n = 200) or BIAsp1-2-3 (n = 203) treatment group. Stepwise insulin intensification was performed at the end of 14, 26 and 38 weeks, depending on HbA1c values. The primary endpoint was change in HbA1c after 50 weeks of treatment. Safety variables were hypoglycaemia incidence, occurrence of adverse events and weight gain. RESULTS: Non-inferiority of the IDet+IAsp versus BIAsp1-2-3 treatment regimen was demonstrated by their similar HbA1c levels at the end of trial (IDet+IAsp: baseline 8.6%, 50 weeks 7.4%; BIAsp1-2-3: baseline 8.7%, 50 weeks 7.3%; full analysis set difference: 0.1% [95% CI: -0.1, 0.3]; per protocol: 0.2% [95% CI: -0.1, 0.4]). At week 50, 40.3 and 44.9% of patients achieved HbA1c <7.0% with IDet+IAsp and BIAsp1-2-3, respectively. The rate of overall hypoglycaemia during the trial was also similar in both groups (IDet+IAsp: 9.4 events/patient-year; BIAsp1-2-3: 9.8 events/patient-year). CONCLUSION: Insulin initiation and intensification using IDet+IAsp was not inferior to BIAsp1-2-3 in insulin-naive patients with T2DM not controlled by OGLDs. Both regimens led to similar reductions in HbA1c values after 50 weeks of treatment.

Therapeutic Potential of 5-HT6 Antagonist SB399885 in Traumatic Stress Disorder.

BACKGROUND: Post-traumatic stress disorder is an anxiety disorder for which current therapies are not effective. The 5-Hydroxytryptamine6 receptor antagonist SB399885 has been reported to have an anxiolytic effect. Hence, the current investigation was undertaken to evaluate its efficacy in post-traumatic stress disorder. METHODS: Rats were placed in the operant box and given 3 foot shocks at intervals of 1 min. The following day the duration of freezing was recorded. For the enhanced sustained prolonged stress (ESPS), the rats were subjected to various stressors such as restraint stress (2 h), forced swim (20 min), and anesthesia, followed by a foot shock for 4 s. The rats were then subjected to the elevated plus maze. RESULTS: Treatment with SB399885 (1 and 3 mg/kg, I. p.) was found to significantly decrease the freezing time in the contextual fear conditioning model. Rats subjected to ESPS spent greater time in the open arm of the elevated plus maze when administered SB399885 at the above mentioned doses. The treatment had no effect on locomotor activity. SB399885 decreased the 5-hydroxytryptamine levels in the amygdala at doses that were effective in the above animal models. CONCLUSION: 5-Hydroxytryptamine6 antagonists may hold potential in the treatment of post-traumatic stress.

Growth performance of lambs fed diet supplemented with rice bran oil as such or as calcium soap.

Forty two Malpura lambs (21 d old) were divided into three groups of 14 each consisting of 8 females and 6 males. Lambs were allowed to suckle their respective dams twice daily up to weaning (13 wks) and offered free choice concentrate and roughage in a cafeteria system. The lambs in control group were fed conventional concentrate mixture, in RBO group concentrate mixture fortified with 4% industrial grade rice bran oil and in Ca-soap rice bran oil (as in RBO group) was supplemented in the form of calcium soap. The concentrate intake decreased(p≤0.05) in RBO group as a result total dry matter, crude protein and metabolizable energy intake decreased compared to control whereas Ca-soap prepared from the same rice bran oil stimulated the concentrate intake leading to higher total dry matter, crude protein and energy intakes. The digestibility of dry matter (p≤0.05), organic matter (p≤0.05) and crude protein (p≤0.05) was higher in RBO group followed by Ca-soap and control whereas no effect was observed for ether extract digestibility. Higher cholesterol (p≤0.05) content was recorded in serum of oil supplemented groups (RBO and Ca-soap) while no effect was recorded for other blood parameters. Rice bran oil as such adversely affected and reduced the body weight gain (p≤0.001) of lambs in comparison to control whereas the Ca-soap of rice bran oil improved body weight gain and feed conversion efficiency in lambs. Fat supplementation decreased total volatile fatty acids (p≤0.05) and individual volatile fatty acid concentration which increased at 4 h post feeding. Fat supplementation also reduced (p≤0.05) total protozoa count. Ca-soap of rice bran oil improved pre slaughter weight (p≤0.05) and hot carcass weight (p≤0.05). It is concluded from the study that rice bran oil in the form of calcium soap at 40 g/kg of concentrate improved growth, feed conversion efficiency and carcass quality as compared to rice bran oil as such and control groups.

Messenger RNA degradation may be inhibited in sporadic inclusion body myositis.

OBJECTIVE: To integrate an immune-mediated mechanism and the disturbed protein expression in sporadic inclusion body myositis (IBM). BACKGROUND: In IBM, abnormal fibers harbor inclusions of some proteins found in the brains of patients with Alzheimer disease (AD). Poly(A)-binding protein 1 (PABP1) is the RNA binding protein that attaches to the poly(A) tail of mRNA and is involved in translation and mRNA degradation. Under stresses, mRNA combined with PABP1 forms cytoplasmic granules called stress granules. METHODS: Using 12 muscle biopsies with sporadic IBM and 46 controls, the authors localized PABP1 by immunohistochemistry, and poly(A)-containing RNA (poly(A)+ RNA) using the in situ hybridization method. They also immuno-localized HuR, one of the components of stress granules. RESULTS: In IBM, a proportion of fibers, including those vacuolated, showed an abnormal accumulation of PABP1 immuno-positive deposits. An immunofluorescence study indicated that large PABP1 positive deposits formed conglomerates with poly(A)+ RNA and PABP1 colocalized with HuR. Although PABP1-positive cytoplasmic inclusions were found in disease controls, their aggregates combined with poly(A)+ RNA were only detected in IBM. CONCLUSIONS: The localization of PABP1 positive deposits in inclusion body myositis (IBM) and other diseases may correspond to the stress granules that are formed under exposure to cellular stresses and the sites of mRNA turnover. The concomitant aggregation of poly(A)+ RNA that is specifically found in IBM may be due to the inhibition of mRNA degradation, which may affect translation. The authors speculate that an autoantibody against mRNA degradation machinery could play a role in this inhibition.

MAP kinase phosphatase-1 is induced in abnormal fibers in inclusion body myositis.

OBJECTIVE: To investigate alterations in protein kinases and phosphatases that regulate the activity of mitogen activated protein kinase (MAPK) in sporadic inclusion body myositis (IBM). BACKGROUND: In vacuolated fibers in IBM, several studies reported upregulation of the extracellular regulated kinase (ERK) subclass of MAPK family. Whereas MAPK kinases (MKK) activate MAPK, MAPK phosphatases (MKP) inactivate MAPK. MKP-1 is involved in muscle fiber differentiation and it is downregulated during myotube formation. METHODS: Immunolocalization of MKK1 through MKK4 and MKP-1 to MKP-3 was tested in muscle specimens from 10 patients with IBM and controls. RESULTS: In IBM, strong and focal deposits of MKP-1 were observed in vacuolated fibers. The MKP-1-positive deposits were colocalized with ERK. MKP-2, MKP-3, and MKK were not associated with vacuolated fibers. CONCLUSIONS: In IBM, MKP-1 is abnormally induced in vacuolated fibers probably to inactivate ERK. Although direct activators other than those tested in the current study might induce ERK, the absence of activation of MKK suggests that the aggregation of ERK protein itself causes the seeming upregulation of the protein kinase in IBM. Like ERK and its nuclear substrate, MKP-1 is an enzyme that forms aggregates in vacuolated fibers and is involved in myogenesis.

[A patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma].

We here reported a 54-year-old female patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. She was found to have scattered tumor in 1990. Although the tumor had slowly grown for the last 10 years, she showed no clinical symptoms. Numbness and weakness of lower extremities began in June 1999, and she was referred to Kyoto University Hospital on Oct. 21 1999 for evaluation of progressive symptoms. She had skin pigmentation, edema of the lower extremities, lymphadenopathy, muscle weakness and sensory disturbance in a glove-and-stocking distribution. Serological examination showed monoclonal IgG-lambda gammopathy. Serum vascular endothelial growth factor (VEGF) was markedly elevated. Microscopic studies on biopsied sural nerve demonstrated mild decrease of myelinated fibers. Immunohistochemically, the pulmonary tumor was defined as an IgG (lambda type) plasmacytoma. After treatment with melphalan-prednisolone therapy, the neurological symptoms improved along with decrease of serum VEGF levels as well as the size of pulmonary plasmacytoma. This is the first report of a patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. This case suggests that growth of pulmonary plasmacytoma might have played an important role in the overproduction of VEGF and thus development of Crow-Fukase syndrome.

Inclusion body myositis: expression of extracellular signal-regulated kinase and its substrate.

OBJECTIVE: To assess abnormal intracellular signal transduction in inclusion body myositis (IBM). BACKGROUND: Mitogen-activated protein kinases (MAPKs) play pivotal roles in intracellular signal transduction and regulate cell growth and differentiation. Upon their activation, MAPKs translocate from the cytoplasm into the nucleus. DESIGN/METHODS: The authors investigated the localization of several forms of the MAPK family-extracellular signal-regulated kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 MAPK (p38)-in 10 patients with sporadic IBM and in 52 control subjects. The relationship between the localization of immunopositive deposits and nuclei was tested with bis-benzimide. RESULTS: Vacuolated fibers in IBM displayed very strong focal immunoreactivity of ERK, but not of JNK or p38. The ERK-positive deposits in these vacuolated fibers colocalized with the nuclear substrate of ERK, Elk-1. ERK- and Elk-1-positive deposits were located frequently on the surface of the nuclei in vacuolated fibers in IBM. Similar findings to those of sporadic IBM were observed in three patients with distal myopathy with rimmed vacuoles, but not in eight normal or the other 41 disease controls. CONCLUSION: There is evidence for impaired molecular transport to the nucleus from the cytoplasm in the vacuolated fibers in IBM. This could be due to cytoplasmic aggregation of ERK and Elk-1 or to abnormal nuclear pore machinery involved in the transport of ERK and its substrate upon ERK activation.

[A patient of MELAS with 3271 mutation with fatal outcome after alcohol intake].

A patient of MELAS is reported. A 28-year-old woman was admitted to Shimada Municipal Hospital because of nausea, vomiting, and right homonymous hemianopsia. She had past history of dizziness and convulsion. A brain magnetic resonance imaging showed an ischemic lesion in the left occipital lobe, which disappeared in the follow-up study. Laboratory examination indicated elevated lactate and pyruvate levels in both blood and cerebrospinal fluid. The muscle biopsy demonstrated ragged-red fibers and strongly SDH-reactive blood vessels. PCR-RFLP analysis of DNA extracted from her muscle and blood as well as her mother's blood revealed a T to C mutation at nucleophile position of 3271 in mitochondrial DNA. She was diagnosed as having MELAS and discharged. One year after the first admission, she re-visited our hospital because of three days' duration of fatigability and generalized muscle pain after alcohol intake. She had severe lactic acidosis, rhabdomyolysis and acute renal failure. Despite a continuous hemodialysis and other intensive efforts, the patient died 20 hours later. Alcohol intake has been reported to induce rhabdomyolysis in myopathy with mitochondrial DNA deletions. The course of this patient suggests that alcohol intake can be an aggravating factor also in MELAS.

Human CYP1B1 Leu432Val gene polymorphism: ethnic distribution in African-Americans, Caucasians and Chinese; oestradiol hydroxylase activity; and distribution in prostate cancer cases and controls.

Cytochrome P4501B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones, including 17beta-oestradiol (E2) and testosterone. We report a significant difference in the allele frequencies of two point mutations in the coding region of the CYP1B1 gene among Caucasian (n = 189), African-American (n = 52) and Chinese (Linxian) (n = 109) populations. A (C to G) transversion at position 1666 in exon 3, which results in an amino acid substitution of Leu432 to Val, was present in African-Americans with an allele frequency for Va1432 of 0.75, in Caucasians of 0.43, and in Chinese of 0.17. A (C to T) transition at position 1719 in exon 3, with no amino acid change (Asp449), appeared to be closely linked with the Val432 variant. Results using human lung microsomal preparations from individuals with the CYP1B1Val/Val and CYP1B1Leu/Leu genotypes indicate that Val432 variant may be a high activity allele and thus may contribute to the interindividual differences in CYP1B1 activity. Because CYP1B1 is involved in hormone and carcinogen metabolism, and given the disparate rates of prostate cancer among ethnic groups, we also evaluated the association of the CYP1B1 Leu432Val polymorphism with prostate cancer risk in a pilot case-control study. Among Caucasians, 34% of men with cancer (n = 50) were homozygous for the Val432 polymorphism, while only 12% of matched control subjects (n = 50) had this genotype. These preliminary data indicate that genetic polymorphisms in CYP1B1 might play an important role in human prostate carcinogenesis.