Comparison of the Effect of Propranolol Combination with Cinnarizine and Propranolol in the Prevention of Acute Migraine Attacks.

Acute migraine attacks disrupt performance and reduce the quality of life. Therefore, efforts to prevent these attacks continue using different medications. This study aimed to compare the effect of cinnarizine combination with propranolol and propranolol with placebo in preventing acute migraine attacks. This study was a semi-experimental study performed on 120 adult patients with migraine referred to Department of Neurology in Rezgary Teaching Hospital in Erbil.. Participants were randomly allocated to two groups control (propranolol) and intervention (propranolol with cinnarizine). The frequency, duration and severity of headache attacks were recorded and followed within two months. Data were analyzed with SPSS ver23 software and T-paired, independent T-tests and ANOVA. The average age of the participants was 34.54 years. 60% were female and 55% had a family history of migraine. The average frequency of headache attacks in the intervention group decreased by 75 % (from 15 times to 3 times) and a 50 % decrease in the control group (from 12 times to 6 times). The duration and severity of headaches in both intervention and control groups decreased (p <0.001), respectively. The average frequency, duration and severity of headache attacks in the first- and second months during treatment in the intervention group and control group were statistically different (p <0.001). The drug combination of propranolol with cinnarizine has an additional effect on reducing acute migraine attacks compared to propranolol alone.

Docking analysis for identification of lead compound and 3d pharmacophore generation against gsk-3ß involved in bipolar disorder.

Bipolar disorder is a psychiatric illness that strikes between mania and depression, caused by both genetic and environmental factors. It is the sixth leading cause of disability worldwide and 3% of the global population suffers from this disorder. Focusing on the drugs used for psychotherapy and their associated side effects, there is a need to design and develop new anti-bipolar drugs with lesser side effects and improved efficacy. Molecular docking and pharmacophore modeling were performed to identify lead and the construction of pharmacophore triangle. One compound demonstrated best docking results that fit appropriately in the pocket of protein. In this study, an efficient compound for GSK-3B involved in bipolar disorder was identified through docking analysis. Distances were calculated among pharmacophore features like Aromatic Ring, Hydrophobic, HBD and HBA. Pharmacophore triangle was designed for three different classes that are Aromatic, HBD and HBA. This pharmacophore modeling can be useful for designing of novel drugs because this 3D pharmacophore showed best merging properties.

Evaluation of the p53 Arg72Pro polymorphism and its association with cancer risk: a HuGE review and meta-analysis.

Codon 72 is a hotspot of polymorphisms in the TP53 gene, which encodes a hub protein in the protein-protein interaction network of p53. It is thus a central player in the apoptotic pathway, preventing cancer. A large number of articles have been published exploring its association with an increased susceptibility to most common cancers. However, these studies have produced inconclusive results, which may be due to their small sample sizes or study designs. To comprehensively evaluate the potential correlation between the TP53 Pro72Arg polymorphism and cancer risk and to better characterize the Pro72Arg polymorphism, we performed a systematic HuGE review and meta-analysis of candidate studies through online resources, according to the proposal of MOOSE and the PRISMA statement. The identified articles were carefully examined according to the inclusion criteria. Pooled odds ratios were calculated on the basis of different genetic models, while heterogeneity was assessed through a chi-based Q-test and I2. After applying the inclusion filters, we obtained a pool of 54 eligible studies, representing 18 718 cases and 21 261 controls. Overall, non-significant cancer risk was observed in all the genetic models but their observed heterogeneity was extremely significant. In subgroup analysis, an increased susceptibility was observed in the case of colorectal cancer, while in cancers of the female reproductive system, significantly increased risk was detected in all the genetic models except the dominant model. In another subgroup analysis, significantly increased cancer risk was observed among Asians in homozygous and recessive models, while in Americans increased cancer risk was observed only in dominant and recessive models. No association was observed in the rest of the populations. In conclusion, pooled subgroup analysis on the basis of ethnicity proved that the TP53 Arg72Pro polymorphism is associated with an increased risk of cancer in Asians and Americans only and is not associated in other populations. It can therefore be concluded that this meta-analysis of available data suggests partial confirmation of the association between the TP53 Arg72Pro polymorphism and cancer risk susceptibility.

Effect of missense mutations on structure and interaction of anaplastic Lymphoma kinase (ALK) in neuroblastom.

Neuroblastoma is a cancer of the sympathetic nervous system, accounting for upto 15% of childhood cancer mortality. It can occur in many areas but most of them begin in the abdomen in the adrenal gland and can spread to the bones and other areas. http://en.wikipedia.org/wiki/Neuroblastoma-cite_note-pmid19383347-3. Unfortunately, like other cancers, its causes are still poorly understood. Anaplastic lymphoma kinase (ALK), a membrane associated tyrosine kinase was recently found to be mutated in neuroblastoma. Protein sequence of ALK was retrieved from UniProt and the seven identified mutations were substituted in native sequence to get its mutant proteins. Significant changes were explored in the mutant secondary structures when compared with the native protein. Changes were also observed in the physiochemical properties and it can therefore be inferred that, these changes may be translated in the tertiary structures due to their effects on the folding pattern. Tertiary structure of the protein modeled after refinement and validation was submitted to Protein Model Database (PMDB) and was assigned with the PMDB ID P0077827. RMSD values of the mutant structures were observed deviated from the native structure when compared with probability < 0.05. It was observed that there are a total of 15 Disordered Regions in the protein having a total of 290 Disordered Residues. Protein-ligand interaction analysis was performed to investigate the effects of mutations damaging its interactions and it was observed that the mutations understudy affects its interactions with ATP which ultimately results in causing neuroblastoma. This study was based on the in silico mutation analysis of Seven missense mutations of anaplastic lymphoma kinase which can better explain why missense mutations in ALK protein cause neuroblastoma. Structure and sequence based computations were systematically and comprehensively evaluated applied to the mutants in anaplastic lymphoma kinase and on the basis of our observations a detailed structural explanations have been developed for the measured and predicted impact of these missense substitutions.

In silico structural and functional characterization and phylogenetic study of alkaline phosphatase in bacterium, Rhizobium leguminosarum (Frank 1879).

Phosphorus is one of the primary macronutrient of plants, which is present in soil. It is essential for normal growth and development of plants. Plants use inorganic form of phosphate but organic form can also be assimilated with the help of soil inhabiting bacteria. Alkaline phosphatase is an enzyme present in Rizobium bacteria. This enzyme is responsible for solubilization and mineralization of organic phosphate and makes it readily available for plants. In the present study, nine different strains of Rhizobium leguminosarum were selected for a detailed computational structural and functional characterization and phylogenetic studies of alkaline phosphatase. Amino acid sequences were retrieved from UniProt and saved in FASTA format for use in analysis. Phylogenetic analysis of these strains was done by using MEGA7. 3D structure prediction was performed by using online server I-Tasser. Galaxy Web and 3D Refine were used for structure refinement. The refined structures were evaluated using two validation servers, QMEAN and SAVES. Protein-protein interaction analysis was done by using STRING. For detailed functional characterization, Cofactor, Coach, RaptorX, PSORT and MEME were used. Overall quality of predicted protein models was above 80%. Refined and validated models were submitted into PMDB. Seven out of nine strains were closely related and other two were distantly related. Protein-Protein interaction showed no significant co-expression among the interaction partners.

Silver nanoparticles and silver salt (AgNO3) elicits morphogenic and biochemical variations in callus cultures of sugarcane.

The research work was arranged to check the role of AgNPs and silver ions on callus cells of sugarcane (Saccharum spp. cv CP-77,400). AgNPs were synthesized chemically and characterized by UV-Vis spectra, XRD and SEM. AgNPs and silver ions were applied in various concentrations (0, 20, 40, 60 ppm) to sugarcane calli and the induced stress was characterized by studying various morphological and biochemical parameters. AgNPs and silver ions treatments produced high levels of malondialdehyde, proline, proteins, TP and TF contents. Similarly, CAT, SOD and POX activity was also significant in both treatments. The lower concentration of AgNPs and silver ions (20 ppm) provided maximum intracellular GSH level. This work mainly showed effects of AgNPs and silver ions on sugarcane calli in terms of morphological aberrations and cell membrane damage due to severe oxidative stress and production of enhanced levels of enzymatic and non-enzymatic antioxidants as self-defence to tolerate oxidative stress by scavenging reactive oxygen species. These preliminary findings will provide the way to study ecotoxicity mechanism of the metal ions and NPs in medicine industry and in vitro toxicity research. Furthermore, silver ions alone and their chemically synthesised AgNPs can be used for various biomedical applications in future.

Physical and chemical mutagens improved Sporotrichum thermophile, strain ST20 for enhanced Phytase activity.

OBJECTIVE: Phosphorous is an essential micronutrient of plants and involved in critical biological functions. In nature, phosphorous is mostly present in immobilized inorganic mineral and in the fixed organic form including phytic acid and phosphoesteric compounds. However, the bioavailability of bound phosphorous could be enhanced by the use of phosphate solubilizing microorganisms such as bacteria and fungi. The phytases are widespread in an environment and have been isolated from different sources comprising bacteria and fungi. METHODOLOGY: In current studies, we show the successful use of gamma rays and EMS (Ethyl Methane Sulphonate) mutagenesis for enhanced activity of phytases in a fungal strain Sporotrichum thermophile. RESULTS: We report an improved strain ST2 that could produce a clear halo zone around the colony, up to 24 mm. The maximum enzymatic activity was found of 382 U/mL on pH 5.5. However, the phytase activity was improved to 387 U/ml at 45 °C. We also report that the mutants produced through EMS showed the greater potential for phytase production. CONCLUSION: The current study highlights the potential of EMS mutagenesis for strain improvement over physical mutagens.

Polypharmacology Approach Against Migraine with Aura and Brain Edema for the Development of an Efficient Inhibitor and its Analogues.

BACKGROUND: Polypharmacology is a design or use of pharmaceutical agents in which single drug is used to treat multiple diseases. Aquaporin proteins are identified to treat migraine with aura and brain edema. This study focuses on Aquaporin-1 and Aquaporin-4. AQP-1 is expressed in small afferent sensory nerve fibers. Over-expression of peripheral nervous system causes migraine. METHODS: AQP-4 is an abundant channel water protein in brain that regulates water transport to prevent homeostasis. Over-expression of AQP-4 contributes to water imbalance in ischemic pathology resulting in cerebral edema. Purpose of this study is to identify a potent inhibitor for the treatment of migraine with aura and brain edema. RESULTS: As in the recent studies, no conventional methodologies have been focused through the approach of polypharmacology. Structures of AQP-1 and AQP- 4 proteins were retrieved from PDB (Protein Data Bank). PyRx software was used to perform molecular docking. CONCLUSION: Analogues of ligands were analyzed which contained significant similarities of associated proteins to get efficient inhibitor. Toxicity of lead compound was measured through admetSAR. A lead compound was predicted to treat these diseases.

Potential Risk Factors for Breast Cancer in Pakistani Women.

BACKGROUND: Breast cancer is the most common female malignancy worldwide and its incidence is on the rise in Pakistan. The aim of this case-control study was to quantify the association of various risk factors with breast cancer risk among Pakistani women. MATERIALS AND METHODS: A total of 2,246 women were studied, including 1,238 women with histologically confirmed breast cancer patients and age matched control subjects (N=1008) without breast cancer and other chronic diseases. Subjects were interviewed using a specifically designed questionnaire. Unconditional logistic regression was applied. Subsequent disease-specific mortality was also measured. RESULTS: In this study, majority of the breast cancer patients (69.59%) were in age ranges of 40s and 50s. BMI greater than 25kg/m2 (OR=1.57; 95%CI, 1.26-1.90 and OR=1.60; 95%CI, 1.26-2.03), marital status of unmarried (OR=2.03; 95%CI, 1.69-2.44), lack of breast feeding, smoking (current or ever), lack of physical activity and post-menopausal status were found to have significant positive associations with breast cancer. It was also observed that increased parity reduced the disease risk. A larger number of cases (58.1%) had their right breast affected while 22.8% had other complications as well. CONCLUSIONS: This exploratory analysis indicated a number of risk factors to be associated with increased risk of breast cancer. It was also observed that mean age at diagnosis is a decade earlier than in western countries. It is hoped that our findings will facilitate establishment of adequate evidence-based awareness and preventive measures for Pakistani women.

Expression of Rice Chitinase Gene in Genetically Engineered Tomato Confers Enhanced Resistance to Fusarium Wilt and Early Blight.

This is the first study reporting the evaluation of transgenic lines of tomato harboring rice chitinase (RCG3) gene for resistance to two important fungal pathogens Fusarium oxysporum f. sp. lycopersici (Fol) causing fusarium wilt and Alternaria solani causing early blight (EB). In this study, three transgenic lines TL1, TL2 and TL3 of tomato Solanum lycopersicum Mill. cv. Riogrande genetically engineered with rice chitinase (RCG 3) gene and their R1 progeny was tested for resistance to Fol by root dip method and A. solani by detached leaf assay. All the R0 transgenic lines were highly resistant to these fungal pathogens compared to non-transgenic control plants. The pattern of segregation of three independent transformant for Fol and A. solani was also studied. Mendelian segregation was observed in transgenic lines 2 and 3 while it was not observed in transgenic line 1. It was concluded that introduction of chitinase gene in susceptible cultivar of tomato not only enhanced the resistance but was stably inherited in transgenic lines 2 and 3.

Gel-free quantitative proteomic approach to identify cotyledon proteins in soybean under flooding stress.

Flooding stress causes growth inhibition and ultimately death in most crop species by limiting of energy production. To better understand plant responses to flooding stress, here, flooding-responsive proteins in the cotyledons of soybean were identified using a gel-free quantitative proteomic approach. One hundred forty six proteins were commonly observed in both control and flooding-stressed plants, and 19 were identified under only flooding stress conditions. The main functional categories were protein and development-related proteins. Protein-protein interaction analysis revealed that zincin-like metalloprotease and cupin family proteins were found to highly interact with other proteins under flooding stress. Plant stearoyl acyl-carrier protein, ascorbate peroxidase 1, and secretion-associated RAS superfamily 2 were down-regulated, whereas ferretin 1 was up-regulated at the transcription level. Notably, the levels of all corresponding proteins were decreased, indicating that mRNA translation to proteins is impaired under flooding conditions. Decreased levels of ferritin may lead to a strong deregulation of the expression of several metal transporter genes and over-accumulation of iron, which led to increased levels of reactive oxygen species, resulting to detoxification of these reactive species. Taken together, these results suggest that ferritin might have an essential role in protecting plant cells against oxidative damage under flooding conditions. BIOLOGICAL SIGNIFICANCE: This study reported the comparative proteomic analysis of cotyledon of soybean plants between non-flooding and flooding conditions using the gel-free quantitative techniques. Mass spectrometry analysis of the proteins from cotyledon resulted in the identification of a total of 165 proteins under flooding stress. These proteins were assigned to different functional categories, such as protein, development, stress, redox, and glycolysis. Therefore, this study provides not only the comparative proteomic analysis but also the molecular mechanism underlying the flooding responsive protein functions in the cotyledon.

Kinetics and thermodynamics of the native and mutated extracellular endo-glucanases from Cellulomonas biazotea.

The mutation had dramatic effect on the kinetic and thermodynamic parameters inferring thermostability of endo-glucanase from Cellulomonas biazotea mutant 51 SM(r). The denaturation activation energies of native and mutated enzymes were 73.3 and 68.8 kJ/mol respectively. They showed compensation effect at 55 degrees C. Both enthalpy and entropy values of irreversible thermal inactivation for mutated enzyme were decreased suggesting that the mutation partly stabilized the enzyme.

Association of the rs1042522 polymorphism with increased risk of prostate adenocarcinoma in the Pakistani population and its HuGE review.

Prostate adenocarcinoma is one of the leading causes of cancer related mortality in men but still limited knowledge is available about its associated functional SNPs including rs1042522 (Pro72Arg). The present study was undertaken to explore the association of this SNP with susceptibility to prostate adenocarcinoma along with its structural and functional impacts in the Pakistani population in a case-control study. Three-dimensional structure of human TP53 with Pro72Arg polymorphism was predicted through homology modeling, refined and validated for detailed structure-based assessment. We also carried out a HuGE review of the previous available data for this polymorphism. Different genetic models were used to evaluate the genotypes association with the increased risk of PCa (Allelic contrast: OR=0.0.34, 95%CI 0.24-0.50, p=0.000; GG vs CC: OR=0.17, 95%CI 0.08-0.38, p=0.000; Homozygous: OR=0.08, 95%CI 0.04-0.15, p=0.000; GC vs CC: OR=2.14, 95%CI 1.01-4.51, p=0.046; Recessive model: OR=0.10, 95%CI 0.05-0.18, p=0.000; Log Additive: OR=3.54, 95%CI 2.13-5.89, p=0.000) except the Dominant model (OR=0.77, 95%CI 0.39-1.52, p=0.46). Structure and functional analysis revealed that the SNP in the proline rich domain is responsible for interaction with HRMT1L2 and WWOX. In conclusion, it was observed that the Arg coding G allele is highly associated with increased risk of prostate adenocarcinoma in the Pakistani population (p=0.000).

Ligand based pharmacophore model development for the identification of novel antiepileptic compound.

Epilepsy is a common neurological disorder throughout the world which is characterized by recurrent unprovoked epileptic seizures. A need exists for the development of new antiseizure drugs with improved efficacy and tolerability, as several of the currently available antiepileptic drugs (AEDs) have been associated with severe side effects. A ligand based pharmacophore approach has been generated for 44 new antiepileptic compounds with emphasis on the development of new drugs by using LigandScout software and distance estimation using Jmol. The pharmacophore of the compounds contained three features hydrophobic unit, hydrogen bonding domain and electron donor. The pharmacophore models derived were then filtered using the Lipinski's rule of five criteria and orally bio-available compounds were obtained. Thus, this approach was able to reclaim few leads which had projected inhibitory activity alike to most active compounds with suitable calculated drug-like properties and therefore they could be recommended for further studies.

Receptor modification as a therapeutic approach against viral diseases.

Poliovirus causes flaccid paralysis through the destruction of motor neurons in the CNS. Susceptibility to its infection is mainly due to the interaction in between the surface capsid proteins and its receptors on the host cell surface, important for binding, penetration and other necessary events during early infection. Receptor modification is a new approach to treat viral diseases by the modification of target proteins structure. Binding domains are modified in an effective way to make it difficult for the virus to recognize it. In this study, tolerant and intolerant induced mutations in the poliovirus receptor, VP1 and VP2 were identified and substituted in the seed sequence to get the modified versions. Substitutions causing changes in initial folding were short listed and further analyzed for high level folding, physiochemical properties and interactions. Highest RMSD values were observed in between the seed and the mutant K90F (3.265 Å) and Q130W (3.270Å) respectively. The proposed substitutions were found to have low functional impact and thus can be further tested and validated by the experimental researchers. Interactions analyses proved most of the substitutions having decreased affinity for both the VP1 and VP2 and thus are of significant importance against poliovirus. This study will play an important role for bridging computational biology to other fields of applied biology and also will provide an insight to develop resistance against viral diseases. It is also expected that same approach can also be applicable against other viruses like HCV, HIV and other in near future.

Abberent expression analysis of LMNA gene in hutchinson-gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by de novo dominant point mutations of the genes encoding nuclear lamina proteins, leading towards premature aging. A protein sequence is subjected to mutations in nature which can affect the function and folding pattern of the protein by different ways. Mutations involved in HGPS were identified and were substituted in the seed sequence retrieved from the UniProt database to get the mutated versions. Tertiary structure of the Lamin A protein was previously unpredicted so was performed for all the mutated as well as for the seed protein to analyze the effects of mutations on the protein structure, folding and interactions. All the predicted models were refined and validated through multiple servers for multiple parameters. The validated 3D structure of seed protein was then successfully submitted to the Protein Model Database and was assigned with the PMDB ID PM0077829. All the predicted structures were superimposed with a root mean square deviation value of 7.0 Å and a high Dali Z-score of 1.9. It was observed that mutations affected physiochemical properties as well as instability index and thus is affecting the domains in specific and the whole structure in general. It was further analyzed that HGPS is the result of affected Lamin a protein interactions with other integral and binding proteins in the inner nuclear membrane affecting the link in between the nuclear membrane and the network of the lamina.

Sequence and structure based assessment of nonsynonymous SNPs in hypertrichosis universalis.

Hairs are complex structures, making a protective layer and serves different biological functions. TRPS1, a transcription factor is one of the candidate genes causing congenital hypertrichosis, an excessive hair growth at inappropriate body parts. SNPs of TRPS1 were retrieved from dbSNP which were screened by SIFT and PolyPhen servers based on their functional impacts. Out of the screened SNPs, rs181507248 and rs146506752 were predicted as intolerant and damaging by both the servers. The predicted tertiary structure of the native TRPS1 after refinement and validation was successfully submitted to the Protein Model Database and was assigned with PMDB ID PM0077843, as it was previously unpredicted. It was observed through the structure based analysis that, the SNPs rs181507248 and rs146506752 caused significant changes in the secondary and tertiary structures as well as the physiochemical properties of TRPS1 protein. It can thus be concluded that the changed properties due to these single nucleotide polymorphisms effect the interactions of TRPS1 which result in congenital hypertrichosis.

Identification of type-specific anticancer histone deacetylase inhibitors: road to success.

Cancer is a serious and life-eliminating disease. Majority of anticancer agents are non-selective. Along with the cancerous cells they also target the normal ones. An important aspect is to hit the developing mechanism of the tumor, which is highlighted by in silico drug designing. On the basis of novel molecular targets, in silico (computational approach) drug discovery has emerged as today's need. Histone deacetylases are an important therapeutic target for many human cancers. The first and only approved (in 2006) histone deacetylase inhibitors (HDACIs) is Zolinza. Depending on the types of the histone deacetylase (HDAC) enzymes, discovery of type-specific inhibitors is important. With continued research and development, in near future HDACIs are likely to figure prominently in cancer treatment plans. This review presents the overview of HDACs, their role in cancer, their structural classes, activity, catalytic domain and the inhibitors of HDACs for cancer therapy. Also it helps in understanding the open directions in this area of research and highlights the importance of computational approaches in discovering specific drugs for cancer therapy.