2-Methanesulfonamidobenzoic acid

In the title compound, C8H9NO4S, an intra­molecular N—H⋯O hydrogen bond gives rise to a six-membered ring. In the crystal structure, two mol­ecules are connected by O—H⋯O hydrogen bonds, forming a centrosymmetric dimer. These dimers are further connected by C—H⋯O hydrogen bonds

Curcumin: Synthesis optimization and in silico interaction with cyclin dependent kinase

Curcumin is a natural product with enormous biological potential. In this study, curcumin synthesis was revisited using different reaction solvents, a catalyst (n-butylamine) and a water scavenger [(n-BuO)3B], to develop the optimal procedure for its rapid acquisition. During synthesis, solvent choice was found to be an important parameter for better curcumin yield and high purity. In a typical reaction, acetyl acetone was treated with boron trioxide, followed by condensation with vanillin in the presence of tri-n-butyl borate as water scavenger and n-butylamine as catalyst at 80 °C in ethyl acetate to afford curcumin. Moreover, curcumin was also extracted from turmeric powder and spectroscopic properties such as IR, MS, 1H NMR and 13C NMR with synthetic curcumin were established to identify any impurity. The purity of synthetic and extracted curcumin was also checked by TLC and HPLC-DAD. To computationally assess its therapeutic potential against cyclin dependent kinases (CDKs), curcumin was docked in different isoforms of CDKs. It was observed that it did not dock at the active sites of CDK2 and CDK6. However, it could enter into weak interactions with CDK4 protein

Ramadan-specific nutrition education improves cardio-metabolic health and inflammation—a prospective nutrition intervention study from Pakistan

There are recent reports that Ramadan fasting (RF) results in weight gain instead of weight loss. In addition, the data on the efficacy of brief nutrition education on healthy eating practices in Ramadan for better health are scarce. Therefore, a study was conducted to investigate the effects of brief nutrition education before the start of RF on healthy eating practices during RF. For this purpose, a prospective observational study focused on “Dietary Education and Awareness for Ramadan (DEAR)” as an intervention was carried out. The participants (n = 74) were recruited and divided into two groups, i.e., intervention and control groups (n = 37 each). As an intervention, nutrition education lessons were given before and during RF month. The control group did not attend these nutrition education lessons. Data on anthropometrics, dietary intake, and other parameters were collected at three time points: before, in the end, and 4 weeks after RF. Weight was measured in kg; height, waist circumference (WC), and hip circumference (HC) were measured in cm; and body mass index (BMI) was calculated. Waist-to-hip ratio (WHR) was calculated by dividing the waist value by the hip value. Body composition analysis was performed by the body composition analyzer (BF-907). Blood pressure (BP) was measured using a validated automated blood pressure. A 3–5 ml of venous blood was collected, and plasma and serum were separated. Serum and plasma samples were processed for general blood chemistry (blood lipid profile, glucose, and CRP) within 2 h. CRP was determined by the immunoturbidimetry method using an auto-analyzer. An enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine/chemokines. Adherence to nutrition education (intervention) was assessed. The results show that nutrition education has positive effects on overall nutrition. Significant improvement in dietary adherence to dietary advice in the intervention group was noted. Significant BW loss (mean loss: 1.21 kg) in the intervention group was observed. The majority (63.3%) had lost BW ≥ 1.0 kg. Other changes observed as a result of the intervention included improvements in blood glucose, cholesterol, CRP levels, and systolic and diastolic BP. There was a notable shift in pro- and anti-inflammatory cytokine concentrations: IL-7, IL-4, and TGF-α decreased, while IL-2, TNF-α and resistin, IL-1 RA, IL-17 A, and sCD40 increased. In conclusion, RF resulted in a loss in mean BW and an improvement in related blood chemistry and cytokine profiles. Furthermore, nutrition education before RF resulted in better nutrition practices during RF and a desirable healthy BW, blood lipid, and cytokine profiles

Study protocol of DIVERGE, the first genetic epidemiological study of major depressive disorder in Pakistan

INTRODUCTION: Globally, 80% of the burdenof major depressive disorder (MDD) pertains to low- and middle-income countries. Research into genetic and environmental risk factors has the potential to uncover disease mechanisms that may contribute to better diagnosis and treatment of mental illness, yet has so far been largely limited to participants with European ancestry from high-income countries. The DIVERGE study was established to help overcome this gap and investigate genetic and environmental risk factors for MDD in Pakistan. METHODS: DIVERGE aims to enrol 9000 cases and 4000 controls in hospitals across the country. Here, we provide the rationale for DIVERGE, describe the study protocol and characterise the sample using data from the first 500cases. Exploratory data analysis is performed to describe demographics, socioeconomic status, environmental risk factors, family history of mental illness and psychopathology. RESULTS AND DISCUSSION: Many participants had severe depression with 74% of patients who experienced multiple depressive episodes. It was a common practice to seek help for mental health struggles from faith healers and religious leaders. Socioeconomic variables reflected the local context with a large proportion of women not having access to any education and the majority of participants reporting no savings. CONCLUSION: DIVERGE is a carefully designed case-control study of MDD in Pakistan that captures diverse risk factors. As the largest genetic study in Pakistan, DIVERGE helps address the severe underrepresentation of people from South Asian countries in genetic as well as psychiatric research

Study protocol of DIVERGE, the first genetic epidemiological study of major depressive disorder in Pakistan.

INTRODUCTION: Globally, 80% of the burdenof major depressive disorder (MDD) pertains to low- and middle-income countries. Research into genetic and environmental risk factors has the potential to uncover disease mechanisms that may contribute to better diagnosis and treatment of mental illness, yet has so far been largely limited to participants with European ancestry from high-income countries. The DIVERGE study was established to help overcome this gap and investigate genetic and environmental risk factors for MDD in Pakistan. METHODS: DIVERGE aims to enrol 9000 cases and 4000 controls in hospitals across the country. Here, we provide the rationale for DIVERGE, describe the study protocol and characterise the sample using data from the first 500 cases. Exploratory data analysis is performed to describe demographics, socioeconomic status, environmental risk factors, family history of mental illness and psychopathology. RESULTS AND DISCUSSION: Many participants had severe depression with 74% of patients who experienced multiple depressive episodes. It was a common practice to seek help for mental health struggles from faith healers and religious leaders. Socioeconomic variables reflected the local context with a large proportion of women not having access to any education and the majority of participants reporting no savings. CONCLUSION: DIVERGE is a carefully designed case-control study of MDD in Pakistan that captures diverse risk factors. As the largest genetic study in Pakistan, DIVERGE helps address the severe underrepresentation of people from South Asian countries in genetic as well as psychiatric research

Molecular modelling and bioinformatics studies of CDK4 and related proteins

Cyclin-dependent kinases play a key role in the regulation of the eukaryotic cell cycle. CDK4 regulates the G1/S phase transition and the entry into the S-phase of the cell cycle. The activity of CDK4 is misregulated in many human cancers. The natural product fascaplysin inhibits CDK4 specifically, and is considered as a lead compound for specific CDK4 inhibitors. In the present work the structural features of the active sites of CDKs are compared, the evolution of CDKs is studied and homology models of CDK4 are generated and used to gain insights into its sequential and structural features. Also the CDK4-ligand interactions of fascaplysin and its tryptamine based derivatives are predicted and the fascaplysin specificity for CDK4 is at least partially explained using thermodynamic integration. CDK4 homology models were generated based on CDK2 templates. However, after the availability of experimentally determined X-ray structures of CDK4 in an inactive form, CDK4 models were built in a putative active form by incorporating the structural information from both CDK4 and CDK2 for its later use in molecular modelling. Docking studies on fascaplysin with CDK4 predict a polar contact between His95CDK4 and fascaplysin in addition to bidentate hydrogen bonds with Val96. This interaction partly explains the selectivity for CDK4 compared to CDK2. The effect of the positive charge of fascaplysin on specificity is studied in thermodynamic integration MD simulations by the isoelectronic substitution of the positively charged nitrogen into a carbon atom. From these thermodynamics integration calculations it is concluded that fascaplysin shows a preference for CDK4 due to better stabilization of the positive charge. ChemScores for tryptamine based derivatives docked into CDK4 show a weak correlation with experimental IC50 values. This indicates that the ChemScores can be used as a weak predictor for relative affinities of CDK4 inhibitors. A new class of α- carboline based inhibitors is proposed, and based on docking studies, predicted to have improved binding affinities for CDK4

Molecular modelling and bioinformatics studies of CDK4 and related proteins

Cyclin-dependent kinases play a key role in the regulation of the eukaryotic cell cycle. CDK4 regulates the G1/S phase transition and the entry into the S-phase of the cell cycle. The activity of CDK4 is misregulated in many human cancers. The natural product fascaplysin inhibits CDK4 specifically, and is considered as a lead compound for specific CDK4 inhibitors. In the present work the structural features of the active sites of CDKs are compared, the evolution of CDKs is studied and homology models of CDK4 are generated and used to gain insights into its sequential and structural features. Also the CDK4-ligand interactions of fascaplysin and its tryptamine based derivatives are predicted and the fascaplysin specificity for CDK4 is at least partially explained using thermodynamic integration. CDK4 homology models were generated based on CDK2 templates. However, after the availability of experimentally determined X-ray structures of CDK4 in an inactive form, CDK4 models were built in a putative active form by incorporating the structural information from both CDK4 and CDK2 for its later use in molecular modelling. Docking studies on fascaplysin with CDK4 predict a polar contact between His95CDK4 and fascaplysin in addition to bidentate hydrogen bonds with Val96. This interaction partly explains the selectivity for CDK4 compared to CDK2. The effect of the positive charge of fascaplysin on specificity is studied in thermodynamic integration MD simulations by the isoelectronic substitution of the positively charged nitrogen into a carbon atom. From these thermodynamics integration calculations it is concluded that fascaplysin shows a preference for CDK4 due to better stabilization of the positive charge. ChemScores for tryptamine based derivatives docked into CDK4 show a weak correlation with experimental IC50 values. This indicates that the ChemScores can be used as a weak predictor for relative affinities of CDK4 inhibitors. A new class of α- carboline based inhibitors is proposed, and based on docking studies, predicted to have improved binding affinities for CDK4.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Sequence, Structure, and Binding Analysis of Cyclodextrinase (TK1770) from T. kodakarensis (KOD1) Using an In Silico Approach

Thermostable cyclodextrinase (Tk1770 CDase) from hyperthermophilic archaeon Thermococcus kodakarensis (KOD1) hydrolyzes cyclodextrins into linear dextrins. The sequence of Tk1770 CDase retrieved from UniProt was aligned with sequences of sixteen CD hydrolyzing enzymes and a phylogenetic tree was constructed using Bayesian inference. The homology model of Tk1770 CDase was constructed and optimized with Modeller v9.14 program. The model was validated with ProSA server and PROCHECK analysis. Four conserved regions and the catalytic triad consisting of Asp411, Glu437, and Asp502 of GH13 family were identified in catalytic site. Also an additional fifth conserved region downstream to the fourth region was also identified. The structure of Tk1770 CDase consists of an additional N′-domain and a helix-loop-helix motif that is conserved in all archaeal CD hydrolyzing enzymes. The N′-domain contains an extended loop region that forms a part of catalytic domain and plays an important role in stability and substrate binding. The docking of substrate into catalytic site revealed the interactions with different conserved residues involved in substrate binding and formation of enzyme-substrate complex

Thyroid Peroxidase Antibodies in Non-Interferon Treated Hepatitis C Patients in Pakistan

Objective. Interferon therapy of HCV infected patients is associated with development of thyroid dysfunctions. Patients with pretreatment presence of antithyroid peroxidase (TPO-Ab) are at greater risk. This study, probably the first in Pakistan, was planned to determine TPO-Ab in sera of treatment-naive local HCV patients. Setting. Centre for Nuclear Medicine (CENUM), Mayo Hospital, Lahore. Patients and Methods. During July to December 2012, 190 patients (140 females, 50 males) newly diagnosed for HCV infection were selected for this study. Their age range was 15–55 years (mean: 35.3 ± 9.1 years). 262 age matched healthy subjects (211 females and 50 males) were recruited as control. Serum-free thyroxin (FT4) and thyroid stimulating hormone (TSH) were detected by radioimmunoassay techniques. Serum TPO-Ab titer was determined by ELISA method using commercial kits. Results. Serum FT4 and TSH levels in HCV patients and controls were within normal range. Between two groups there was no significant difference in mean value of FT4 (16.0 ± 3.0 versus 16.2 ± 3.9; P=0.619) but mean TSH value was significantly lower in HCV patients (1.5 ± 0.8 versus 1.8 ± 0.9; P=0.003). Among HCV patients 51 (26.8%) were TPO-Ab positive and among control subjects 18 (6.9%) were TPO-Ab positive. The difference was statistically significant (P<0.001). Further analysis showed that among HCV patients 39 (27.8%) females and 12 (24.0%) males were TPO-Ab positive, respectively, and difference was not statistically significant (P=0.873). Moreover, TPO-Ab positive patients were older and had significantly higher serum TSH as compared to TPO-Ab negative HCV patients. Conclusion. Independent of patient’s gender and increasing with advancing age, about one-fourth of local untreated HCV patients are TPO-Ab positive and are at greater risk of developing thyroid disorders during and after interferon treatment