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  1. Fulltext Delay In Diagnosis Of Oral Cancer In Malaysia: A Study Of Five Centres
    Khoo, Suan Phaik, Shanmuhasuntharam, P., Mahadzir, W.M., Tay, K.K., Latif, A., Nair, S.
    Ann Dent, 1996;3(1):-.
    MyJurnal
    The diagnosis of oral cancer have been variously reported as being due to delay by clinicians, patients or both. The purpose of this study was to evaluate the referral pattern of 65 patients eventually diagnosed as having oral squamous cell carcinoma. The results showed that 50% of the patients delayed seeking professional help for more than 3 months after being aware of the lesion. The majority of the patients consulted medical practitioners as the first source of help. The mean clinicians' and patients' delay were 10.3 weeks and 28.9 weeks respectively. Dental practitioners showed a tendency to refer on more advanced lesions compared to the medical practitioners. The findings raise the concern that lack of patients' awareness, misdiagnosis by clinicians and late detection by dental practitioners prevail thus calling for urgent measures towards early detection of the disease.
  2. Fulltext The Spetzler-Martin Grading System and management of patients with intracranial arteriovenous malformation in a tertiary referral hospital
    Al-Edrus, S. A., Suhaimi, S. N., Noor Azman, A. R., Latif, A. Z., Sobri, M.
    Malaysian Journal of Medicine and Health Sciences, 2010;6(1):91-99.
    MyJurnal
    Introduction: An arteriovenous malformation (AVM) is an abnormal collection of blood vessels in which arterial blood flows directly into the draining vein without the normal interposed capillaries. The Spetzler-Martin grading system has been widely accepted worldwide to estimate the pretreatment risks and predict the outcome of patients with intracranial AVM. In Malaysia, we still do not have the baseline data of this grading system. Methods: A total of 33 patients from a tertiary referral hospital diagnosed with intracranial AVM based on neuroimaging findings over a 4-year period were studied. Medical
    records were traced and neuroimaging findings were analysed. The AVMs were graded according to the Spetzler-Martin grading system and Fisher’s exact test was used to assess statistical difference between the grades of the AVM and management plan for the patients. Results: Four patients were graded as Grade 1, 9 patients as Grade II, 10 patients as Grade III, 6 patients as Grade IV and 4 patients as Grade V. Ten patients were treated conservatively; six patients underwent surgery and embolisation respectively. Four patients underwent radiosurgery and a combination of embolisation while surgery and radiosurgery were given to 5 patients and 2 patients respectively. Statistically significant difference (p=0.016) was found between the Spetzler-Martin grading system and the management of intracranial AVMs. Conclusion: The management decision was not made based on the
    grading of the AVMs. It is recommended that all AVM patients be routinely graded according to this system prior to treatment.
  3. Fulltext Giant serpentine middle cerebral artery aneurysm
    Pany A, Sobri M, Valarmathi S, Latif AZ
    Med J Malaysia, 2004 Aug;59(3):422-4.
    PMID: 15727392
    A rare case of partially thrombosed giant serpentine right middle cerebral artery aneurysm presented. A 26 year old man initially presented with headache and 3 months later developed neurological deficit. Various stages of clot with patent residual lumen seen on neuroimaging, led to the diagnosis. Catheter angiography is the investigation of choice for evaluating the location, flow dynamics and extent of the serpentine aneurysm. The patient had embolisation done for the giant serpentine aneurysm.
  4. Fulltext Immunology of tuberculosis: clinical and research persepctives
    Mohd Noh L, Wan Omar A, Abdul Latif A
    Malaysian Journal of Medicine and Health Sciences, 2005;1(2):71-85.
  5. Fulltext Giant aneurysm or pituitary macroadenoma: a diagnostical misconstrue
    Pany A, Sobri M, Valarmathi S, Nazihah M, Latif AZ, Adnan JS
    Med J Malaysia, 2004 Mar;59(1):123-5.
    PMID: 15535350
    We describe a case of a giant thrombosed intrasellar internal carotid artery aneurysm initially diagnosed as pituitary macroadenoma. The differentiating neuroimaging features were discussed.
  6. Factors involved in the diagnosis of oral squamous cell carcinoma in Malaysia
    Khoo SP, Shanmuhasuntharam P, Mahadzir WM, Tay KK, Latif A, Nair S
    Asia Pac J Public Health, 1998;10(1):49-51.
    PMID: 10050209 DOI: 10.1177/101053959801000111
    The delay in the diagnosis of oral cancer has been variously reported as being contributed by the clinicians, patients or both. The purpose of this study was to evaluate the referral pattern of 65 patients eventually diagnosed as having oral squamous cell carcinoma. The results showed that 50% of the patients delayed seeking professional help for more than 3 months after being aware of the lesion. The majority of the patients consulted medical practitioners as the first source of help. The mean clinicians' and patients' delay were 10.3 weeks and 28.9 weeks respectively. Dental practitioners showed a tendency to refer more advanced lesions compared to the medical practitioners. The findings raise the concern that lack of patients' awareness, misdiagnosis by clinicians and late detection by dental practitioners prevail thus calling for urgent measures towards early detection of the disease.
  7. A nucleic acid-based surface-enhanced Raman scattering of gold nanorods in N-gene integrated principal component analysis for COVID-19 detection
    Mustapa MA, Yuzir A, Latif AA, Ambran S, Abdullah N
    Spectrochim Acta A Mol Biomol Spectrosc, 2024 Apr 15;311:123977.
    PMID: 38310743 DOI: 10.1016/j.saa.2024.123977
    A rapid, simple, sensitive, and selective point-of-care diagnosis tool kit is vital for detecting the coronavirus disease (COVID-19) based on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Currently, the reverse transcriptase-polymerase chain reaction (RT-PCR) is the best technique to detect the disease. Although a good sensitivity has been observed in RT-PCR, the isolation and screening process for high sample volume is limited due to the time-consuming and laborious work. This study introduced a nucleic acid-based surface-enhanced Raman scattering (SERS) sensor to detect the nucleocapsid gene (N-gene) of SARS-CoV-2. The Raman scattering signal was amplified using gold nanoparticles (AuNPs) possessing a rod-like morphology to improve the SERS effect, which was approximately 12-15 nm in diameter and 40-50 nm in length. These nanoparticles were functionalised with the single-stranded deoxyribonucleic acid (ssDNA) complemented with the N-gene. Furthermore, the study demonstrates method selectivity by strategically testing the same virus genome at different locations. This focused approach showcases the method's capability to discern specific genetic variations, ensuring accuracy in viral detection. A multivariate statistical analysis technique was then applied to analyse the raw SERS spectra data using the principal component analysis (PCA). An acceptable variance amount was demonstrated by the overall variance (82.4 %) for PC1 and PC2, which exceeded the desired value of 80 %. These results successfully revealed the hidden information in the raw SERS spectra data. The outcome suggested a more significant thymine base detection than other nitrogenous bases at wavenumbers 613, 779, 1219, 1345, and 1382 cm-1. Adenine was also less observed at 734 cm-1, and ssDNA-RNA hybridisations were presented in the ketone with amino base SERS bands in 1746, 1815, 1871, and 1971 cm-1 of the fingerprint. Overall, the N-gene could be detected as low as 0.1 nM within 10 mins of incubation time. This approach could be developed as an alternative point-of-care diagnosis tool kit to detect and monitor the COVID-19 disease.
  8. Anticoccidial and hepatoprotective effects of artemisinin liquid extract, cinnamon essential oil and clove essential oil against Eimeria stiedae infection in rabbits
    Sorour SS, Abou Asa S, Elhawary NM, Ghazy EW, Abd El Latif A, El-Abasy MA, et al.
    Trop Biomed, 2018 Dec 01;35(4):926-943.
    PMID: 33601842
    Coccidiosis is one of the most dangerous diseases that affect poultry, resulting in worldwide economic losses. Plant extracts and essential oils have been used as potential alternatives for chemotherapeutics, because they don't have the negative consequence of creating tissue residue and drug resistance. Therefore, this study had been conducted to determine the efficacy of artemisinin liquid extract, cinnamon essential oil and clove essential oil against Eimeria stiedae in rabbits. Sixty New Zealand white rabbits were divided into six equal groups, where group 1 and group 2 represented the negative and the positive controls, respectively, and groups 3-6 were infected with Eimeria stiedae and received 15 ppm toltrazuril, 200 ppm artemisinin, 100 mg/kg cinnamon oil, and 100 mg/kg clove oil, respectively. The results showed that artemisinin had a significant beneficial role in protection against hepatic coccidiosis: it mitigated the clinical symptoms, reduced the mortality rates, improved body weight and feed conversion, decreased the oocyst output, prevented oxidative stress, improved biochemical parameters, and decreased the lesion formation. Moreover, it has been found that cinnamon and clove essential oils induced partial protection against hepatic coccidiosis. Our findings suggested that artemisinin liquid extract and cinnamon and clove essential oils could be used for protection against hepatic coccidiosis. However, further investigations are needed in order to elucidate the active components, optimal doses, and mode of action of these extracts and essential oils before their clinical applications.
  9. Glutathione sulfotransferase inhibition activity of a self-fermented beverage, Kanji
    Latif A, Hussain K, Shehzadi N, Islam M, Khan MT, Anwar R, et al.
    Pharm Biol, 2017 Dec;55(1):547-553.
    PMID: 27951746
    CONTEXT: Kanji, a liquid preparation of roots of Daucus carota L. ssp. sativus (Hoffm.) Arcang. var. vavilovii Mazk. (Apiaceae), may inhibit glutathione sulfotransferase (GST) activity due to ferulic acid content.

    OBJECTIVES: GST inhibition activity and characterization of Kanji and methanol extract of D. carota roots, and oral absorption pattern of ferulic acid from Kanji in rats.

    MATERIALS AND METHODS: GST inhibition activity of Kanji and methanol extract of D. carota roots in concentration range 0.001-100.00 mg/mL was determined using Sprague Dawley rat liver cytosolic fraction. Methanol extract upon column chromatography gave ferulic acid, which was used to characterize Kanji and determine its oral absorption pattern in Wistar rats.

    RESULTS: The GST inhibition activity of Kanji (100.00 μg/mL), methanol extract of D. carota roots (100.00 μg/mL) and tannic acid (10.00 μg/mL, positive control) was found to be 0.162 ± 0.016, 0.106 ± 0.013 and 0.073 ± 0.004 μM/min/mg, respectively. Different Kanji samples and methanol extract contained ferulic acid (0.222-0.316 mg/g) and 0.77 mg/g, respectively. Ferulic acid did not appear in plasma after oral administration of Kanji.

    DISCUSSION: Kanji having solid contents 80.0 μg/mL, equivalent to 0.0025 μg/mL ferulic acid, does not inhibit the activity of GST. The oral administration of Kanji, in human equivalent dose (528 mg/kg, 16.67 μg ferulic acid), to rats indicated poor absorption of ferulic acid.

    CONCLUSION: Kanji having solid contents 14-36 mg/mL does not inhibit GST activity, hence may not interfere with drugs that are the substrates of GST, if taken concomitantly.

  10. Fulltext Theorizing how the brain encodes consciousness based on negentropic entanglement
    Poznanski RR, Cacha LA, Latif AZA, Salleh SH, Ali J, Yupapin P, et al.
    J Integr Neurosci, 2019 03 30;18(1):1-10.
    PMID: 31091842 DOI: 10.31083/j.jin.2019.01.105
    The physicality of subjectivity is explained through a theoretical conceptualization of guidance waves informing meaning in negentropically entangled non-electrolytic brain regions. Subjectivity manifests its influence at the microscopic scale of matter originating from de Broglie 'hidden' thermodynamics as action of guidance waves. The preconscious experienceability of subjectivity is associated with a nested hierarchy of microprocesses, which are actualized as a continuum of patterns of discrete atomic microfeels (or "qualia"). The mechanism is suggested to be through negentropic entanglement of hierarchical thermodynamic transfer of information as thermo-qubits originating from nonpolarized regions of actin-binding proteinaceous structures of nonsynaptic spines. The resultant continuous stream of intrinsic information entails a negentropic action (or experiential flow of thermo-quantum internal energy that results in a negentropic force) which is encoded through the non-zero real component of the mean approximation of the negentropic force as a 'consciousness code'. Consciousness consisting of two major subprocesses: (1) preconscious experienceability and (2) conscious experience. Both are encapsulated by nonreductive physicalism and panexperiential materialism. The subprocess (1) governing "subjectivity" carries many microprocesses leading to the actualization of discrete atomic microfeels by the 'consciousness code'. These atomic microfeels constitute internal energy that results in the transfer intrinsic information in terms of thermo-qubits. These thermo-qubits are realized as thermal entropy and sensed by subprocess (2) governing "self-awareness" in conscious experience.
  11. Detection of Vancomycin-Resistant Enterococcus Spp. (VRE) from Poultry
    Toosa H, Radu S, Rusul G, Latif AR, Rahim RA, Ahmad N, et al.
    Malays J Med Sci, 2001 Jan;8(1):53-8.
    PMID: 22973157
    Twenty-eight isolates of E. faecalis and 5 isolates of E. hirae were isolated from chicken samples obtained from markets in Sri Serdang, Selangor. They were tested for susceptibility to vancomycin and other antimicrobial agents. All of the isolates showed multiple resistance to the antibiotic tested. All Enterococcus spp. were resistant (100%) to ceftaxidime, cephalothin, erythromycin, gentamicin, kanamycin, nalidixic acid and streptomycin. Resistance was also observed to norfloxacin (97%), tetracycline (91%), penicillin (85%), bacitracin (82%), chloramphenicol (61%) and the least resistance was to ampicillin (27%). High prevalence to vancomycin resistance was detected among the E. faecalis (27of 28) and E. hirae (4 of 5) isolates. The multiple antibiotic resistance index ranging between 0.64 to 1.0 showed that all strains tested originated from high-risk contamination. Plasmid profile analysis of Enterococcus spp. revealed plasmid DNA bands ranging in size from 1.3 to 35.8 megadalton but some isolates were plasmidless. No correlation could be made between plasmid patterns and antibiotic resistance.
  12. Fulltext Treatment Outcomes of Extensively Drug-Resistant Tuberculosis in Pakistan: A Countrywide Retrospective Record Review
    Abubakar M, Ahmad N, Ghafoor A, Latif A, Ahmad I, Atif M, et al.
    Front Pharmacol, 2021;12:640555.
    PMID: 33867989 DOI: 10.3389/fphar.2021.640555
    Background: The current study is conducted with the aim to the fill the gap of information regarding treatment outcomes and variables associated with unsuccessful outcome among XDR-TB patients from Pakistan. Methods: A total of 404 culture confirmed XDR-TB patients who received treatment between 1st May 2010 and June 30, 2017 at 27 treatment centers all over Pakistan were retrospectively followed until their treatment outcomes were reported. A p-value <0.05 reflected a statistical significant association. Results: The patients had a mean age 32.9 ± 14.1 years. The overall treatment success rate was 40.6% (95% confidence interval [CI]:35.80-45.60%). A total of 155 (38.4%) patients were declared cured, 9 (2.2%) completed treatment, 149 (36.9%) died, 60 (14.9%) failed treatment and 31 (7.7%) were lost to follow up (LTFU). The results of the multivariate binary logistic regression analysis revealed that the patients' age of >60 years (OR = 4.69, 95%CI:1.57-15.57) and receiving high dose isoniazid (OR = 2.36, 95%CI:1.14-4.85) had statistically significant positive association with death, whereas baseline body weight >40 kg (OR = 0.43, 95%CI:0.25-0.73) and sputum culture conversion in the initial two months of treatment (OR = 0.33, 95%CI:0.19-0.58) had statistically significant negative association with death. Moreover, male gender had statistically significant positive association (OR = 1.92, 95%CI:1.04-3.54) with LTFU. Conclusion: The treatment success rate (40.6%) of XDR-TB patients in Pakistan was poor. Providing special attention and enhanced clinical management to patients with identified risk factors for death and LTFU in the current cohort may improve the treatment outcomes.
  13. Effective connectivity between precuneus and supramarginal gyrus in healthy subjects and temporal lobe epileptic patients
    Husbani MAR, Shuhada JM, Hamid AIA, Suardi KPS, Abdullah MS, Latif AZA, et al.
    Med J Malaysia, 2021 05;76(3):360-368.
    PMID: 34031335
    INTRODUCTION: The effective connectivity (EC) when the brain is resting and how a neuronal system exerts influence over other regions of the brain, in different groups of subjects are still being investigated. Limited information was seen about the relationship between precuneus (PRE) which is a wellknown resting state hub with supramarginal gyrus (SMG) in healthy subjects (HS) and temporal lobe epilepsy (TLE) participants.

    MATERIALS AND METHODS: Fourteen HS and 14 TLE patients with age and gender matched underwent resting state functional magnetic resonance imaging (rsfMRI) scanning using a 3-Tesla MRI machine to investigate the EC and percentage of amplitude fluctuation (PerAF) involving SMG and PRE. The rsfMRI data were analysed using Statistical Parametric Mapping (SPM12) and Spectral Dynamic Causal Modelling (spDCM) from which causal models were specified, estimated and inferred.

    RESULTS: Model with bidirectional connections between PRE and SMG was chosen as the winning model. The EC from PRE to SMG is positive but the EC from SMG to PRE is negative in both hemispheres and in HS and TLE. Based on the findings from the EC analysis, there is an excitatory effect shown by PRE to SMG connection indicating a dominant role of PRE over SMG in both groups.

    CONCLUSION: There is important evidence showing that PRE might also have influence on areas outside resting state network and the influence changes in the presence of brain abnormality.

  14. Selective dual cholinesterase inhibitors from Aconitum laeve
    Ahmad H, Ahmad S, Shah SAA, Khan HU, Khan FA, Ali M, et al.
    J Asian Nat Prod Res, 2018 Feb;20(2):172-181.
    PMID: 28463565 DOI: 10.1080/10286020.2017.1319820
    New lycoctonine-type dual cholinesterase inhibitor, swatinine-C (1), along with three known norditerpenoid alkaloids, hohenackerine (2), aconorine (5) and lappaconitine (6) and two synthetically known but phytochemically new benzene derivatives, methyl 2-acetamidobenzoate (3) and methyl 4-[2-(methoxycarbonyl)anilino]-4-oxobutanoate (4), was isolated from the roots of A. laeve. Structures of new and known compounds (1-6) were established on the basis of latest spectroscopic techniques and by close comparison with the data available in literature. In vitro, compounds (1-6) were tested against AChE and BChE inhibitory activities. Compounds 1 and 2 showed competitive inhibition against AChE (IC50 = 3.7 μM, 4.53 μM) and BChE (IC50 = 12.23 μM, 9.94 μM), respectively. Compounds 5 and 6 showed promising noncompetitive type of inhibitory profile against AChE (IC50 = 2.51 and 6.13 μM) only. Compounds 3 and 4 showed weak inhibitory profile against both AChE and BChE.
  15. Antioxidant and anticholinesterase potential of diterpenoid alkaloids from Aconitum heterophyllum
    Ahmad H, Ahmad S, Shah SAA, Latif A, Ali M, Khan FA, et al.
    Bioorg Med Chem, 2017 07 01;25(13):3368-3376.
    PMID: 28457693 DOI: 10.1016/j.bmc.2017.04.022
    Extensive chromatographic separations performed on the basic (pH=8-10) chloroform soluble fraction of Aconitum heterophyllum resulted in the isolation of three new diterpenoid alkaloids, 6β-Methoxy, 9β-dihydroxylheteratisine (1), 1α,11,13β-trihydroxylhetisine (2), 6,15β-dihydroxylhetisine (3), and the known compounds iso-atisine (4), heteratisine (5), hetisinone (6), 19-epi-isoatisine (7), and atidine (8). Structures of the isolated compounds were established by means of mass and NMR spectroscopy as well as single crystal X-ray crystallography. Compounds 1-8 were screened for their antioxidant and enzyme inhibition activities followed by in silico studies to find out the possible inhibitory mechanism of the tested compounds. This work is the first report demonstrating significant antioxidant and anticholinesterase potentials of diterpenoid alkaloids isolated from a natural source.
  16. Norditerpenoid alkaloids of Delphinium denudatum as cholinesterase inhibitors
    Ahmad H, Ahmad S, Ali M, Latif A, Shah SAA, Naz H, et al.
    Bioorg Chem, 2018 08;78:427-435.
    PMID: 29698893 DOI: 10.1016/j.bioorg.2018.04.008
    Three new norditerpenoids alkaloids, 1β-hydroxy,14β-acetyl condelphine (1), jadwarine-A (2), jadwarine-B (3) along with two known alkaloids isotalatizidine hydrate (4) and dihydropentagynine (5) were isolated from medicinal plant Delphinium denudatum. The structures of natural products 1-5 were established on the basis of HR-EIMS, 1H and 13C NMR (1D & 2D) spectroscopic data as well as by comparison from literature data. The structures of compound 1 and 4 were also confirmed by single crystal X-ray diffraction studies. In-vitro AChE and BChE enzyme inhibitory activities of compounds 1-5 and molecular docking studies were performed to investigate the possible molecular inhibitory mechanism of the isolated natural products. Compound 2, 4 and 5 showed competitive inhibitory effects by inhibiting AChE and BChE, respectively, while 1 and 3 showed non-competitive inhibition. This work is the first report that provides a supporting evidence about the use of constituents of Delphinium denudatum in cerebral dementia and Alzheimer diseases.
  17. Novel acyl hydrazide derivatives of polyhydroquinoline as potent anti-diabetic and anti-glycating agents: Synthesis, in vitro α-amylase, α-glucosidase inhibition and anti-glycating activity with molecular docking insights
    Ur Rahman S, Alam A, Parveen Z, Zainab, Assad M, Adnan Ali Shah S, et al.
    Bioorg Chem, 2024 Sep;150:107501.
    PMID: 38865858 DOI: 10.1016/j.bioorg.2024.107501
    In this study, eleven novel acyl hydrazides derivative of polyhydroquinoline were synthesized, characterized and screened for their in vitro anti-diabetic and anti-glycating activities. Seven compounds 2a, 2d, 2i, 2 h, 2j, 2f, and 2 g exhibited notable α-amylase inhibitory activity having IC50 values from 3.51 ± 2.13 to 11.92 ± 2.30 µM. Similarly, six compounds 2d, 2f, 2 h, 2i, 2j, and 2 g displayed potent α-glucosidase inhibitory activity compared to the standard acarbose. Moreover, eight derivatives 2d, 2 g, 2f, 2j, 2a, 2i, 2 g, and 2e showed excellent anti-glycating activity with IC50 values from 6.91 ± 2.66 to 15.80 ± 1.87 µM when compared them with the standard rutin (IC50 = 22.5 ± 0.90 µM). Molecular docking was carried out to predict the binding modes of all the compounds with α-amylase and α-glucosidase. The docking analysis revealed that most of the compounds established strong interactions with α-amylase and α-glucosidase. All compounds fitted well into the binding pockets of α-amylase and α-glucosidase. Among all compounds 2a and 2f were most potent based on docking score -8.2515 and -7.3949 against α-amylase and α-glucosidase respectively. These results hold promise for the development of novel candidates targeted at controlling postprandial glucose levels in individuals with diabetes.
  18. Synthesis of 2,4-dihydroxyacetophenone derivatives as potent PDE-1 and -3 inhibitors: in vitro and in silico insights
    Alam A, Gul S, Zainab, Khan M, Elhenawy AA, Islam MS, et al.
    Future Med Chem, 2024;16(12):1185-1203.
    PMID: 38989989 DOI: 10.1080/17568919.2024.2342707
    Aim: Synthesis of novel bis-Schiff bases having potent inhibitory activity against phosphodiesterase (PDE-1 and -3) enzymes, potentially offering therapeutic implications for various conditions. Methods: Bis-Schiff bases were synthesized by refluxing 2,4-dihydroxyacetophenone with hydrazine hydrate, followed by treatment of substituted aldehydes with the resulting hydrazone to obtain the product compounds. After structural confirmation, the compounds were screened for their in vitro PDE-1 and -3 inhibitory activities. Results: The prepared compounds exhibited noteworthy inhibitory efficacy against PDE-1 and -3 enzymes by comparing with suramin standard. To clarify the binding interactions between the drugs, PDE-1 and -3 active sites, molecular docking studies were carried out. Conclusion: The potent compounds discovered in this study may be good candidates for drug development.
  19. Novel hydrazone schiff's base derivatives of polyhydroquinoline: synthesis, in vitro prolyl oligopeptidase inhibitory activity and their Molecular docking study
    Talab F, Alam A, Zainab, Ullah S, Elhenawy AA, Shah SAA, et al.
    J Biomol Struct Dyn, 2024 Feb 22.
    PMID: 38385366 DOI: 10.1080/07391102.2024.2319677
    This research work reports the synthesis of new derivatives of the hydrazone Schiff bases (1-17) based on polyhydroquinoline nucleus through multistep reactions. HR-ESIMS,1H- and 13C-NMR spectroscopy were used to structurally infer all of the synthesized compounds and lastly evaluated for prolyl oligopeptidase inhibitory activity. All the prepared products displayed good to excellent inhibitory activity when compared with standard z-prolyl-prolinal. Three derivatives 3, 15 and 14 showed excellent inhibition with IC50 values 3.21 ± 0.15 to 5.67 ± 0.18 µM, while the remaining 12 compounds showed significant activity. Docking studies indicated a good correlation with the biochemical potency of compounds estimated in the in-vitro test and showed the potency of compounds 3, 15 and 14. The MD simulation results confirmed the stability of the most potent inhibitors 3, 15 and 14 at 250 ns using the parameters RMSD, RMSF, Rg and number of hydrogen bonds. The RMSD values indicate the stability of the protein backbone in complex with the inhibitors over the simulation time. The RMSF values of the binding site residues indicate that the potent inhibitors contributed to stabilizing these regions of the protein, through formed stable interactions with the protein. The Rg. analysis assesses the overall size and compactness of the complexes. The maintenance of stable hydrogen bonds suggests the existence of favorable binding interactions. SASA analysis suggests that they maintained stable conformations without large-scale exposure to the solvent. These results indicate that the ligand-protein interactions are stable and could be exploited to design new drugs for disease treatment.Communicated by Ramaswamy H. Sarma.
  20. Fulltext Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations
    Laitman Y, Feng BJ, Zamir IM, Weitzel JN, Duncan P, Port D, et al.
    Eur J Hum Genet, 2013 Feb;21(2):212-6.
    PMID: 22763381 DOI: 10.1038/ejhg.2012.124
    The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.
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