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Earlier onset of motor complications in Parkinson's patients with comorbid diabetes mellitus

Mohamed Ibrahim N, Ramli R, Koya Kutty S, Shah SA

Mov Disord, 2018 12;33(12):1967-1968.
PMID: 30427552 DOI: 10.1002/mds.27526
Overview on Epigenetic Re-programming: A Potential Therapeutic Intervention in Triple Negative Breast Cancers

Mohamad Hanif EA, Shah SA

Asian Pac J Cancer Prev, 2018 Dec 25;19(12):3341-3351.
PMID: 30583339

Breast cancer treatments leads to variable responses. Hormonal therapy is beneficial to receptor positive breast cancer
subtypes and display better clinical outcome than triple negative breast cancers (TNBCs) with FEC (5-Fluorouracil,
Epirubicin and Cyclophosphamide) the mainstay chemotherapy regiment. Owning to their negative expressions of
estrogen (ER), progesterone (PR) and HER2 receptors, disease recurrence and metastasis befalls some patients indicating
resistance to FEC. Involvement of epigenetic silencing through DNA methylation, histone methylation, acetylation and
sumoylation may be the key player in FEC chemoresistance. Epigenetic and molecular profiling successfully classified
breast cancer subtypes, indicating potential driver mechanisms to the progression of TNBCs but functional mechanisms
behind chemoresistance of these molecular markers are not well defined. Several epigenetic inhibitors and drugs have
been used in the management of cancers but these attempts are mainly beneficial in hematopoietic cancers and not
specifically favourable in solid tumours. Hypothetically, upon administration of epigenetic drugs, recovery of tumour
suppressor genes is expected. However, high tendency of switching on global metastatic genes is predicted. Polycomb
repressive complex (PRC) such as EZH2, SETD1A, DNMT, is known to have repressive effects in gene regulation and
shown to inhibit cell proliferation and invasion in breast cancers. Individual epigenetic regulators may be an option
to improve chemo-drug delivery in cancers. This review discussed on molecular signatures of various breast cancer
subtypes and on-going attempts in understanding underlying molecular mechanisms of epigenetic regulators as well
as providing insights on possible ways to utilize epigenetic enzymes/inhibitors with responses to chemotherapeutic
drugs to re-program cellular and biological outcome in TNBCs.
Fulltext Role of febuxostat in retarding progression of diabetic kidney disease with asymptomatic hyperuricemia: A 6-months open-label, randomized controlled trial

Mukri MNA, Kong WY, Mustafar R, Shaharir SS, Shah SA, Abdul Gafor AH, et al.

EXCLI J, 2018;17:563-575.
PMID: 30108461 DOI: 10.17179/excli2018-1256

Introduction: Hyperuricemia is associated with chronic kidney disease (CKD) progression and poor cardiovascular outcomes. We studied the effect of febuxostat on estimated glomerular filtration rate (eGFR), proteinuria and monitored the safety profile of the medication.
Material and Methods: This is a prospective open-label, randomized study in CKD stage 3 and 4 patients with diabetic nephropathy and asymptomatic hyperuricemia. Patients were randomized into febuxostat 40 mg daily and no treatment group using block randomization method and were followed up for 6 months. Their usual care for diabetes mellitus, hypertension and dyslipidemia were continued in the study. Blood and urine investigations were monitored at baseline, 3 months and 6 months.
Results: The eGFR in febuxostat group was stabilized at 6 months with no significant reduction [26.2 (IQR 14.30) at baseline to 26.3 (IQR 15.2) ml/min/1.73 m2]. Whereas, there was a significant reduction of the eGFR in no treatment group from 28.2 (IQR 17.9) to 27.6 (IQR 19.3) ml/min/1.73 m2 (p value < 0.01). We found the HbA1c (glycosylated hemoglobin) was significantly increased in febuxostat group from 7.2 ± 0.5 % at baseline to 7.6 ± 1.4 at 6 months (p value 0.04) but no significant change of HbA1c in the no treatment group. Proteinuria level was unchanged in both groups. The commonest adverse event was joint pain.
Conclusions: Febuxostat was able to preserve eGFR in CKD patients with diabetic nephropathy and this effect was beyond glycemic control. Increment of HbA1c level in febuxostat group needs further larger trials.
Study site: Chronic kidney disease clinic, Hospital Canselor Tuanku Muhriz, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Fulltext 10-Year Cardiovascular Disease Risk Estimation Based on Lipid Profile-Based and BMI-Based Framingham Risk Scores across Multiple Sociodemographic Characteristics: The Malaysian Cohort Project

Borhanuddin B, Mohd Nawi A, Shah SA, Abdullah N, Syed Zakaria SZ, Kamaruddin MA, et al.

ScientificWorldJournal, 2018;2018:2979206.
PMID: 30111990 DOI: 10.1155/2018/2979206

Cardiovascular disease (CVD) leads to high morbidity and mortality rate worldwide. Therefore, it is important to determine the risk of CVD across the sociodemographic factors to strategize preventive measures. The current study consisted of 53,122 adults between the ages of 35 and 65 years from The Malaysian Cohort project during recruitment phase from year 2006 to year 2012. Sociodemographic profile and physical activity level were assessed via self-reported questionnaire, whereas relevant CVD-related biomarkers and biophysical variables were measured to determine the Framingham Risk Score (FRS). The main outcome was the 10-year risk of CVD via FRS calculated based on lipid profile and body mass index (BMI) associated formulae. The BMI-based formula yielded a higher estimation of 10-year CVD risk than the lipid profile-based formula in the study for both males (median = 13.2% and 12.7%, respectively) and females (median = 4.3% and 4.2%, respectively). The subgroup with the highest risk for 10-year CVD events (based on both FRS formulae) was the Malay males who have lower education level and low physical activity level. Future strategies for the reduction of CVD risk should focus on screening via BMI-based FRS in this at-risk subpopulation to increase the cost-effectiveness of the prevention initiatives.
Study name: The Malaysian Cohort (TMC) project
Fulltext Evaluation of the Enzyme Inhibitory and Antioxidant Activities of Entada spiralis Stem Bark and Isolation of the Active Constituents

Roheem FO, Mat Soad SZ, Ahmed QU, Ali Shah SA, Latip J, Zakaria ZA

Molecules, 2019 Mar 13;24(6).
PMID: 30871172 DOI: 10.3390/molecules24061006

Digestive enzymes and free radical inhibitors are used to prevent complications resulting from diabetes. Entadaspiralis (family Leguminosae), which is a well-known medicinal plant in herbal medicine due to its various traditional and medicinal applications, was studied. Crude extracts were successively obtained from the stem bark using petroleum ether, chloroform and methanol as extracting solvents. The antioxidant activity of all the extracts, fractions and isolated compounds were estimated using 2,2-diphenyl-1-picrylhydrazyl (DPPH), β-carotene and 2,2'-azinobis(-3-ethylbenzothiazine-6-sulfonic acid) (ABTS) assays, while digestive enzymes inhibitory activity was assessed using α-amylase and α-glucosidase inhibitory methods. Structure elucidation of pure compounds was achieved through different spectroscopic analysis methods. Fractionation and purification of the most active methanol extract resulted in the isolation of a ferulic ester namely; (e)-hexyl 3-(4-hydroxy-3-methoxyphenyl) acrylate (FEQ-2) together with five known phenolic constituents, identified as kaempferol (FEQ-3), 5,4'-dihydroxy-3,7,3'-trimethoxyflavone (FEQ-2), gallic acid (FEQ-5), (+)-catechin (FEQ-7) and (-)-epicatechin (FEQ-8). FEQ-5 exhibited the strongest antioxidant and enzyme inhibitory activities followed by FEQ-3 and FEQ-4. FEQ-2 also displayed potent free radical scavenging activity with IC50 values of 13.79 ± 2.13 (DPPH) and 4.69 ± 1.25 (ABTS) µg/mL, respectively. All other compounds were found active either against free radicals or digestive enzymes.
Natural and synthetic polymer-based smart biomaterials for management of ulcerative colitis: a review of recent developments and future prospects

Sohail M, Mudassir, Minhas MU, Khan S, Hussain Z, de Matas M, et al.

Drug Deliv Transl Res, 2019 04;9(2):595-614.
PMID: 29611113 DOI: 10.1007/s13346-018-0512-x

Ulcerative colitis (UC) is an inflammatory disease of the colon that severely affects the quality of life of patients and usually responds well to anti-inflammatory agents for symptomatic relief; however, many patients need colectomy, a surgical procedure to remove whole or part of the colon. Though various types of pharmacological agents have been employed for the management of UC, the lack of effectiveness is usually predisposed to various reasons including lack of target-specific delivery of drugs and insufficient drug accumulation at the target site. To overcome these glitches, many researchers have designed and characterized various types of versatile polymeric biomaterials to achieve target-specific delivery of drugs via oral route to optimize their targeting efficiency to the colon, to improve drug accumulation at the target site, as well as to ameliorate off-target effects of chemotherapy. Therefore, the aim of this review was to summarize and critically discuss the pharmaceutical significance and therapeutic feasibility of a wide range of natural and synthetic biomaterials for efficient drug targeting to colon and rationalized treatment of UC. Among various types of biomaterials, natural and synthetic polymer-based hydrogels have shown promising targeting potential due to their innate pH responsiveness, sustained and controlled release characteristics, and microbial degradation in the colon to release the encapsulated drug moieties. These characteristic features make natural and synthetic polymer-based hydrogels superior to conventional pharmacological strategies for the management of UC.
pH-responsive CAP-co-poly(methacrylic acid)-based hydrogel as an efficient platform for controlled gastrointestinal delivery: fabrication, characterization, in vitro and in vivo toxicity evaluation

Shah SA, Sohail M, Minhas MU, Nisar-Ur-Rehman, Khan S, Hussain Z, et al.

Drug Deliv Transl Res, 2019 Apr;9(2):555-577.
PMID: 29450805 DOI: 10.1007/s13346-018-0486-8

Cellulose acetate phthalate-based pH-responsive hydrogel was synthesized for fabrication of polymeric matrix tablets for gastro-protective delivery of loxoprofen sodium. Cellulose acetate phthalate (CAP) was cross-linked with methacrylic acid (MAA) using free radical polymerization technique. Fourier transform infrared (FTIR) spectra confirmed the formation of cross-linked structure of CAP-co-poly(methacrylic acid). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) confirmed the thermal stability of polymeric networks, and scanning electron microscopy (SEM) and energy-dispersive X-ray spectrum (EDS) images unveiled that the prepared formulations were porous in nature and thus the developed formulations had shown better diffusibility. Swelling and in vitro drug release was performed at various pHs and maximum swelling and release was obtained at pH 7.4, while swelling and release rate was very low at pH 1.2 which confirmed the pH-responsive behavior of CAP-co-poly(MAA). CAP-co-poly(MAA) copolymer prevents the release of loxoprofen sodium into the stomach due to reduced swelling at gastric pH while showing significant swelling and drug release in the colon. Cytotoxicity studies revealed higher biocompatibility of fabricated hydrogel. Acute oral toxicity studies were performed for the evaluation and preliminary screening of safety profile of the developed hydrogels. Matrix tablets were evaluated for release behavior at simulated body pH. The investigations performed for analysis of hydrogels and fabricated matrix tablets indicated the controlled drug release and gastro-protective drug delivery of CAP-co-poly(MAA) hydrogels and pH-sensitive matrix tablets for targeted delivery of gastro-sensitive/irritative agents. Graphical abstract.
Chitosan based thermosensitive injectable hydrogels for controlled delivery of loxoprofen: development, characterization and in-vivo evaluation

Ahmad U, Sohail M, Ahmad M, Minhas MU, Khan S, Hussain Z, et al.

Int J Biol Macromol, 2019 May 15;129:233-245.
PMID: 30738157 DOI: 10.1016/j.ijbiomac.2019.02.031

Oral drug delivery is natural, most acceptable and desirable route for nearly all drugs, but many drugs like NSAIDs when delivered by this route cause gastrointestinal irritation, gastric bleeding, ulcers, and many undesirable effects which limits their usage by oral delivery. Moreover, it is almost impossible to control the release of a drug in a targeted location in body. We developed thermo-responsive chitosan-co-poly(N-isopropyl-acrylamide) injectable hydrogel as an alternative for the gastro-protective and controlled delivery of loxoprofen sodium as a model drug. A free radical polymerization technique was used to synthesize thermo-responsive hydrogel by cross-linking chitosan HCl with NIPAAM using glutaraldehyde as cross-linker. Confirmation of crosslinked hydrogel structure was done by Fourier transform infrared spectra (FTIR). The thermal stability of hydrogel was confirmed through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The scanning electron microscopy (SEM) was performed to evaluate the structural morphology of cross-linked hydrogel. To evaluate the rheological behavior of hydrogel with increasing temperature, rheological study was performed. Swelling and in vitro drug release studies were carried out under various temperature and pH conditions. The swelling study revealed that maximum swelling was observed at low pH (pH 1.2) and low temperature (25 °C) compared to the high range of pH and temperature and it resulted in quick release of the drug. The high range of pH (7.4) and temperature (37 °C) however caused controlled release of the drug. The in vivo evaluation of the developed hydrogel in rabbits demonstrated the controlled release behavior of fabricated system.
13C-Urea Breath Test Accuracy for Helicobacter pylori Infection in the Asian Population: A Meta-Analysis

Abd Rahim MA, Johani FH, Shah SA, Hassan MR, Abdul Manaf MR

Ann Glob Health, 2019 Jul 24;85(1).
PMID: 31348624

BACKGROUND: Helicobacter pylori (H. pylori) infection is known to be associated with peptic ulcer and gastric cancer. Detection of H. pylori infection is a significant part of peptic ulcer and gastric cancer prevention and management. 13C-urea breath test (UBT) provides a good option for the pathogen detection due to its accuracy and safety.
OBJECTIVE: This review aims to evaluate the 13C-UBT diagnostic accuracy studies conducted among Asian population and validate its use for the Asian population.
METHODS: Original articles were systematically searched in PubMed, Scopus, and Google Scholar using the PICOS strategy by applying relevant keywords. Only studies published in English and conducted in Asia were included. Our search returned 276 articles. After assessment, 11 articles which answered our research question and met the criteria set for systematic review and meta-analysis were accepted. A total of 15 study protocols were extracted from the 11 accepted articles.
FINDINGS: Majority of the studies were conducted in Hong Kong (six), followed by Taiwan (five), Japan (two), and one each in Singapore and Israel. All studies had used histology as part of its gold standard of reference. All but one study was performed on adult populations. The summary estimate for sensitivity was 97% (95% CI: 96, 98%), and specificity was 96% (95% CI: 95, 97%), with significant heterogeneity between studies. Adjusting for the dose (50 mg) and breath sample collection time (20 minutes) had improved both accuracy estimates and significantly reduced heterogeneity.
CONCLUSION: This review supports the test-and-treat strategy for H. pylori infection management. Prevalence and cost-effectiveness studies are mandatory for health authorities to adopt this strategy into national policy.
Fulltext Perception of Cancer Risk and Its Associated Risk Factors among Young Iraqis living in Baghdad

Alaa H, Shah SA

Asian Pac J Cancer Prev, 2019 08 01;20(8):2339-2343.
PMID: 31450904 DOI: 10.31557/APJCP.2019.20.8.2339

Cancer is responsible for substantial burden on communities and more specifically on less developed countries. The incidence of cancer is on the rise due to population growth and aging, also due to increment of the risk factors such as smoking, increasing weight, low physical activity associated with adoption of western lifestyle. Around 14 million cases of new cancer and 8 million deaths from cancer is estimated to occur by 2012. This cross-sectional study was conducted in Baghdad from June 2016 to October 2016. Participants were selected according to our inclusion criteria, namely aged between 18 to 40 years and not being diagnosed with any chronic diseases. Those who fulfilled the inclusion criteria were 700 participants who completed the questionnaire. Results showed that most of our participants had low perceived susceptibility to cancer risk (62.4%), low perceived severity (59.8%), but good perceived benefits of screening (56.6%). Hierarchal linear regression analysis showed that sociodemographic factors of gender, marital status, and education level were statistically significant. Moreover, factors of health behaviour such as practice towards health and preventive behaviour were associated with the outcome. Finally, treatment control and emotional factors were mostly predicting the outcome. Perceived susceptibility to cancer along with its psychological factors and behaviour were important contributors to self-perceived health in this study. Hence there is association between perception and future morbidity and mortality, thus it is crucial for public health policy. Comprehensive health programs that include health promotion campaigns and proper health care services that deals with secondary prevention.
Serum and urine interleukin-17A levels as biomarkers of disease activity in systemic lupus erythematosus

Nordin F, Shaharir SS, Abdul Wahab A, Mustafar R, Abdul Gafor AH, Mohamed Said MS, et al.

Int J Rheum Dis, 2019 Aug;22(8):1419-1426.
PMID: 31179646 DOI: 10.1111/1756-185X.13615

OBJECTIVES: This study examined the correlations of both serum and urine interleukin-17A (IL-17A) levels with disease activity in systemic lupus erythematosus (SLE). This study was also aimed at determining their sensitivity and specificity as biomarkers of disease activity in SLE.
METHODS: A cross-sectional study was performed involving SLE patients (n = 120 patients) from Universiti Kebangsaan Malaysia Medical Centre (UKMMC). Serum and urinary IL-17A levels were determined by immunoassay while disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) and British Isles Lupus Assessment Group's 2004 index (BILAG 2004) scores. The correlations between serum and urinary IL-17A levels with total SLEDAI-2K and BILAG 2004 scores were determined using bivariate correlation analyses. Receiver operating characteristic curves were calculated to determine their sensitivity and specificity as disease activity biomarkers.
RESULTS: Both serum and urinary IL-17A levels correlated with total scores of BILAG 2004, BILAG renal, BILAG mucocutaneous, and SLEDAI-2K (P
Synthesis of some new N-(alkyl/aralkyl)-N-(4-methoxyphenethyl) benzene sulfonamides as antibacterial agents against Escherichia

Abbasi MA, Fatima Z, Rehman AU, Siddiqui SZ, Ali Shah SA, Shahid M, et al.

Pak J Pharm Sci, 2019 Sep;32(5):1957-1964.
PMID: 31813858

The present study comprises the synthesis of a new series of benzenesulfonamides derived from N-sulfonation of 2-(4-methoxyphenyl)-1-ethanamine (1). The synthesis was initiated by the reaction of 2-(4-methoxyphenyl)-1-ethanamine (1) with benzenesulfonyl chloride (2), to yield N-(4-methoxyphenethyl)benzenesulfonamide (3). This parent molecule 3 was subsequently treated with various alkyl/aralkyl halides (4a-j) in N,N-dimethylformamide (DMF) and in the presence of a weak base lithium hydride (LiH) to obtain various N-(alkyl/aralkyl)-N-(4-methoxyphenethyl) benzenesulfonamides (5a-j). The characterization of these derivatives was carried out by spectroscopic techniques like IR, 1H-NMR, and 13C-NMR. Elemental analysis also supported this data. The biofilm inhibitory action of all the synthesized compounds was carried out on Escherichia coli and some of the compounds were identified to be very suitable inhibitors of this bacterial strain. Furthermore, the molecules were also tested for their cytotoxicity behavior to assess their utility as less cytotoxic therapeutic agents.
α-Glucosidase inhibitory potential and hemolytic evaluation of newly synthesized 3,4,5-trisubstituted-1,2,4-triazole derivatives

Nafeesa K, Aziz-Ur-Rehman -, Abbasi MA, Siddiqui SZ, Rasool S, Ali Shah SA, et al.

Pak J Pharm Sci, 2019 Nov;32(6):2651-2658.
PMID: 31969298

A series of 1, 2, 4-triazole derivatives bearing piperidine moiety has been introduced as new anti-diabetic drug candidates with least cytotoxicity. p-Chlorophenylsulfonyl chloride (1) and ethyl nipecotate (2) were the starting reagents that resulted into corresponding 3,4,5-trisubstituted-1,2,4-triazole (6) through a series of steps. A series of electrophiles, 9a-e, were synthesized by reacting 4-bromobutyryl chloride (7) with differently substituted aromatic amines (8a-e) under basic aqueous medium. Target derivatives, 10a-e, were synthesized by the reaction of compound 6 with N-aryl-4-bromobutanamides (9a-e) in an aprotic solvent. Structures of all the derivatives were verified by spectroscopic analysis using IR, 1H-NMR, 13C-NMR and EIMS. Most of the derivatives revealed moderate to good α-glucosidase inhibitory activity with reference to acarbose. The moderate hemolytic potential demonstrated least toxicity.
Synthesis of new S-substituted derivatives of 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazol-2-ylhydrosulfide as suitable antibacterial and anticancer agents with moderate cytotoxicity

Nazir M, Abbasi MA, Aziz-Ur-Rehman -, Siddiqui SZ, Ali Shah SA, Shahid M, et al.

Pak J Pharm Sci, 2019 Nov;32(6):2585-2597.
PMID: 31969290

In the study presented here, the nucleophilic substitution reaction of 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazol-2-ylhydrosulfide was carried out with different alkyl/aralkyl halides (5a-r) to form its different S-substituted derivatives (6a-r), as depicted in scheme 1. The structural confirmation of all the synthesized compounds was done by IR, 1H-NMR, 13C-NMR and CHN analysis data. Bacterial biofilm inhibitory activity of all the synthesized compounds was carried out against Bacillus subtilis and Escherichia coli. The anticancer activity of these molecules was ascertained using anti-proliferation (SRB) assay on HCT 116 Colon Cancer Cell lines while the cytotoxicity of these molecules was profiled for their haemolytic potential. From this investigation it was rational that most of the compounds exhibited suitable antibacterial and anticancer potential along with a temperate cytotoxicity.
Impact of ethnic disparities on the treatment outcomes of HIV-negative drug-resistant tuberculosis patients in Kuala Lumpur, Malaysia: A call for a culturally-sensitive community intervention approach

Shariff NM, Shah SA, Kamaludin F

J Glob Antimicrob Resist, 2019 12;19:274-279.
PMID: 31100500 DOI: 10.1016/j.jgar.2019.05.009

OBJECTIVE: Little is known about the treatment outcomes of HIV-negative drug-resistant tuberculosis (TB) patients in Malaysia. With respect to this issue, this study aimed to determine factors associated with unsuccessful treatment outcomes among drug-resistant TB patients at the Institute of Respiratory Medicine, Kuala Lumpur, Malaysia.
METHODS: This retrospective cohort study involved laboratory-confirmed drug-resistant TB patients from January 2009 to June 2013. Multiple logistic regression was used to model the outcome, which was subsequently defined according to the recent definition by the WHO. Data were analysed using IBM SPSS Statistics for Windows version 22.0.
RESULTS: Among the 403 patients who were analysed, 66.7% of them were found to have achieved successful outcomes (cured or completed treatment) while the remaining 33.3% had unsuccessful treatment outcomes (defaulted, treatment failure or died). Multivariable analysis showed that the type of resistance [polyresistant (aOR = 3.00, 95% CI 1.14-7.91), multidrug resistant (MDR) (aOR = 5.37, 95% CI 2.65-10.88)], ethnicity [Malay (aOR = 2.86, 95% CI 1.44-5.71), Indian (aOR = 3.04, 95% CI 1.20-7.70)], and treatment non-compliance (aOR = 26.93, 95% CI 14.47-50.10) were the independent risk factors for unsuccessful treatment outcomes among this group of patients. Notably, the odds of unsuccessful treatment outcome was also amplified among Malay MDR-TB patients in this study (aOR = 13.44, 95% CI 1.99-90.58).
CONCLUSION: In order to achieve better treatment outcomes for TB, effective behavioural intervention and thorough investigation on ethnic disparities in TB treatment are needed to promote good compliance.
The diagnostic utility of cytokeratin 19 in differentiating malignant from benign thyroid lesions

Wa Kammal WS, Yahaya A, Shah SA, Abdullah Suhaimi SN, Mahasin M, Mustangin M, et al.

Malays J Pathol, 2019 Dec;41(3):293-301.
PMID: 31901914

INTRODUCTION: Thyroid carcinoma is classically diagnosed based on certain histological criteria. In some cases, definitive diagnoses may be challenging when morphological features are equivocal. This study evaluated the usefulness of Cytokeratin 19 (CK 19) as an immunohistochemical marker to differentiate the different histological types of malignant thyroid neoplasms, particularly papillary thyroid carcinoma (PTC) from benign thyroid lesions.
MATERIALS AND METHODS: We collected 54 malignant and 65 benign thyroid lesions diagnosed by histology in Universiti Kebangsaan Malaysia Medical Centre between January 2010 and December 2015. All cases were immunohistochemically stained with CK 19 and evaluated by 3 independent observers. The immunostaining patterns were scored based on the intensity and proportion of staining and finally graded as negative, weak positive, moderate positive or strong positive. In addition, the immunostaining scores of the malignant cases were correlated with their TNM pathological tumour stages.
RESULTS: Cytokeratin 19 staining expression was higher in malignant than benign thyroid lesions (p < 0.001) which was most prominent among classical PTC. The four PTC cases that showed negative or weak staining were all follicular variant of PTC. Benign conditions were mostly negative or showed weak positivity. There was no correlation between CK 19 expression and TNM primary tumour stage (pT).
CONCLUSION: Cytokeratin 19 is a useful marker in differentiating malignant from benign thyroid conditions particularly the classical PTC, provided its interpretation is by correlation with morphology and takes into consideration the intensity and proportion of positive staining.
Renin-Angiotensin-Aldosterone System Gene Polymorphisms and Type 2 Diabetic Nephropathy in Asian Populations: An Updated Meta-analysis

Ahmad N, Jamal R, Shah SA, Gafor AHA, Murad NAA

Curr Diabetes Rev, 2019;15(4):263-276.
PMID: 29984662 DOI: 10.2174/1573399814666180709100411

BACKGROUND: The association of polymorphisms in the renin-angiotensin-aldosterone system candidate genes, namely Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D), Angiotensinogen (AGT) M235T and Angiotensin II Receptor Type 1 (AGTR1) A1166C with Diabetic Nephropathy (DN) has been studied for decades.
OBJECTIVE: This meta-analysis aimed to assess the updated pooled effects of these polymorphisms with DN among Asian populations with type 2 diabetes mellitus.
METHODS: The PubMed electronic database was searched without duration filter until August 2017 and the reference list of eligible studies was screened. The association of each polymorphism with DN was examined using odds ratio and its 95% confidence interval based on dominant, recessive and allele models. Subgroup analyses were conducted based on region, DN definition and DM duration.
RESULTS: In the main analysis, the ACE I/D (all models) and AGTR1 A1166C (dominant model) showed a significant association with DN. The main analysis of the AGT M235T polymorphism did not yield significant findings. There were significant subgroup differences and indication of significantly higher odds for DN in terms of DM duration (≥10 years) for ACE I/D (all models), AGT M235T (recessive and allele models) and AGTR1 A1166C (recessive model). Significant subgroup differences were also observed for DN definition (advanced DN group) and region (South Asia) for AGTR1 A1166C (recessive model).
CONCLUSION: In the Asian populations, ACE I/D and AGTR1 A1166C may contribute to DN susceptibility in patients with T2DM by different genetic models. However, the role of AGT M235T needs to be further evaluated.
Cytotoxicity of Anchusa arvensis Against HepG-2 Cell Lines: Mechanistic and Computational Approaches

Hussain S, Ullah F, Sadiq A, Ayaz M, Shah AA, Ali Shah SA, et al.

Curr Top Med Chem, 2019;19(30):2805-2813.
PMID: 31702502 DOI: 10.2174/1568026619666191105103801

BACKGROUND: Liver cancer is a devastating cancer with increasing incidence and mortality rates worldwide. Plants possess numerous therapeutic properties, therefore the search for novel, naturally occurring cytotoxic compounds is urgently needed.
METHODS: The anticancer activity of plant extracts and isolated compounds from Anchusa arvensis (A. arvensis) were studied against the cell culture of HepG-2 (human hepatocellular carcinoma cell lines) using 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) assay. Apoptosis was investigated by performing Acridine orange -ethidium bromide staining, styox green assay and DNA interaction study. We also used tools for computational chemistry studies of isolated compounds with the tyrosine kinase.
RESULTS: In MTT assay, the crude extract caused a significant cytotoxic effect with IC50 of 34.14 ± 0.9 μg/ml against HepG-2 cell lines. Upon fractionation, chloroform fraction (Aa.Chm) exhibited the highest antiproliferative activity with IC50 6.55 ± 1.2 μg/ml followed by ethyl acetate (Aa.Et) fraction (IC50, 24.59 ± 0.85 μg/ml) and n-hexane (Aa.Hex) fraction (IC50 29.53 ± 1.5μg/ml). However, the aqueous (Aa.Aq) fraction did not show any anti-proliferative activity. Bioactivity-guided isolation led to the isolation of two compounds which were characterized as para-methoxycatechol (1) and decane (2) through various spectroscopic techniques. Against HepG-2 cells, compound 1 showed marked potency with IC50 6.03 ± 0.75 μg/ml followed by 2 with IC50 18.52 ± 1.9 μg/ml. DMSO was used as a negative control and doxorubicin as a reference standard (IC50 1.3 ± 0.21 μg/ml). It was observed that compounds 1-2 caused apoptotic cell death evaluated by Acridine orange -ethidium bromide staining, styox green assay and DNA interaction study, therefore both compounds were tested for molecular docking studies against tyrosine kinase to support cytotoxic activity.
CONCLUSION: This study revealed that the plant extracts and isolated compounds possess promising antiproliferative activity against HepG-2 cell lines via apoptotic cell death.
Fulltext In Silico, Cytotoxic and Antioxidant Potential of Novel Ester, 3-hydroxyoctyl -5- trans-docosenoate Isolated from Anchusa arvensis (L.) M.Bieb. Against HepG-2 Cancer Cells

Hussain S, Ullah F, Ayaz M, Ali Shah SA, Ali Shah AU, Shah SM, et al.

Drug Des Devel Ther, 2019;13:4195-4205.
PMID: 31849451 DOI: 10.2147/DDDT.S228971

Background: Cancer is one of the chronic health conditions worldwide. Various therapeutically active compounds from medicinal plants were the current focus of this research in order to uncover a treatment regimen for cancer. Anchusa arvensis (A. anchusa) (L.) M.Bieb. contains many biologically active compounds.
Methods: In the current study, new ester 3-hydroxyoctyl -5- trans-docosenoate (compound-1) was isolated from the chloroform soluble fraction of A. anchusa using column chromatography. Using MTT assay, the anticancer effect of the compound was determined in human hepatocellular carcinoma cells (HepG-2) compared with normal epithelial cell line (Vero). DPPH and ABTS radical scavenging assays were performed to assess the antioxidant potential. The Molecular Operating Environment (MOE-2016) tool was used against tyrosine kinase.
Results: The structure of the compound was elucidated based on IR, EI, and NMR spectroscopy technique. It exhibited a considerable cytotoxic effect against HepG-2 cell lines with IC50 value of 6.50 ± 0.70 µg/mL in comparison to positive control (doxorubicin) which showed IC50 value of 1.3±0.21 µg/mL. The compound did not show a cytotoxic effect against normal epithelial cell line (Vero). The compound also exhibited significant DPHH scavenging ability with IC50 value of 12 ± 0.80 µg/mL, whereas ascorbic acid, used as positive control, demonstrated activity with IC50 = 05 ± 0.15 µg/mL. Similarly, it showed ABTS radical scavenging ability (IC50 = 130 ± 0.20 µg/mL) compared with the value obtained for ascorbic acid (06 ± 0.85 µg/mL). In docking studies using MOE-2016 tool, it was observed that compound-1 was highly bound to tyrosine kinase by having two hydrogen bonds at the hinge region. This good bonding network by the compound might be one of the reasons for showing significant activity against this enzyme.
Conclusion: Our findings led to the isolation of a new compound from A. anchusa which has significant cytotoxic activity against HepG-2 cell lines with marked antioxidant potential.
Fulltext Reduction in Urinary Chemokine (C-C Motif) Ligand 2 (CCL2) After Surgery-Induced Weight Loss

Said SB, Loo GH, Kosai NR, Rajan R, Mohd R, Wahab AA, et al.

Sci Rep, 2020 01 21;10(1):790.
PMID: 31964990 DOI: 10.1038/s41598-020-57763-8

Kidney dysfunction, a deleterious effect of obesity, is now recognized as a relevant health risk. Chemokine (C-C Motif) Ligand 2 (CCL2) is one of the critical chemokines that play a vital role in the development of obesity-related metabolic disease. We aim to measure the changes in urinary CCL2 in our patients before and after their bariatric procedure and examine the correlation between CCL2 and renal function. A prospective cohort study was conducted at our teaching university hospital. Ethics approval was obtained from our institutional review board. Patients with a BMI of ≥37.5 kg/m2 with no history of renal disease were included. They underwent single anastomosis gastric bypass (SAGB), Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG), all performed via laparoscopic approach. Venous blood and urine samples were obtained preoperatively and six months after surgery. A total of 58 patients were recruited, with SG being performed in 74.1% of patients. At six-months follow-up, median (IQR) body weight reduced from 101.35 kgs (20.25) to 76.95 kg (24.62) p

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