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Fulltext Dose-dependent cholesterolemic activity of tocotrienols

Khor H, Ng T, Rajendran R

Malays J Nutr, 2002 Sep;8(2):157-66.
PMID: 22692474

Tocotrienols and tocopherols are isoforms of vitamin E. Vitamin E may exhibit antioxidant, prooxidant and non-antioxidant activities depending upon circumstances. In this study, the effect of tocotrienols and a-tocopherol on the activities of HMG CoA reductase and cholesterol 7 a-hydroxylase was investigated. Pure tocotrienols were isolated from palm fatty acid distillate and pure a-tocopherol was obtained commercially. Guinea pigs were treated with different dosages of tocotrienols and a-tocopherol. After the treatment period, animals were sacrificed and liver microsomes were prepared. HMG CoA reductase and cholesterol 7a-hydroxylase were assayed using tracer techniques. Our results showed that the effects of tocotrienols and a-tocopherol on the activities of both the enzymes were dose-dependent. At low dosages, both tocotrienols and a-tocopherol exhibited an inhibitory effect on both the enzymes. Moreover, tocotrienols were a much stronger inhibitors than a-tocopherol. At high dosages, on the other hand, tocotrienols and a-tocopherol showed opposite effects on the enzymes. While tocotrienols continued to exhibit an inhibitory effect, a-tocopherol actually exhibited a stimulatory effect on both the enzymes. A possible explanation for this observation is suggested.
Extracellular urease from Arthrobacter creatinolyticus MTCC 5604: scale up, purification and its cytotoxic effect thereof

Rajendran R, Pandi A, Ramchary A, Thiagarajan H, Panneerselvam J, Niraikulam A, et al.

Mol Biol Rep, 2019 Feb;46(1):133-141.
PMID: 30374769 DOI: 10.1007/s11033-018-4453-8

Urease is a potent metalloenzyme with diverse applications. This paper describes the scale up and purification of an extracellular urease from Arthrobacter creatinolyticus MTCC 5604. The urease production was scaled-up in 3.7 L and 20 L fermentor. A maximum activity of 27 and 27.8 U/mL and a productivity of 0.90 and 0.99 U/mL/h were obtained at 30 h and 28 h in 3.7 and 20 L fermentor, respectively. Urease was purified to homogeneity with 49.85-fold purification by gel filtration and anion exchange chromatography with a yield of 36% and a specific activity of 1044.37 U/mg protein. The enzyme showed three protein bands with molecular mass of 72.6, 11.2 and 6.1 kDa on SDS-PAGE and ~ 270 kDa on native PAGE. The cytotoxic effect of urease was assessed in vitro using cancer cell lines (A549 and MG-63) and normal cell line (HEK 293). Urease showed its inhibitory effects on cancer cell lines through the generation of toxic ammonia, which in turn increased the pH of the surrounding medium. This increase in extracellular pH, enhanced the cytotoxic effect of weak base chemotherapeutic drugs, doxorubicin (50 µM) and vinblastine (100 µM) in the presence of urease (5 U/mL) and urea (0-4 mM) significantly.
Fulltext Inhibition of breast cancer xenografts in a mouse model and the induction of apoptosis in multiple breast cancer cell lines by lactoferricin B peptide

Rahman R, Fonseka AD, Sua SC, Ahmad M, Rajendran R, Ambu S, et al.

J Cell Mol Med, 2021 08;25(15):7181-7189.
PMID: 34236134 DOI: 10.1111/jcmm.16748

Breast cancer has a diverse aetiology characterized by the heterogeneous expression of hormone receptors and signalling molecules, resulting in varied sensitivity to chemotherapy. The adverse side effects of chemotherapy coupled with the development of drug resistance have prompted the exploration of natural products to combat cancer. Lactoferricin B (LfcinB) is a natural peptide derived from bovine lactoferrin that exhibits anticancer properties. LfcinB was evaluated in vitro for its inhibitory effects on cell lines representing different categories of breast cancer and in vivo for its suppressive effects on tumour xenografts in NOD-SCID mice. The different breast cancer cell lines exhibited varied levels of sensitivity to apoptosis induced by LfcinB in the order of SKBR3>MDA-MB-231>MDA-MB-468>MCF7, while the normal breast epithelial cells MCF-10A were not sensitive to LfcinB. The peptide also inhibited the invasion of the MDA-MB-231 and MDA-MB-468 cell lines. In the mouse xenograft model, intratumoural injections of LfcinB significantly reduced tumour growth rate and tumour size, as depicted by live imaging of the mice using in vivo imaging systems (IVIS). Harvested tumour volume and weight were significantly reduced by LfcinB treatment. LfcinB, therefore, is a promising and safe candidate that can be considered for the treatment of breast cancer.
Effect of madecassoside in reducing oxidative stress and blood glucose in streptozotocin-nicotinamide-induced diabetes in rats

Tan SC, Rajendran R, Bhattamisra SK, Krishnappa P, Davamani F, Chitra E, et al.

J Pharm Pharmacol, 2023 Aug 01;75(8):1034-1045.
PMID: 37402616 DOI: 10.1093/jpp/rgad063

OBJECTIVES: Madecassoside (MAD) is a triterpenoid constituent of Centella asiatica (L.) Urb., an ethnomedical tropical plant, extracts of which were shown to reduce blood glucose in experimental diabetes. This study examines MAD for its anti-hyperglycaemic effects and tests the hypothesis that it reduces the blood glucose in experimentally induced diabetic rats by protecting the β-cells.
METHODS: Diabetes was induced using streptozotocin (60 mg/kg, i.v.) followed by nicotinamide (210 mg/kg, intraperitoneal (i.p.)). MAD (50 mg/kg) was administered orally for 4 weeks, commencing 15 days after induction of diabetes; resveratrol (10 mg/kg) was used as a positive control. Fasting blood glucose, plasma insulin, HbA1c, liver and lipid parameters were measured, along with antioxidant enzymes and malondialdehyde as an index of lipid peroxidation; histological and immunohistochemical studies were also undertaken.
KEY FINDINGS: MAD normalized the elevated fasting blood glucose levels. This was associated with increased plasma insulin concentrations. MAD alleviated oxidative stress by improving enzymatic antioxidants and reducing lipid peroxidation. Histopathological examination showed significant recovery of islet structural degeneration and an increased area of islets. Immunohistochemical staining showed increased insulin content in islets of MAD-treated rats.
CONCLUSIONS: The results demonstrate an antidiabetic effect of MAD associated with preservation of β-cell structure and function.
Fulltext The roles of circular RNAs in human development and diseases

Lee ECS, Elhassan SAM, Lim GPL, Kok WH, Tan SW, Leong EN, et al.

Biomed Pharmacother, 2019 Mar;111:198-208.
PMID: 30583227 DOI: 10.1016/j.biopha.2018.12.052

For many years, circular ribonucleic acids (circRNAs) have been counted as aberrant splicing by-products. Advanced bioinformatics analysis and deep sequencing techniques have allowed researchers to discover more interesting facts about circRNAs. Intriguing evidence has shed light on the functions of circRNAs in many tissues. Furthermore, emerging reports showed that circRNAs are found abundantly in saliva and blood samples, suggesting that circRNAs are potential clinical biomarkers for human embryonic development, diseases progression and prognosis, in addition to its role in organogenesis and pathogenesis. The implementation of circRNAs in human developmental stages and diseases would be a tremendous discovery in the science and medical field. Therefore, circRNAs have been studied for its biological function as well as its implication in various human diseases. The aim of this review is to highlight the importance of circRNAs in cardiac, respiratory, nervous, endocrine and digestive systems. In addition, the role and impact of circRNAs in, cardiogenesis, neurogenesis and cancer have been discussed.
Fulltext Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

Qattan MY, Bakker EY, Rajendran R, Chen DW, Saha V, Liu J, et al.

PLoS One, 2017;12(6):e0178606.
PMID: 28582465 DOI: 10.1371/journal.pone.0178606

Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy.