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Fulltext Design of a randomised intervention study: the effect of dumbbell exercise therapy on physical activity and quality of life among breast cancer survivors in Malaysia

Rufa'i AA, Muda WAMW, Yen SH, Abd Shatar AK, Murali BVK, Tan SW

BMJ Glob Health, 2016;1(1):e000015.
PMID: 28588911 DOI: 10.1136/bmjgh-2015-000015

BACKGROUND: Participation in physical activity has a positive impact on the overall health and quality of life, whereas physical inactivity is associated with a poor prognosis among breast cancer survivors. Despite the health-enhancing benefits of physical activity, the majority of Malaysian breast cancer survivors are not physically active. This paper presents the design of a randomised study to evaluate the feasibility and effect of exercise therapy intervention using light resistance dumbbell exercise to promote active lifestyle and improve the quality of life of breast cancer survivors in Malaysia.
METHODS/DESIGN: This is an intervention study of a 12-week exercise therapy that will explore and compare the effects of light resistance and aerobic exercise on physical activity level and quality of life components in 102 female breast cancer survivors. Major eligibility criteria include histologically confirmed diagnosis of breast cancer stages I-III, 3-12 months post-diagnosis, and absence of any disorder contraindicating exercise. Participants will be stratified based on menopausal status (pre-menopause vs post-menopause) and then assigned randomly to one of three groups. Participants in group A will participate in a three-times weekly supervised resistance exercise using light resistance dumbbells; participants in group B will participate in a three-times weekly supervised aerobic exercise; while participants in group C (control group) will be given aerobic exercise after completion of the intervention. The primary end points include physical activity level and quality of life components. The secondary end points are body mass index, body composition, total caloric intake, and waist-to-hip ratio.
DISCUSSION: Although there have been many studies of resistance exercise in breast cancer survivors, this is the first study using this specific mode of resistance. Findings will contribute data on the feasibility and effects of light resistance dumbbell exercises, and provide knowledge on the physical activity intervention programme that will maximally promote better overall health and well-being of survivors.
Fabrication and in vitro biological activity of βTCP-Chitosan-Fucoidan composite for bone tissue engineering

Puvaneswary S, Talebian S, Raghavendran HB, Murali MR, Mehrali M, Afifi AM, et al.

Carbohydr Polym, 2015 Dec 10;134:799-807.
PMID: 26428187 DOI: 10.1016/j.carbpol.2015.07.098

We developed tricalcium phosphate-chitosan-fucoidan biocomposite scaffold (TCP-Ch-Fu) by using the freeze-drying technique. The fabricated biocomposite scaffolds were analyzed by spectroscopy and porosity measurement. The biomechanical properties of scaffolds were assessed by compression test and the results suggested that the incorporation of Fucoidan into the biocomposite improves the compression strength of scaffolds. Biomineralization of scaffolds was evaluated by soaking them in simulated body fluid and the results revealed that the addition of Fucoidan into the scaffolds enhanced the formation of apatite layer on the surface of biocomposite after 7 days of immersion. Alamar Blue assay confirmed that the cell viability of human-derived bone marrow stromal cell was superior in the TCP-Ch-Fuscaffold. The addition of Fucoidan to TCP-Ch increased the release of osteocalcin, confirming that it can support osteogenic differentiation of human mesenchymal stromal cells in in vitro culture. Thus, TCP-Ch-Fu could be a potential candidate for bone-tissue engineering applications.
Fulltext Forecasting daily confirmed COVID-19 cases in Malaysia using ARIMA models

Singh S, Murali Sundram B, Rajendran K, Boon Law K, Aris T, Ibrahim H, et al.

J Infect Dev Ctries, 2020 09 30;14(9):971-976.
PMID: 33031083 DOI: 10.3855/jidc.13116

INTRODUCTION: The novel coronavirus infection has become a global threat affecting almost every country in the world. As a result, it has become important to understand the disease trends in order to mitigate its effects. The aim of this study is firstly to develop a prediction model for daily confirmed COVID-19 cases based on several covariates, and secondly, to select the best prediction model based on a subset of these covariates.
METHODOLOGY: This study was conducted using daily confirmed cases of COVID-19 collected from the official Ministry of Health, Malaysia (MOH) and John Hopkins University websites. An Autoregressive Integrated Moving Average (ARIMA) model was fitted to the training data of observed cases from 22 January to 31 March 2020, and subsequently validated using data on cases from 1 April to 17 April 2020. The ARIMA model satisfactorily forecasted the daily confirmed COVID-19 cases from 18 April 2020 to 1 May 2020 (the testing phase).
RESULTS: The ARIMA (0,1,0) model produced the best fit to the observed data with a Mean Absolute Percentage Error (MAPE) value of 16.01 and a Bayes Information Criteria (BIC) value of 4.170. The forecasted values showed a downward trend of COVID-19 cases until 1 May 2020. Observed cases during the forecast period were accurately predicted and were placed within the prediction intervals generated by the fitted model.
CONCLUSIONS: This study finds that ARIMA models with optimally selected covariates are useful tools for monitoring and predicting trends of COVID-19 cases in Malaysia.
Effect of Chitosan Nanoparticle-Loaded Thymus serpyllum on Hydrogen Peroxide-Induced Bone Marrow Stromal Cell Damage

Baig S, Azizan AHS, Raghavendran HRB, Natarajan E, Naveen S, Murali MR, et al.

Stem Cells Int, 2019;2019:5142518.
PMID: 30956670 DOI: 10.1155/2019/5142518

We have determined the protective effects of Thymus serpyllum (TS) extract and nanoparticle-loaded TS on hydrogen peroxide-induced cell death of mesenchymal stromal cells (MSCs) in vitro. Gas chromatography-mass spectroscopy confirmed the spectrum of active components in the extract. Out of the three different extracts, the hexane extract showed significant free radical scavenging activity. Treatment of MSCs with H2O2 (hydrogen peroxide) significantly increased intracellular cell death; however, pretreatment with TS extract and nanoparticle-loaded TS (200 μg/ml) suppressed H2O2-induced elevation of Cyt-c and MMP13 and increased the survival rates of MSCs. H2O2-induced (0.1 mM) changes in cytokines were attenuated in the extract and nanoparticles by pretreatment and cotreatment at two time points (p < 0.05). H2O2 increased cell apoptosis. In contrast, treatment with nanoparticle-loaded TS suppressed the percentage of apoptosis considerably (p < 0.05). Therefore, TS may be considered as a potential candidate for enhancing the effectiveness of MSC transplantation in cell therapy.
Biomineralization, mechanical, antibacterial and biological investigation of larnite and rankinite bioceramics

Venkatraman SK, Choudhary R, Krishnamurithy G, Raghavendran HRB, Murali MR, Kamarul T, et al.

Mater Sci Eng C Mater Biol Appl, 2021 Jan;118:111466.
PMID: 33255048 DOI: 10.1016/j.msec.2020.111466

This work is aimed to develop a biocompatible, bactericidal and mechanically stable biomaterial to overcome the challenges associated with calcium phosphate bioceramics. The influence of chemical composition on synthesis temperature, bioactivity, antibacterial activity and mechanical stability of least explored calcium silicate bioceramics was studied. The current study also investigates the biomedical applications of rankinite (Ca3Si2O7) for the first time. Sol-gel combustion method was employed for their preparation using citric acid as a fuel. Differential thermal analysis indicated that the crystallization of larnite and rankinite occurred at 795 °C and 1000 °C respectively. The transformation of secondary phases into the desired product was confirmed by XRD and FT-IR. TEM micrographs showed the particle size of larnite in the range of 100-200 nm. The surface of the samples was entirely covered by the dominant apatite phase within one week of immersion. Moreover, the compressive strength of larnite and rankinite was found to be 143 MPa and 233 MPa even after 28 days of soaking in SBF. Both samples prevented the growth of clinical pathogens at a concentration of 2 mg/mL. Larnite and rankinite supported the adhesion, proliferation and osteogenic differentiation of hBMSCs. The variation in chemical composition was found to influence the properties of larnite and rankinite. The results observed in this work signify that these materials not only exhibit faster biomineralization ability, excellent cytocompatibility but also enhanced mechanical stability and antibacterial properties.
Fulltext Platelet-rich concentrate in serum free medium enhances osteogenic differentiation of bone marrow-derived human mesenchymal stromal cells

Samuel S, Ahmad RE, Ramasamy TS, Karunanithi P, Naveen SV, Murali MR, et al.

PeerJ, 2016;4:e2347.
PMID: 27651984 DOI: 10.7717/peerj.2347

Previous studies have shown that platelet concentrates used in conjunction with appropriate growth media enhance osteogenic differentiation of human mesenchymal stromal cells (hMSCs). However, their potential in inducing osteogenesis of hMSCs when cultured in serum free medium has not been explored. Furthermore, the resulting osteogenic molecular signatures of the hMSCs have not been compared to standard osteogenic medium. We studied the effect of infrequent supplementation (8-day interval) of 15% non-activated platelet-rich concentrate (PRC) in serum free medium on hMSCs proliferation and differentiation throughout a course of 24 days, and compared the effect with those cultured in a standard osteogenic medium (OM). Cell proliferation was analyzed by alamar blue assay. Gene expression of osteogenic markers (Runx2, Collagen1, Alkaline Phosphatase, Bone morphogenetic protein 2, Osteopontin, Osteocalcin, Osteonectin) were analyzed using Q-PCR. Immunocytochemical staining for osteocalcin, osteopontin and transcription factor Runx2 were done at 8, 16 and 24 days. Biochemical assays for the expression of ALP and osteocalcin were also performed at these time-points. Osteogenic differentiation was further confirmed qualitatively by Alizarin Red S staining that was quantified using cetylpyridinium chloride. Results showed that PRC supplemented in serum free medium enhanced hMSC proliferation, which peaked at day 16. The temporal pattern of gene expression of hMSCs under the influence of PRC was comparable to that of the osteogenic media, but at a greater extent at specific time points. Immunocytochemical staining revealed stronger staining for Runx2 in the PRC-treated group compared to OM, while the staining for Osteocalcin and Osteopontin were comparable in both groups. ALP activity and Osteocalcin/DNA level were higher in the PRC group. Cells in the PRC group had similar level of bone mineralization as those cultured in OM, as reflected by the intensity of Alizarin red stain. Collectively, these results demonstrate a great potential of PRC alone in inducing proliferation of hMSCs without any influence from other lineage-specific growth media. PRC alone has similar capacity to enhance hMSC osteogenic differentiation as a standard OM, without changing the temporal profile of the differentiation process. Thus, PRC could be used as a substitute medium to provide sufficient pool of pre-differentiated hMSCs for potential clinical application in bone regeneration.
Incorporation of Human-Platelet-Derived Growth Factor-BB Encapsulated Poly(lactic-co-glycolic acid) Microspheres into 3D CORAGRAF Enhances Osteogenic Differentiation of Mesenchymal Stromal Cells

Mohan S, Raghavendran HB, Karunanithi P, Murali MR, Naveen SV, Talebian S, et al.

ACS Appl Mater Interfaces, 2017 Mar 22;9(11):9291-9303.
PMID: 28266827 DOI: 10.1021/acsami.6b13422

Tissue engineering aims to generate or facilitate regrowth or healing of damaged tissues by applying a combination of biomaterials, cells, and bioactive signaling molecules. In this regard, growth factors clearly play important roles in regulating cellular fate. However, uncontrolled release of growth factors has been demonstrated to produce severe side effects on the surrounding tissues. In this study, poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) incorporated three-dimensional (3D) CORAGRAF scaffolds were engineered to achieve controlled release of platelet-derived growth factor-BB (PDGF-BB) for the differentiation of stem cells within the 3D polymer network. Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, scanning electron microscopy, and microtomography were applied to characterize the fabricated scaffolds. In vitro study revealed that the CORAGRAF-PLGA-PDGF-BB scaffold system enhanced the release of PDGF-BB for the regulation of cell behavior. Stromal cell attachment, viability, release of osteogenic differentiation markers such as osteocalcin, and upregulation of osteogenic gene expression exhibited positive response. Overall, the developed scaffold system was noted to support rapid cell expansion and differentiation of stromal cells into osteogenic cells in vitro for bone tissue engineering applications.
Fulltext The physicochemical and biomechanical profile of forsterite and its osteogenic potential of mesenchymal stromal cells

Krishnamurithy G, Mohan S, Yahya NA, Mansor A, Murali MR, Raghavendran HRB, et al.

PLoS One, 2019;14(3):e0214212.
PMID: 30917166 DOI: 10.1371/journal.pone.0214212

It has been demonstrated that nanocrystalline forsterite powder synthesised using urea as a fuel in sol-gel combustion method had produced a pure forsterite (FU) and possessed superior bioactive characteristics such as bone apatite formation and antibacterial properties. In the present study, 3D-scaffold was fabricated using nanocrystalline forsterite powder in polymer sponge method. The FU scaffold was used in investigating the physicochemical, biomechanics, cell attachment, in vitro biocompatibility and osteogenic differentiation properties. For physicochemical characterisation, Fourier-transform infrared spectroscopy (FTIR), Energy dispersive X-ray (EDX), X-ray diffraction (XRD), Raman spectroscopy, X-ray photoemission spectrometer (XPS) and Brunauer-Emmett-Teller (BET) were used. FTIR, EDX, XRD peaks and Raman spectroscopy demonstrated correlating to FU. The XPS confirmed the surface chemistry associating to FU. The BET revealed FU scaffold surface area of 12.67 m2/g and total pore size of 0.03 cm3/g. Compressive strength of the FU scaffold was found to be 27.18 ± 13.4 MPa. The human bone marrow derived mesenchymal stromal cells (hBMSCs) characterisation prior to perform seeding on FU scaffold verified the stromal cell phenotypic and lineage commitments. SEM, confocal images and presto blue viability assay suggested good cell attachment and proliferation of hBMSCs on FU scaffold and comparable to a commercial bone substitutes (cBS). Osteogenic proteins and gene expression from day 7 onward indicated FU scaffold had a significant osteogenic potential (p<0.05), when compared with day 1 as well as between FU and cBS. These findings suggest that FU scaffold has a greater potential for use in orthopaedic and/or orthodontic applications.
Fulltext Impact of COVID-19 on Breast Cancer Management in a Multiethnic Middle-Income Asian Country Setting

Hui NJ, Hoong SM, Min TJ, Sze TM, Danaee M, Latiff NSA, et al.

Eur J Breast Health, 2023 Apr;19(2):177-183.
PMID: 37025571 DOI: 10.4274/ejbh.galenos.2023.2022-12-6

OBJECTIVE: Coronavirus disease-2019 (COVID-19) has caused hospitals to suspend routine procedures. As the world recovers, there is concern that the outcome of many diseases has been impaired. This study aimed to assess the impact of the pandemic on breast cancer demography, clinicopathological characteristics and patient management at a teaching hospital in Kuala Lumpur, Malaysia.
MATERIALS AND METHODS: Pre-COVID data were collected between January 1, 2019, to March 18, 2020, when a national lockdown was implemented, which caused the suspension of services at the breast clinic of University Malaya Medical Centre (UMMC). COVID data was obtained from March 2020 until June 2021.
RESULTS: This study compared 374 breast cancer patients in the COVID-19 period with 382 patients in the pre-COVID period. There was no significant difference in the median (range) time to surgery between pre-COVID [45 (26.50-153.50) days] and COVID [44 (24.75-156.25) days] periods. The clinicopathological features of breast cancer showed reduction in in situ carcinoma and increase in Stage 4 diagnoses during the COVID period. There was a reduction in screening-detected carcinoma (9% vs. 12.3%), mastectomy followed by immediate reconstruction (5.6% vs. 14.5%) and adjuvant chemotherapy (25.8% vs. 32.9%) in the COVID period.
CONCLUSION: In this center COVID-19 caused operational changes in breast cancer management, including a reduction in reconstructive procedures and adjuvant treatment. Healthcare disruption and fear of COVID may have caused delayed diagnosis, resulting in a higher frequency of Stage 4 disease and lower proportion of in situ carcinoma during the pandemic. However, there was no delay in the time to surgery, reduction in surgical volume, or change in surgery types.
Fulltext Fluoroscopy assisted minimally invasive transplantation of allogenic mesenchymal stromal cells embedded in HyStem reduces the progression of nucleus pulposus degeneration in the damaged ntervertebral [corrected] disc: a preliminary study in rabbits

Subhan RA, Puvanan K, Murali MR, Raghavendran HR, Shani S, Abdullah BJ, et al.

ScientificWorldJournal, 2014;2014:818502.
PMID: 24983002 DOI: 10.1155/2014/818502

This study was conducted to develop a technique for minimally invasive and accurate delivery of stem cells to augment nucleus pulposus (NP) in damaged intervertebral discs (IVD). IVD damage was created in noncontiguous discs at L4-L5 level; rabbits (N = 12) were randomly divided into three groups: group I treated with MSCs in HyStem hydrogel, group II treated with HyStem alone, and group III received no intervention. MSCs and hydrogel were administered to the damaged disc under guidance of fluoroscopy. Augmentation of NP was assessed through histological and MRI T2 mapping of the NP after eight weeks of transplantation. T2 weighted signal intensity was higher in group I than in groups II and III (P < 0.05). Disc height index showed maximum disc height in group I compared to groups II and III. Histological score of the degenerative index was significantly (P < 0.05) lower in group I (8.6 ± 1.8) than that in groups II (11.6 ± 2.3) and III (18.0 ± 5.7). Immunohistochemistry staining for collagen type II and aggrecan staining were higher in group I as compared to other groups. Our results demonstrate that the minimally invasive administration of MSCs in hyaluronan hydrogel (HyStem) augments the repair of NP in damaged IVD.
Fulltext Palm Oil Fuel Ash-Based Eco-Friendly Concrete Composite: A Critical Review of the Long-Term Properties

Amran M, Lee YH, Fediuk R, Murali G, Mosaberpanah MA, Ozbakkaloglu T, et al.

Materials (Basel), 2021 Nov 22;14(22).
PMID: 34832474 DOI: 10.3390/ma14227074

Rapid global infrastructural developments and advanced material science, amongst other factors, have escalated the demand for concrete. Cement, which is an integral part of concrete, binds the various individual solid materials to form a cohesive mass. Its production to a large extent emits many tons of greenhouse gases, with nearly 10% of global carbon (IV) oxide (CO2) emanating from cement production. This, coupled with an increase in the advocacy for environmental sustainability, has led to the development of various innovative solutions and supplementary cementitious materials. These aims to substantially reduce the overall volume of cement required in concrete and to meet the consistently increasing demand for concrete, which is projected to increase as a result of rapid construction and infrastructural development trends. Palm oil fuel ash (POFA), an industrial byproduct that is a result of the incineration of palm oil wastes due to electrical generation in power plants has unique properties, as it is a very reactive materials with robust pozzolanic tendencies, and which exhibits adequate micro-filling capabilities. In this study, a review on the material sources, affecting factors, and durability characteristics of POFA are carefully appraised. Moreover, in this study, a review of correlated literature with a broad spectrum of insights into the likely utilization of POFA-based eco-friendly concrete composites as a green material for the present construction of modern buildings is presented.
Fulltext The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration

Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R

Cytotherapy, 2016 Jan;18(1):13-24.
PMID: 26631828 DOI: 10.1016/j.jcyt.2015.10.008

The unique properties of mesenchymal stromal/stem cells (MSCs) to self-renew and their multipotentiality have rendered them attractive to researchers and clinicians. In addition to the differentiation potential, the broad repertoire of secreted trophic factors (cytokines) exhibiting diverse functions such as immunomodulation, anti-inflammatory activity, angiogenesis and anti-apoptotic, commonly referred to as the MSC secretome, has gained immense attention in the past few years. There is enough evidence to show that the one important pathway by which MSCs participate in tissue repair and regeneration is through its secretome. Concurrently, a large body of MSC research has focused on characterization of the MSC secretome; this includes both soluble factors and factors released in extracellular vesicles, for example, exosomes and microvesicles. This review provides an overview of our current understanding of the MSC secretome with respect to their potential clinical applications.
Fulltext Intrastrain comparison of the chemical composition and antioxidant activity of an edible mushroom, Pleurotus giganteus, and its potent neuritogenic properties

Phan CW, David P, Tan YS, Naidu M, Wong KH, Kuppusamy UR, et al.

ScientificWorldJournal, 2014;2014:378651.
PMID: 25121118 DOI: 10.1155/2014/378651

Two strains of Pleurotus giganteus (commercial and wild) were tested for their ability to induce neurite outgrowth in rat pheochromocytoma (PC12) and mouse neuroblastoma-2a (N2a) cells. Treatment with the mushroom extracts resulted in neuronal differentiation and neuronal elongation, but not nerve growth factor (NGF) production. Linoleic acid (4.5-5.0%, w/w) which is a major fatty acid present in the ethanol extract promoted NGF biosynthesis when augmented with low concentration of NGF (5 ng/mL). The two strains of mushroom were found to be high in protein (154-192 g kg(-1)), total polysaccharides, phenolics, and flavonoids as well as vitamins B1, B2, and B3. The total phenolics present in the mushroom extracts were positively correlated to the antioxidant activity (free radical scavenging, ferric reducing power, and lipid peroxidation inhibition). To conclude, P. giganteus could potentially be used in well-balanced diet and as a source of dietary antioxidant to promote neuronal health.
Fingolimod affects gene expression profile associated with LPS-induced memory impairment

Omidbakhsh R, Rajabli B, Nasoohi S, Khallaghi B, Mohamed Z, Naidu M, et al.

Exp Brain Res, 2014 Nov;232(11):3687-96.
PMID: 25098558 DOI: 10.1007/s00221-014-4052-4

Lipopolysaccharide is an endotoxin to induce sickness behavior in several animal models to explore the link between immune activation and cognition. Neuroinflammation playing a pivotal role in disease progress is evidently influenced by sphingosine-1-phosphate. As one of the sphingosine analogs in clinical use for multiple sclerosis, fingolimod (FTY720) was shown to substantially affect gene expression profile in the context of AD in our previous experiments. The present study was designed to evaluate the drug efficacy in the context of the mere inflammatory context leading to memory impairment. FTY720 was repeatedly administered for a few days before or after intracerebral lipopolysaccharide (LPS) injection in rats. Animal's brains were then assigned to histological as well as multiplex mRNA assay following memory performance test. Both FTY720 pre-treatment and post-treatment were similarly capable of ameliorating LPS-induced memory impairment as assessed by passive avoidance test. Such amending effects may be partly accountable by the concomitant alterations in transcriptional levels of mitogen-activated protein kinases as well as inflammatory genes determined by QuantiGene Plex analysis. These findings confirming FTY720 application benefits suggest its efficacy may not differ significantly while considered either as a preventive or as a therapeutic approach against neuroinflammation.
Neurorestorative effect of FTY720 in a rat model of Alzheimer's disease: comparison with memantine

Hemmati F, Dargahi L, Nasoohi S, Omidbakhsh R, Mohamed Z, Chik Z, et al.

Behav Brain Res, 2013 Sep 1;252:415-21.
PMID: 23777795 DOI: 10.1016/j.bbr.2013.06.016

Alzheimer's disease (AD) as a neurodegenerative brain disorder is the most common cause of dementia. To date, there is no causative treatment for AD and there are few preventive treatments either. The sphingosine-1-phosphate receptor modulator FTY720 (fingolimod) prevents lymphocytes from contributing to an autoimmune reaction and has been approved for multiple sclerosis treatment. In concert with other studies showing the anti-inflammatory and protective effect of FTY720 in some neurodegenerative disorders like ischemia, we have recently shown that FTY720 chronic administration prevents from impairment of spatial learning and memory in AD rats. Here FTY720 was examined on AD rats in comparison to the only clinically approved NMDA receptor antagonist, Memantine. Passive avoidance task showed significant memory restoration in AD animals received FTY720 comparable to Memantine. Upon gene profiling by QuantiGene Plex, this behavioral outcomes was concurrent with considerable alterations in some genes transcripts like that of mitogen activated protein kinases (MAPKs) and some inflammatory markers that may particularly account for the detected decline in hippocampal neural damage or memory impairment associated with AD. From a therapeutic standpoint, our findings conclude that FTY720 may suggest new opportunities for AD management probably based on several modulatory effects on genes involved in cell death or survival.
Cell therapy in critical limb ischemia: current developments and future progress

Mamidi MK, Pal R, Dey S, Bin Abdullah BJ, Zakaria Z, Rao MS, et al.

Cytotherapy, 2012 Sep;14(8):902-16.
PMID: 22731756 DOI: 10.3109/14653249.2012.693156

Critical limb ischemia (CLI) is a syndrome manifested by ischemic rest pain, non-healing ulcers and tissue loss. CLI patients are at very high risk of amputation and experience poor physical function, leading to severe morbidity and mortality. The fundamental goal for CLI treatment is to relieve ischemic rest pain, heal ulcers, prevent limb loss and improve the quality of life, thereby extending the survival of the patient. Surgical or endovascular revascularization aimed at increasing blood flow is currently available for limb salvage in CLI. However, up to 30% of CLI patients are not suitable for such interventions because of high operative risk or unfavorable vascular anatomy. Therefore exploring new and more effective strategies for revascularization of ischemic limbs is imperative for the establishment of a viable therapeutic alternative. With the emergence of new approaches, this review describes up-to-date progress and developments in cell-based therapy as a novel and promising alternative for CLI treatment. Preliminary clinical data have established the safety, feasibility and efficacy of stem cells, and numerous studies are underway to consolidate this evidence further. However, significant hurdles remain to be addressed before this research can be responsibly translated to the bedside. In particular, we need better understanding of the behavior of cells post-transplantation and to learn how to control their survival and migration proliferation/differentiation in the hostile pathologic environment. Future research should focus on methods of isolation, optimal dosage, appropriate cell type, route of administration, role of tissue-derived factors and supportive endogenous stimulation.
Alterations in antioxidant enzyme activities and oxidative damage in alcoholic rat tissues: protective role of Thespesia populnea

Pandanaboina SC, Kondeti SR, Rajbanshi SL, Kunala PN, Pandanaboina S, Pandanaboina MM, et al.

Food Chem, 2012 May 1;132(1):150-9.
PMID: 26434274 DOI: 10.1016/j.foodchem.2011.10.046

Recent advances in our understanding of the pathogenesis of alcohol-induced hepato-renal injury and the development of new approaches to its treatment have been reported in various works. This study involves alcohol-induced oxidative stress linked to the metabolism of ethanol involving both mitochondrial and peroxisomal fractions of liver and kidney. Alcohol treatment resulted in the depletion of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), Glutathione-S-Transferase (GST) activities, and reduced glutathione (GSH) content, higher level of malondialdehyde (MDA) and lower levels of protein carbonyls (PC) causing malfunction of hepatic and renal tissues, when compared to control rats. Thespesia populnea (TP) leaf extracts, administered to chronic alcohol ingested rats, were envisaged to possess significant antioxidant defence properties and help in the recovery of tissues from alcohol-induced oxidative damage. The results showed that degenerative changes in hepatic and renal cells of alcoholic groups were minimized by the administration of TP leaf extracts as also revealed by histopathological examination. The current findings indicate that treatment with TP extracts reduces alcohol-induced oxidative stress, thereby protecting the hepatic and renal tissue from alcohol-induced damage.
Stem cells in stroke repair: current success and future prospects

Gopurappilly R, Pal R, Mamidi MK, Dey S, Bhonde R, Das AK

CNS Neurol Disord Drug Targets, 2011 Sep 1;10(6):741-56.
PMID: 21838668

Stroke causes a devastating insult to the brain resulting in severe neurological deficits because of a massive loss of different neurons and glia. In the United States, stroke is the third leading cause of death. Stroke remains a significant clinical unmet condition, with only 3% of the ischemic patient population benefiting from current treatment modalities, such as the use of thrombolytic agents, which are often limited by a narrow therapeutic time window. However, regeneration of the brain after ischemic damage is still active days and even weeks after stroke occurs, which might provide a second window for treatment. Neurorestorative processes like neurogenesis, angiogenesis and synaptic plasticity lead to functional improvement after stroke. Stem cells derived from various tissues have the potential to perform all of the aforementioned processes, thus facilitating functional recovery. Indeed, transplantation of stem cells or their derivatives in animal models of cerebral ischemia can improve function by replacing the lost neurons and glial cells and by mediating remyelination, and modulation of inflammation as confirmed by various studies worldwide. While initially stem cells seemed to work by a 'cell replacement' mechanism, recent research suggests that cell therapy works mostly by providing trophic support to the injured tissue and brain, fostering both neurogenesis and angiogenesis. Moreover, ongoing human trials have encouraged hopes for this new method of restorative therapy after stroke. This review describes up-to-date progress in cell-based therapy for the treatment of stroke. Further, as we discuss here, significant hurdles remain to be addressed before these findings can be responsibly translated to novel therapies. In particular, we need a better understanding of the mechanisms of action of stem cells after transplantation, the therapeutic time window for cell transplantation, the optimal route of cell delivery to the ischemic brain, the most suitable cell types and sources and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment. An integrated approach of cell-based therapy with early-phase clinical trials and continued preclinical work with focus on mechanisms of action is needed.
Fulltext Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assay

Kong WM, Chik Z, Ramachandra M, Subramaniam U, Aziddin RE, Mohamed Z

Molecules, 2011 Aug 29;16(9):7344-56.
PMID: 21876481 DOI: 10.3390/molecules16097344

The extract from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacological effects. This study investigated the effects of M. speciosa alkaloid extract (MSE) on human recombinant cytochrome P450 (CYP) enzyme activities using a modified Crespi method. As compared with the liquid chromatography-mass spectrometry method, this method has shown to be a fast and cost-effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concentration (IC(50)) values of 0.78 µg/mL and 0.636 µg/mL, respectively. In addition, moderate inhibition was observed for CYP1A2, with an IC(50) of 39 µg/mL, and weak inhibition was detected for CYP2C19. The IC(50) of CYP2C19 could not be determined, however, because inhibition was <50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were ACCESSused as positive controls throughout the experiments. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2.
Fulltext Cell therapy: the final frontier for treatment of neurological diseases

Dutta S, Singh G, Sreejith S, Mamidi MK, Husin JM, Datta I, et al.

CNS Neurosci Ther, 2013 Jan;19(1):5-11.
PMID: 23253099 DOI: 10.1111/cns.12027

Neurodegenerative diseases are devastating because they cause increasing loss of cognitive and physical functions and affect an estimated 1 billion individuals worldwide. Unfortunately, no drugs are currently available to halt their progression, except a few that are largely inadequate. This mandates the search of new treatments for these progressively degenerative diseases. Neural stem cells (NSCs) have been successfully isolated, propagated, and characterized from the adult brains of mammals, including humans. The confirmation that neurogenesis occurs in the adult brain via NSCs opens up fresh avenues for treating neurological problems. The proof-of-concept studies demonstrating the neural differentiation capacity of stem cells both in vitro and in vivo have raised widespread enthusiasm toward cell-based interventions. It is anticipated that cell-based neurogenic drugs may reverse or compensate for deficits associated with neurological diseases. The increasing interest of the private sector in using human stem cells in therapeutics is evidenced by launching of several collaborative clinical research activities between Pharma giants and research institutions or small start-up companies. In this review, we discuss the major developments that have taken place in this field to position stem cells as a prospective candidate drug for the treatment of neurological disorders.

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