Displaying publications 1 - 20 of 41 in total

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  1. Gundamaraju R, Lu W, Manikam R
    Cancers (Basel), 2021 Jan 23;13(3).
    PMID: 33498743 DOI: 10.3390/cancers13030432
    The Warburg effect has immensely succored the study of cancer biology, especially in highlighting the role of mitochondria in cancer stemness and their benefaction to the malignancy of oxidative and glycolytic cancer cells. Mitochondrial genetics have represented a focal point in cancer therapeutics due to the involvement of mitochondria in programmed cell death. The mitochondrion has been well established as a switch in cell death decisions. The mitochondrion's instrumental role in central bioenergetics, calcium homeostasis, and translational regulation has earned it its fame in metastatic dissemination in cancer cells. Here, we revisit and review mechanisms through which mitochondria influence oncogenesis and metastasis by underscoring the oncogenic mitochondrion that is capable of transferring malignant capacities to recipient cells.
  2. Senthilkumaran S, Khamis A, Manikam R, Thirumalaikolundusubramanian P
    Indian J Crit Care Med, 2014 Mar;18(3):186.
    PMID: 24701075 DOI: 10.4103/0972-5229.128715
  3. Wong SY, Manikam R, Muniandy S
    J Infect Dev Ctries, 2015 Sep;9(9):936-44.
    PMID: 26409734 DOI: 10.3855/jidc.5882
    INTRODUCTION: Chronic wounds represent a major health burden worldwide. It has been hypothesized that the polymicrobial nature of wounds plays an important role in their healing process. Thus, a review of pathogen frequency and susceptibility patterns in wounds is necessary to provide appropriate guidelines for antimicrobial usage.
    METHODOLOGY: In this study, microbiota and antimicrobial resistance in both acute and chronic wound patients treated at the University of Malaya Medical Centre, Malaysia, were compared. Wound swabs from 84 patients with acute wounds and 84 patients with chronic wounds were collected. The specimens were cultured using standard microbiological techniques. Isolates were then tested for antibiotic sensitivity with the broth microdilution method.
    RESULTS: Of 210 pathogenic bacteria isolates, Staphylococcus aureus (49; 23.3%) and Pseudomonas aeruginosa (31; 14.8%) were the most prevalent bacteria found in wounds. Staphylococcus aureus was found significantly more often in patients with chronic wounds (41; 48.8%) than in patients with acute wounds (8; 9.5%), while Staphylococcus epidermidis was found predominantly in acute wounds (15; 17.9%). At the time of study, patients with chronic wounds (58.3%) had received more antibiotic treatments in the past previous 12 months compared with patients with acute wounds (16.7%). In the antibiotic susceptibility test, Staphylococcus spp. revealed highest resistance towards penicillin and ampicillin. Isolates showed no decrease in susceptibility against a number of newly developed antibiotics (linezolid, daptomycin, and tigecycline).
    CONCLUSIONS: Our finding showed that bacteria diversity and antimicrobial-resistant strains are more frequently found in chronic wounds than in acute wounds.
  4. Senthilkumaran S, David SS, Manikam R, Thirumalaikolundusubramanian P
    Indian J Crit Care Med, 2014 Jun;18(6):407-8.
    PMID: 24987247 DOI: 10.4103/0972-5229.133953
  5. Tang YQ, Jaganath IB, Manikam R, Sekaran SD
    Int J Med Sci, 2014;11(6):564-77.
    PMID: 24782645 DOI: 10.7150/ijms.7704
    Melanoma is the most fatal form of skin cancer. Different signalling pathways and proteins will be differentially expressed to pace with the tumour growth. Thus, these signalling molecules and proteins are become potential targets to halt the progression of cancer. The present works were attempted to investigate the underlying molecular mechanisms of anticancer effects of Phyllanthus (P.amarus, P.niruri, P.urinaria and P.watsonii) on skin melanoma, MeWo cells.
  6. Tan WC, Jaganath IB, Manikam R, Sekaran SD
    Int J Med Sci, 2013;10(13):1817-29.
    PMID: 24324358 DOI: 10.7150/ijms.6902
    Nucleoside analogues such as acyclovir are effective antiviral drugs against herpes simplex virus infections since its introduction. However, with the emergence of acyclovir-resistant HSV strains particularly in immunocompromised patients, there is a need to develop an alternative antiherpetic drug and plants could be the potential lead. In this study, the antiviral activity of the aqueous extract of four Phyllanthus species were evaluated against herpes simplex virus type-1 (HSV-1) and HSV-2 in Vero cells by quantitative PCR. The protein expressions of untreated and treated infected Vero cells were studied by 2D-gel electrophoresis and Western blot. This is the first study that reported the antiviral activity of P. watsonii. P. urinaria was shown to demonstrate the strongest antiviral activity against HSV-1 and HSV-2, with SI >33.6. Time-of-addition studies suggested that the extract may act against the early infection stage and the replication stage. Protein expression studies indicated that cellular proteins that are involved in maintaining cytoskeletal structure could be potential target for development of antiviral drugs. Preliminary findings indicated that P. urinaria demonstrated potent inhibitory activity against HSV. Hence, further studies such as in vivo evaluation are required for the development of effective antiherpetic drug.
  7. Lee SH, Jaganath IB, Manikam R, Sekaran SD
    BMC Complement Altern Med, 2013 Oct 20;13:271.
    PMID: 24138815 DOI: 10.1186/1472-6882-13-271
    BACKGROUND: Lung cancer constitutes one of the malignancies with the greatest incidence and mortality rates with 1.6 million new cases and 1.4 million deaths each year. Prognosis remains poor due to deleterious development of multidrug resistance resulting in less than 15% lung cancer patients reaching five years survival. We have previously shown that Phyllanthus induced apoptosis in conjunction with its antimetastastic action. In the current study, we aimed to determine the signaling pathways utilized by Phyllanthus to exert its antimetastatic activities.

    METHODS: Cancer 10-pathway reporter array was performed to screen the pathways affected by Phyllanthus in lung carcinoma cell line (A549) to exert its antimetastatic effects. Results from this array were then confirmed with western blotting, cell cycle analysis, zymography technique, and cell based ELISA assay for human total iNOS. Two-dimensional gel electrophoresis was subsequently carried out to study the differential protein expressions in A549 after treatment with Phyllanthus.

    RESULTS: Phyllanthus was observed to cause antimetastatic activities by inhibiting ERK1/2 pathway via suppression of Raf protein. Inhibition of this pathway resulted in the suppression of MMP2, MMP7, and MMP9 expression to stop A549 metastasis. Phyllanthus also inhibits hypoxia pathway via inhibition of HIF-1α that led to reduced VEGF and iNOS expressions. Proteomic analysis revealed a number of proteins downregulated by Phyllanthus that were involved in metastatic processes, including invasion and mobility proteins (cytoskeletal proteins), transcriptional proteins (proliferating cell nuclear antigen; zinc finger protein), antiapoptotic protein (Bcl2) and various glycolytic enzymes. Among the four Phyllanthus species tested, P. urinaria showed the greatest antimetastatic activity.

    CONCLUSIONS: Phyllanthus inhibits A549 metastasis by suppressing ERK1/2 and hypoxia pathways that led to suppression of various critical proteins for A549 invasion and migration.

  8. Senthilkumaran S, Jena NN, Gore SB, Manikam R, Thirumalaikolundusubramanian P
    Indian J Crit Care Med, 2015 Sep;19(9):566-7.
    PMID: 26430349 DOI: 10.4103/0972-5229.164823
  9. Le CF, Gudimella R, Razali R, Manikam R, Sekaran SD
    Sci Rep, 2016 05 26;6:26828.
    PMID: 27225022 DOI: 10.1038/srep26828
    In our previous studies, we generated a short 13 amino acid antimicrobial peptide (AMP), DM3, showing potent antipneumococcal activity in vitro and in vivo. Here we analyse the underlying mechanisms of action using Next-Generation transcriptome sequencing of penicillin (PEN)-resistant and PEN-susceptible pneumococci treated with DM3, PEN, and combination of DM3 and PEN (DM3PEN). DM3 induced differential expression in cell wall and cell membrane structural and transmembrane processes. Notably, DM3 altered the expression of competence-induction pathways by upregulating CelA, CelB, and CglA while downregulating Ccs16, ComF, and Ccs4 proteins. Capsular polysaccharide subunits were downregulated in DM3-treated cells, however, it was upregulated in PEN- and DM3PEN-treated groups. Additionally, DM3 altered the amino acids biosynthesis pathways, particularly targeting ribosomal rRNA subunits. Downregulation of cationic AMPs resistance pathway suggests that DM3 treatment could autoenhance pneumococci susceptibility to DM3. Gene enrichment analysis showed that unlike PEN and DM3PEN, DM3 treatment exerted no effect on DNA-binding RNA polymerase activity but observed downregulation of RpoD and RNA polymerase sigma factor. In contrast to DM3, DM3PEN altered the regulation of multiple purine/pyrimidine biosynthesis and metabolic pathways. Future studies based on in vitro experiments are proposed to investigate the key pathways leading to pneumococcal cell death caused by DM3.
  10. Tang YQ, Jaganath IB, Manikam R, Sekaran SD
    Nutr Cancer, 2015;67(5):783-95.
    PMID: 25996262 DOI: 10.1080/01635581.2015.1040518
    Tumor angiogenesis and metastasis are the major causes for high morbidity and mortality rates in cancer patient. Modulation on tumor angiogenesis and metastasis provides opportunities to halt progression of cancer. From our previous findings, Phyllanthus plant possesses antiproliferative effects on melanoma and prostate cancer cell lines and induction of apoptosis. The main aims of the present work were further investigated on the antimetastatic and antiangiogenic effects on cancer cells (MeWo and PC-3) and human umbilical vein endothelial cells (HUVECs) of 4 Phyllanthus species (P.amarus, P.niruri, P.urinaria and P.watsonii). Phyllanthus extracts significantly inhibited cell adhesion, migration, invasion, and transendothelial migration activities of cancer (MeWo and PC-3) cells in a dose-dependent manner (P < 0.05) by cell-matrix adhesion, Transwell migration, invasion, and transendothelial migration assays. Phyllanthus extracts were exhibited low cytotoxicity on HUVECs up to a concentration of 500.0 μg/ml by MTS reduction assay. Phyllanthus extracts also exhibited antiangiogenic effects through inhibition of migration, invasion, and microcapillary like-tube structure formation in HUVECs. These observations were due to alteration in activities of matrix metalloproteinase (MMP) -2, -7, -9, and -26 in treated-endothelial and cancer cells by zymographies. These findings suggest that Phyllanthus plant has the potential to inhibit tumour metastasis and angiogenesis through the suppression of MMP enzymes.
  11. Vemuri RC, Gundamaraju R, Sekaran SD, Manikam R
    Int J Med Sci, 2015;12(5):387-96.
    PMID: 26005373 DOI: 10.7150/ijms.10608
    Rosacea is a characteristic cutaneous disorder with a diverse clinical manifestations ranging from facial vascular hyper-reactivity to sebaceous gland hyperplasia. Many theories on pathophysiology of rosacea were proposed over the past decade, however the pathogenicity is poorly understood.
  12. Rasiah R, Manikam R, Chandrasekaran SK, Naghavi N, Mubarik S, Mustafa R, et al.
    Am J Transplant, 2016 05;16(5):1540-7.
    PMID: 26602367 DOI: 10.1111/ajt.13603
    Organ donation rates have continued to fall seriously short of needs worldwide, with the lowest rates recorded among developing economies. This study seeks to analyze evidence from a developing economy to explore the usefulness of social psychological theory to solve the problem. The study deployed a large survey (n = 10 412) using a convenience sampling procedure targeted at increasing the number of Malaysians registered with the Ministry of Health, Malaysia who are willing to donate organs upon death. Structural equation modeling was deployed to estimate simultaneously the relative influence of cognitive and noncognitive variables on willingness to donate deceased organs. The cognitive factors of donation perception, socioeconomic status and financial incentives, and the noncognitive factors of demography and fear showed a high statistically significant (1%) relationship with willingness to donate organs after death. While financial incentives were significant, cash rewards showed the least impact. Donation perception showed the highest impact, which shows that the development of effective pedagogic programs with simultaneous improvements to the quality of services provided by medical personnel engaged in retrieving and transplanting deceased donor organs can help raise organ donation rates.
  13. Kuck JY, Azhar AMN, Wee N, Manikam R
    World J Emerg Med, 2023;14(2):122-127.
    PMID: 36911056 DOI: 10.5847/wjem.j.1920-8642.2023.032
    BACKGROUND: To evaluate the diagnostic accuracy of clinical signs combined with the tongue blade test (TBT) to detect maxillary and mandibular fractures.

    METHODS: A cross-sectional study enrolled patients with maxillary and mandibular injuries in the emergency department. Physical examination and the TBT were performed, followed by radiological imaging (facial X-ray or computed tomography [CT]). The diagnostic accuracy was calculated for individuals and a combination of clinical findings at predicting maxillary and mandibular fractures.

    RESULTS: A total of 98 patients were identified, of whom 31.6% had maxillary fractures and 9.2% had mandibular fractures. The combination of malocclusion, tenderness on palpation and swelling with positive TBT had 100% specificity to detect maxillary and mandibular fractures. In the absence of malocclusion, the combination of tenderness on palpation and swelling with positive TBT produced a specificity of 97.8% for maxillary fracture and a specificity of 96.2% for mandibular fracture. A clinical decision tool consisting of malocclusion, tenderness on palpation, swelling and TBT revealed a specificity of 100% and a positive predictive value of 100%.

    CONCLUSION: The clinical decision tool is potentially useful to rule out mandibular fractures, thus preventing unnecessary radiation exposure.

  14. Tang YQ, Jaganath I, Manikam R, Sekaran SD
    PMID: 23690850 DOI: 10.1155/2013/609581
    Phyllanthus is a traditional medicinal plant that has been found to have antihepatitis, antibacterial, and anticancer properties. The present studies were to investigate the in vitro molecular mechanisms of anticancer effects of Phyllanthus (P. amarus, P. niruri, P. urinaria, and P. watsonii) plant extracts in human prostate adenocarcinoma. The cancer ten-pathway reporter array was performed and revealed that the expression of six pathway reporters were significantly decreased (Wnt, NFκB, Myc/Max, hypoxia, MAPK/ERK, and MAPK/JNK) in PC-3 cells after treatment with Phyllanthus extracts. Western blot was conducted and identified several signalling molecules that were affected in the signalling pathways including pan-Ras, c-Raf, RSK, Elk1, c-Jun, JNK1/2, p38 MAPK, c-myc, DSH, β-catenin, Akt, HIF-1α, GSK3β, NFκB p50 and p52, Bcl-2, Bax, and VEGF, in treated PC-3 cells. A proteomics-based approach, 2D gel electrophoresis, was performed, and mass spectrometry (MS/MS) results revealed that there were 72 differentially expressed proteins identified in treated PC-3 cells and were involved in tumour cell adhesion, apoptosis, glycogenesis and glycolysis, metastasis, angiogenesis, and protein synthesis and energy metabolism. Overall, these findings suggest that Phyllanthus can interfere with multiple signalling cascades involved in tumorigenesis and be used as a potential therapeutic candidate for treatment of cancer.
  15. Rasiah R, Thangiah G, Yusoff K, Manikam R, Chandrasekaran SK, Mustafa R, et al.
    BMC Public Health, 2015;15:1242.
    PMID: 26673166 DOI: 10.1186/s12889-015-2577-5
    Numerous studies have shown the importance of physical activity in reducing the morbidity and mortality rates caused by cardiovascular disease (CVD). However, most of these studies emphasise little on the cumulative effect of CVD risk factors. Hence, this study investigates the association between physical exercise and cumulative CVD risk factors among adults in three different age groups.
  16. Gundamaraju R, Vemuri RC, Singla RK, Manikam R, Rao AR, Sekaran SD
    Pharmacogn Mag, 2014 Aug;10(Suppl 3):S557-62.
    PMID: 25298674 DOI: 10.4103/0973-1296.139782
    The myocardium is generally injured in the case of reperfusion injury and arterial damage is caused by hypertension. In reference to these statements, the present study was focused. Cardiac glycosides were said to have protective effects against myocardial infarction and hypertension. Strophanthus hispidus was thus incorporated in the study.
  17. Rasiah R, Yusoff K, Mohammadreza A, Manikam R, Tumin M, Chandrasekaran SK, et al.
    BMC Public Health, 2013;13:886.
    PMID: 24066906 DOI: 10.1186/1471-2458-13-886
    Cardiovascular disease (CVD) related deaths is not only the prime cause of mortality in the world, it has also continued to increase in the low and middle income countries. Hence, this study examines the relationship between CVD risk factors and socioeconomic variables in Malaysia, which is a rapidly growing middle income nation undergoing epidemiologic transition.
  18. Alhoot MA, Rathinam AK, Wang SM, Manikam R, Sekaran SD
    Int J Med Sci, 2013;10(6):719-29.
    PMID: 23630436 DOI: 10.7150/ijms.5037
    Despite the importance of DENV as a human pathogen, there is no specific treatment or protective vaccine. Successful entry into the host cells is necessary for establishing the infection. Recently, the virus entry step has become an attractive therapeutic strategy because it represents a barrier to suppress the onset of the infection. Four putative antiviral peptides were designed to target domain III of DENV-2 E protein using BioMoDroid algorithm. Two peptides showed significant inhibition of DENV when simultaneously incubated as shown by plaque formation assay, RT-qPCR, and Western blot analysis. Both DET4 and DET2 showed significant inhibition of virus entry (84.6% and 40.6% respectively) using micromolar concentrations. Furthermore, the TEM images showed that the inhibitory peptides caused structural abnormalities and alteration of the arrangement of the viral E protein, which interferes with virus binding and entry. Inhibition of DENV entry during the initial stages of infection can potentially reduce the viremia in infected humans resulting in prevention of the progression of dengue fever to the severe life-threatening infection, reduce the infected vector numbers, and thus break the transmission cycle. Moreover these peptides though designed against the conserved region in DENV-2 would have the potential to be active against all the serotypes of dengue and might be considered as Hits to begin designing and developing of more potent analogous peptides that could constitute as promising therapeutic agents for attenuating dengue infection.
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