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Fulltext Experimental Phage Therapy for Burkholderia pseudomallei Infection

Guang-Han O, Leang-Chung C, Vellasamy KM, Mariappan V, Li-Yen C, Vadivelu J

PLoS One, 2016;11(7):e0158213.
PMID: 27387381 DOI: 10.1371/journal.pone.0158213

Burkholderia pseudomallei is an intracellular Gram-negative bacterial pathogen intrinsically resistant to a variety of antibiotics. Phages have been developed for use as an alternative treatment therapy, particularly for bacterial infections that do not respond to conventional antibiotics. In this study, we investigated the use of phages to treat cells infected with B. pseudomallei. Phage C34 isolated from seawater was purified and characterised on the basis of its host range and morphology using transmission electron microscopy (TEM). Phage C34 was able to lyse 39.5% of B. pseudomallei clinical strains. Due to the presence of contractile tail, phage C34 is classified as a member of the family Myoviridae, a tailed double-stranded DNA virus. When 2 × 105 A549 cells were exposed to 2 × 107 PFU of phage C34, 24 hours prior to infection with 2 × 106 CFU of B. pseudomallei, it was found that the survivability of the cells increased to 41.6 ± 6.8% as compared to 22.8 ± 6.0% in untreated control. Additionally, application of phage successfully rescued 33.3% of mice infected with B. pseudomallei and significantly reduced the bacterial load in the spleen of the phage-treated mice. These findings indicate that phage can be a potential antimicrobial agent for B. pseudomallei infections.
Fulltext Eukaryotic pathways targeted by the type III secretion system effector protein, BipC, involved in the intracellular lifecycle of Burkholderia pseudomallei

Kang WT, Vellasamy KM, Vadivelu J

Sci Rep, 2016 09 16;6:33528.
PMID: 27634329 DOI: 10.1038/srep33528

Burkholderia pseudomallei, the etiological agent for melioidosis, is known to secrete a type III secretion system (TTSS) protein into the host's internal milieu. One of the TTSS effector protein, BipC, has been shown to play an important role in the B. pseudomallei pathogenesis. To identify the host response profile that was directly or indirectly regulated by this protein, genome-wide transcriptome approach was used to examine the gene expression profiles of infected mice. The transcriptome analysis of the liver and spleen revealed that a total of approximately 1,000 genes were transcriptionally affected by BipC. Genes involved in bacterial invasion, regulation of actin cytoskeleton, and MAPK signalling pathway were over-expressed and may be specifically regulated by BipC in vivo. These results suggest that BipC mainly targets pathways related to the cellular processes which could modulate the cellular trafficking processes. The host transcriptional response exhibited remarkable differences with and without the presence of the BipC protein. Overall, the detailed picture of this study provides new insights that BipC may have evolved to efficiently manipulate host-cell pathways which is crucial in the intracellular lifecycle of B. pseudomallei.
Fulltext Global Fecal and Plasma Metabolic Dynamics Related to Helicobacter pylori Eradication

Yap TW, Leow AH, Azmi AN, Callahan DL, Perez-Perez GI, Loke MF, et al.

Front Microbiol, 2017;8:536.
PMID: 28424674 DOI: 10.3389/fmicb.2017.00536

Background:Helicobacter pylori colonizes the gastric mucosa of more than half of the world's population. There is increasing evidence H. pylori protects against the development of obesity and childhood asthma/allergies in which the development of these diseases coincide with transient dysbiosis. However, the mechanism underlying the association of H. pylori eradication with human metabolic and immunological disorders is not well-established. In this study, we aimed to investigate the local and systemic effects of H. pylori eradication through untargeted fecal lipidomics and plasma metabolomics approaches by liquid chromatography mass spectrometry (LC-MS). Results: Our study revealed that eradication of H. pylori eradication (i.e., loss of H. pylori and/or H. pylori eradication therapy) changed many global metabolite/lipid features, with the majority being down-regulated. Our findings primarily show that H. pylori eradication affects the host energy and lipid metabolism which may eventually lead to the development of metabolic disorders. Conclusion: These predictive metabolic signatures of metabolic and immunological disorders following H. pylori eradication can provide insights into dynamic local and systemic metabolism related to H. pylori eradication in modulating human health.
Proteomics Analysis Revealed that Crosstalk between Helicobacter pylori and Streptococcus mitis May Enhance Bacterial Survival and Reduces Carcinogenesis

Khosravi Y, Loke MF, Goh KL, Vadivelu J

Front Microbiol, 2016;7:1462.
PMID: 27695448

Helicobacter pylori is the dominant species of the human gastric microbiota and is present in the stomach of more than half of the human population worldwide. Colonization by H. pylori causes persistent inflammatory response and H. pylori-induced gastritis is the strongest singular risk factor for the development of gastric adenocarcinoma. However, only a small proportion of infected individuals develop malignancy. Besides H. pylori, other microbial species have also been shown to be related to gastritis. We previously reported that interspecies microbial interaction between H. pylori and S. mitis resulted in alteration of their metabolite profiles. In this study, we followed up by analyzing the changing protein profiles of H. pylori and S. mitis by LC/Q-TOF mass spectrometry to understand the different response of the two bacterial species in a multi-species micro-environment. Differentially-expressed proteins in mono- and co-cultures could be mapped into 18 biological pathways. The number of proteins involve in RNA degradation, nucleotide excision repair, mismatch repair, and lipopolysaccharide (LPS) biosynthesis were increased in co-cultured H. pylori. On the other hand, fewer proteins involve in citrate cycle, glycolysis/ gluconeogenesis, aminoacyl-tRNA biosynthesis, translation, metabolism, and cell signaling were detected in co-cultured H. pylori. This is consistent with our previous observation that in the presence of S. mitis, H. pylori was transformed to coccoid. Interestingly, phosphoglycerate kinase (PGK), a major enzyme used in glycolysis, was found in abundance in co-cultured S. mitis and this may have enhanced the survival of S. mitis in the multi-species microenvironment. On the other hand, thioredoxin (TrxA) and other redox-regulating enzymes of H. pylori were less abundant in co-culture possibly suggesting reduced oxidative stress. Oxidative stress plays an important role in tissue damage and carcinogenesis. Using the in vitro co-culture model, this study emphasized the possibility that pathogen-microbiota interaction may have a protective effect against H. pylori-associated carcinogenesis.
A review of natural polysaccharides for drug delivery applications: Special focus on cellulose, starch and glycogen

Gopinath V, Saravanan S, Al-Maleki AR, Ramesh M, Vadivelu J

Biomed Pharmacother, 2018 Nov;107:96-108.
PMID: 30086465 DOI: 10.1016/j.biopha.2018.07.136

Natural polysaccharides are renewable with a high degree of biocompatibility, biodegradability, and ability to mimic the natural extracellular matrix (ECM) microenvironment. Comprehensive investigations of polysaccharides are essential for our fundamental understanding of exploiting its potential as bio-composite, nano-conjugate and in pharmaceutical sectors. Polysaccharides are considered to be superior to other polymers, for its ease in tailoring, bio-compatibility, bio-activity, homogeneity and bio-adhesive properties. The main focus of this review is to spotlight the new advancements and challenges concerned with surface modification, binding domains, biological interaction with the conjugate including stability, polydispersity, and biodegradability. In this review, we have limited our survey to three essential polysaccharides including cellulose, starch, and glycogen that are sourced from plants, microbes, and animals respectively are reviewed. We also present the polysaccharides which have been extensively modified with the various types of conjugates for combating last-ditch pharmaceutical challenges.
Antibacterial biocompatible arginine functionalized mono-layer graphene: No more risk of silver toxicity

Rafieerad AR, Bushroa AR, Amiri A, Kalaiselvam K, Vellasamy KM, Vadivelu J

J Hazard Mater, 2018 10 15;360:132-140.
PMID: 30099356 DOI: 10.1016/j.jhazmat.2018.07.107

Antibacterial ability is vital in biological approaches as well as functional biomaterials. Besides, cytocompatibility aspect of biologic media, tissue and organs is always concern for appropriate synthesis. From the past, metallic/oxide phases of silver (Ag) material in various macro, micro or nano configurations have been widely used for antibacterial targets. While, background of Ag toxicity within particle, film and composites is posing gradual ion release affected by molecular bounding. Recent researches conducted to control, optimize and neutralize Ag limitations finding the benefits of ideal (∼ 100%) mediation against both Gram-negative and Gram-positive bacteria. Whereas, non-degradable releases history is still a challenge and its longer accumulation may cause to disrupt biostructures and disease risk. Thus, facile development of large-area organic materials with switchable bacteria toxicity and normal cell compatibility function is interesting for concerned approaches. Here, smart positively-charged stable arginine amino acid incorporated mono layer graphene (Arg-EMGr) nanobiocomposite introduced as useful antibacterial and safe bactericidal agent competitive with Ag direct. The immunity characteristic versus Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) comparably assessed with graphene oxide (GO) and different concentrations GO-AgNPs morphology. As cell viability matter, 1,3,5,7-days vitro culture assay shown attachment proliferation and cytotoxicity due to short interaction.
Fulltext Relapse of chronic melioidosis in a paediatric cystic fibrosis patient: first case report from Malaysia

Mariappan V, Thavagnanam S, Vellasamy KM, Teh CJS, Atiya N, Ponnampalavanar S, et al.

BMC Infect Dis, 2018 Sep 05;18(1):455.
PMID: 30185168 DOI: 10.1186/s12879-018-3371-7

BACKGROUND: Burkholderia pseudomallei is the causative agent of melioidosis, which is a potentially life threatening disease endemic in Southeast Asian countries. In Malaysia, cystic fibrosis (CF) is an uncommon condition. The association between CF and B.pseudomallei infections has been reported previously. However, this is the first case report of a pediatric melioidosis relapse and co-infection with other Gram-negative bacteria in Malaysia.
CASE PRESENTATION: A 14-year-old Chinese Malaysian boy presented with a history of recurrent pneumonia, poor growth and steatorrhoea since childhood, and was diagnosed with CF. B. pseudomallei was cultured from his sputum during three different admissions between 2013 and 2016. However, the patient succumbed to end stage of respiratory failure in 2017 despite antibiotics treatment against B.pseudomallei. The isolates were compared using multilocus-sequence typing and repetitive-element polymerase chain reaction (PCR), and confirmed that two of the isolates were of same sequence type, which may indicate relapse.
CONCLUSIONS: CF patients should be aware of melioidosis in endemic regions, as it is an emerging infectious disease, especially when persistent or recurrent respiratory symptoms and signs of infection occur. The high prevalence rates of melioidosis in Malaysia warrants better management options to improve quality of life, and life expectancy in patients with CF. Travel activities to endemic regions should also be given more consideration, as this would be crucial to identify and initiate appropriate empiric treatment.
Polymorphisms in the host CYP2C19 gene and antibiotic-resistance attributes of Helicobacter pylori isolates influence the outcome of triple therapy

Ram M R, Teh X, Rajakumar T, Goh KL, Leow AHR, Poh BH, et al.

J Antimicrob Chemother, 2019 01 01;74(1):11-16.
PMID: 30403784 DOI: 10.1093/jac/dky401

Objectives: Eradication of Helicobacter pylori is influenced by susceptibility to antimicrobial agents, elevated bacterial load and degree of acid inhibition, which can be affected by genotypes of drug-metabolizing enzymes [cytochrome P450 (CYP) 2C19 polymorphism]. Theoretically, the choice and dose of proton pump inhibitor may also influence the suppression of H. pylori infection. The CYP2C19 genotype has recently been found to have an impact on peptic ulcer healing, H. pylori eradication and therapeutic efficacy of proton pump inhibitors.
Methods: Here, we investigated the impact of the CYP2C19 genotype polymorphism and the success of triple therapy (fluoroquinolones/metronidazole/clarithromycin) on antibiotic-resistant strains in eradicating H. pylori in human subjects with non-ulcer dyspepsia (NUD), in human subjects with peptic ulcer disease (PUD) and in asymptomatic human subjects (positive and negative for H. pylori infection).
Results: Based on the CYP2C19 genotypes, determined by Droplet Digital PCR (ddPCR) analysis, we found 11.2%, 62.5% and 26.3% corresponding to rapid metabolizers, intermediate metabolizers and poor metabolizers, respectively. However, we did not find any significant effect for homozygous ABCB1 or CYP2C19*2 and CYP2C19*3 alleles. We detected several participants heterozygous for both ABCB1 and CYP2C19*2, CYP2C19*3 and CYP2C19*17 loci. The participants heterozygous for both ABCB1 and CYP2C19*2 and *3 loci should be defined as intermediate and poor metabolizers according to the haplotype analysis in the NUD, PUD and asymptomatic subjects.
Conclusions: Consequently, fluoroquinolones/metronidazole/clarithromycin-based triple therapies can be used to eradicate H. pylori infection, if one does not know the CYP2C19 genotype of the patient.
Fulltext Prevalence and association of pks+ Escherichia coli with colorectal cancer in patients at the University Malaya Medical Centre, Malaysia

Iyadorai T, Mariappan V, Vellasamy KM, Wanyiri JW, Roslani AC, Lee GK, et al.

PLoS One, 2020;15(1):e0228217.
PMID: 31990962 DOI: 10.1371/journal.pone.0228217

Escherichia coli (E. coli) from the B2 phylogenetic group is implicated in colorectal cancer (CRC) as it possesses a genomic island, termed polyketide synthetase (pks), which codes for the synthesis of colibactin, a genotoxin that induces DNA damage, cell cycle arrest, mutations and chromosomal instability in eukaryotic cells. The aim of this study was to detect and compare the prevalence of E. coli expressing pks (pks+ E. coli) in CRC patients and healthy controls followed by investigating the virulence triggered by pks+ E. coli using an in-vitro model. Mucosal colon tissues were collected and processed to determine the presence of pks+ E. coli. Thereafter, primary colon epithelial (PCE) and colorectal carcinoma (HCT116) cell lines were used to detect cytopathic response to the isolated pks+ E. coli strains. Our results showed 16.7% and 4.3% of CRC and healthy controls, respectively were pks+ E. coli. Further, PCE displayed syncytia and cell swelling and HCT116 cells, megalocytosis, in response to treatment with the isolated pks+ E. coli strains. In conclusion, pks+ E. coli was more often isolated from tissue of CRC patients compared to healthy individuals, and our in-vitro assays suggest these isolated strains may be involved in the initiation and development of CRC.
Fulltext A Malaysian version of learning space preferences: a validation study

Sim JH, Foong CC, Pallath V, Hong WH, Vadivelu J

Int J Med Educ, 2021 May 27;12:86-93.
PMID: 34049286 DOI: 10.5116/ijme.6082.7c41

Objectives: This study aimed to validate a Malaysian version of a revised learning space questionnaire, as well as to test the utility of the revised questionnaire as a tool to investigate learning space preferences in a Malaysian medical school.
Methods: This is a cross-sectional survey. A convenient sample of 310 preclinical students of a public medical school in Malaysia were invited to participate. Validation data were collected using a revised 40-item, 5-point Likert scale learning space questionnaire. The questionnaires were administered online via a student e-learning platform. Data analysis was conducted using IBM SPSS version 24. Exploratory factor analysis was conducted to examine the factor structure of the revised questionnaire to provide evidence for construct validity. To assess the internal consistency of the revised questionnaire, Cronbach's alpha coefficients (α) were computed across all the items as well as for items within each of the factor.
Results: A total of 223 (71.94%) preclinical students completed and returned the questionnaire. In the final analysis, exploratory factor analysis with principal axis factoring and an oblimin rotation identified a six-factor, 20-item factor solution. Reliability analysis reported good internal consistency for the revised questionnaire, with an overall Cronbach's alpha of 0.845, and Cronbach's alpha ranging from 0.800 to 0.925 for the six factors.
Conclusions: This study established evidence for the construct validity and internal consistency of the revised questionnaire. The revised questionnaire appears to have utility as an instrument to investigate learning space preferences in Malaysian medical schools.
Fulltext Functional characterizations of effector protein BipC, a type III secretion system protein, in Burkholderia pseudomallei pathogenesis

Kang WT, Vellasamy KM, Chua EG, Vadivelu J

J Infect Dis, 2015 Mar 1;211(5):827-34.
PMID: 25165162 DOI: 10.1093/infdis/jiu492

OBJECTIVES: The bsa locus of Burkholderia pseudomallei encodes several proteins that are components of the type III secretion system (TTSS). BipC was postulated as one of the TTSS-3 effector proteins, but its role in the pathogenesis of B. pseudomallei infection is not well understood. Thus, the aim of this study was to determine its role(s) in the virulence of B. pseudomallei pathogenesis.
METHODS: A bipC TTSS-3-deficient strain of B. pseudomallei and complemented strains were generated to assess the role of BipC as a type III translocation apparatus. Human cell lines and a mouse model of melioidosis were used for in vitro and in vivo assays, respectively.
RESULTS: A significant 2-fold reduction was demonstrated in the percentage of adherence, invasion, intracellular survival, and phagosomal escape of the bipC mutant. Interestingly, microscopic studies have shown that BipC was capable of delayed B. pseudomallei actin-based motility. The virulence of the mutant strain in a murine model of melioidosis demonstrated that the bipC mutant was less virulent, compared with the wild type.
CONCLUSION: The results suggested that BipC possesses virulence determinants that play significant roles in host cell invasion and immune evasion.
KEYWORDS: BipC; Burkholderia pseudomallei; host cell invasion; type III secretion system; type III translocation apparatus; virulence
Other Helicobacters, gastric and gut microbiota

Péré-Védrenne C, Flahou B, Loke MF, Ménard A, Vadivelu J

Helicobacter, 2017 Sep;22 Suppl 1.
PMID: 28891140 DOI: 10.1111/hel.12407

The current article is a review of the most important and relevant literature published in 2016 and early 2017 on non-Helicobacter pylori Helicobacter infections in humans and animals, as well as interactions between H. pylori and the microbiota of the stomach and other organs. Some putative new Helicobacter species were identified in sea otters, wild boars, dogs, and mice. Many cases of Helicobacter fennelliae and Helicobacter cinaedi infection have been reported in humans, mostly in immunocompromised patients. Mouse models have been used frequently as a model to investigate human Helicobacter infection, although some studies have investigated the pathogenesis of Helicobacters in their natural host, as was the case for Helicobacter suis infection in pigs. Our understanding of both the gastric and gut microbiome has made progress and, in addition, interactions between H. pylori and the microbiome were demonstrated to go beyond the stomach. Some new approaches of preventing Helicobacter infection or its related pathologies were investigated and, in this respect, the probiotic properties of Saccharomyces, Lactobacillus and Bifidobacterium spp. were confirmed.
Fulltext Host-Adaptation of Burkholderia pseudomallei Alters Metabolism and Virulence: a Global Proteome Analysis

Mariappan V, Vellasamy KM, Vadivelu J

Sci Rep, 2017 08 21;7(1):9015.
PMID: 28827633 DOI: 10.1038/s41598-017-09373-0

Little is known about the evolution, adaptation and pathogenesis of Burkholderia pseudomallei within host during acute melioidosis infection. Melioidosis is a potential life threatening disease contracted through inhalation, ingestion, inoculation or direct entry of the organism into the blood stream via wounds or skin abrasions from contaminated soil and water. Environmental B. pseudomallei strain (Bp MARAN ), isolated during a melioidosis outbreak in Pahang, Malaysia was injected intra-peritoneally into a mouse and passaged strain was recovered from spleen (Bpmouse-adapted). A gel-based comparative proteomics profiling approach was used, to map and identify differentially expressed proteins (fold-change ≥ 2; p-value ≤ 0.05) between the strains. A total of 730 and 685 spots were visualised in the Bp MARAN and Bpmouse-adapted strains, respectively. Of the 730 spots (Bp MARAN as reference gel), 87 spots were differentially regulated (44 up- and 43 down-regulated). The identified proteins were classified as proteins related to metabolism, stress response, virulence, signal transduction, or adhesion. In comparison, it was found that those proteins related to adhesins, virulence factors and stress- response were up-regulated and could possibly explain the adaptation of the bacteria in the host. Investigating the differentially expressed proteins may provide better perspective of bacterial factors which aid survivability of B. pseudomallei in host.
Helicobacter pylori outer inflammatory protein A (OipA) suppresses apoptosis of AGS gastric cells in vitro

Al-Maleki AR, Loke MF, Lui SY, Ramli NSK, Khosravi Y, Ng CG, et al.

Cell. Microbiol., 2017 12;19(12).
PMID: 28776327 DOI: 10.1111/cmi.12771

Outer inflammatory protein A (OipA) is an important virulence factor associated with gastric cancer and ulcer development; however, the results have not been well established and turned out to be controversial. This study aims to elucidate the role of OipA in Helicobacter pylori infection using clinical strains harbouring oipA "on" and "off" motifs. Proteomics analysis was performed on AGS cell pre-infection and postinfection with H. pylori oipA "on" and "off" strains, using liquid chromatography/mass spectrometry. AGS apoptosis and cell cycle assays were performed. Moreover, expression of vacuolating cytotoxin A (VacA) was screened using Western blotting. AGS proteins that have been suggested previously to play a role or associated with gastric disease were down-regulated postinfection with oipA "off" strains comparing to oipA "on" strains. Furthermore, oipA "off" and ΔoipA cause higher level of AGS cells apoptosis and G0/G1 cell-cycle arrest than oipA "on" strains. Interestingly, deletion of oipA increased bacterial VacA production. The capability of H. pylori to induce apoptosis and suppress expression of proteins having roles in human disease in the absence of oipA suggests that strains not expressing OipA may be less virulent or may even be protective against carcinogenesis compared those expressing OipA. This potentially explains the higher incidence of gastric cancer in East Asia where oipA "on" strains predominates.
Adhesion and invasion attributes of Burkholderia pseudomallei are dependent on airway surface liquid and glucose concentrations in lung epithelial cells

Mariappan V, Thimma J, Vellasamy KM, Shankar EM, Vadivelu J

Environ Microbiol Rep, 2018 04;10(2):217-225.
PMID: 29393577 DOI: 10.1111/1758-2229.12624

Physiological constituents in airway surface liquids (ASL) appear to impact the adherence and invasion potentials of Burkholderia pseudomallei contributing to recrudescent melioidosis. Here, we investigated the factors present in ASL that is likely to influence bacterial adhesion and invasion leading to improved understanding of bacterial pathogenesis. Six B. pseudomallei clinical isolates from different origins were used to investigate the ability of the bacteria to adhere and invade A549 human lung epithelial cells using a system that mimics the physiological ASL with different pH, NaCl, KCl, CaCl2 and glucose concentrations. These parameters resulted in markedly differential adherence and invasion abilities of B. pseudomallei to the lung epithelial cells. The concentration of 20 mM glucose dramatically increased adherence and invasion by increasing the rate of pili formation in depiliated bacteria. Glucose significantly increased adherence and invasion of B. pseudomallei to A549 cells, and presence of NaCl, KCl and CaCl2 markedly ablated the effect despite the presence of glucose. Our data established a link between glucose, enhanced adhesion and invasion potentials of B. pseudomallei, hinting increased susceptibility of individuals with diabetes mellitus to clinical melioidosis.
Naturally Occurring Phytochemicals to Target Breast Cancer Cell Signaling

Barathan M, Vellasamy KM, Mariappan V, Venkatraman G, Vadivelu J

Appl Biochem Biotechnol, 2023 Sep 29.
PMID: 37773580 DOI: 10.1007/s12010-023-04734-0

Almost 70% of clinically used antineoplastic drugs are originated from natural products such as plants, marine organism, and microorganisms and some of them are also structurally modified natural products. The naturally occurring drugs may specifically act as inducers of selective cytotoxicity, anti-metastatic, anti-mutagenic, anti-angiogenesis, antioxidant accelerators, apoptosis inducers, autophagy inducers, and cell cycle inhibitors in cancer therapy. Precisely, several reports have demonstrated the involvement of naturally occurring anti-breast cancer drugs in regulating the expression of oncogenic and tumor suppressors associated with carcinogen metabolism and signaling pathways. Anticancer therapies based on nanotechnology have the potential to improve patient outcomes through targeted therapy, improved drug delivery, and combination therapies. This paper has reviewed the current treatment for breast cancer and the potential disadvantages of those therapies, besides the various mechanism used by naturally occurring phytochemicals to induce apoptosis in different types of breast cancer. Along with this, the contribution of nanotechnology in improving the effectiveness of anticancer drugs was also reviewed. With the development of sciences and technologies, phytochemicals derived from natural products are continuously discovered; however, the search for novel natural products as chemoprevention drugs is still ongoing, especially for the advanced stage of breast cancer. Continued research and development in this field hold great promise for advancing cancer care and improving patient outcomes.
Polymorphism of virulence genes and biofilm associated with in vitro induced resistance to clarithromycin in Helicobacter pylori

Rosli NA, Al-Maleki AR, Loke MF, Chua EG, Alhoot MA, Vadivelu J

Gut Pathog, 2023 Oct 28;15(1):52.
PMID: 37898785 DOI: 10.1186/s13099-023-00579-4

BACKGROUND: Clarithromycin-containing triple therapy is commonly used to treat Helicobacter pylori infections. Clarithromycin resistance is the leading cause of H. pylori treatment failure. Understanding the specific mutations that occur in H. pylori strains that have evolved antibiotic resistance can help create a more effective and individualised antibiotic treatment plan. However, little is understood about the genetic reprogramming linked to clarithromycin exposure and the emergence of antibiotic resistance in H. pylori. Therefore, this study aims to identify compensatory mutations and biofilm formation associated with the development of clarithromycin resistance in H. pylori. Clarithromycin-sensitive H. pylori clinical isolates were induced to develop clarithromycin resistance through in vitro exposure to incrementally increasing concentration of the antibiotic. The genomes of the origin sensitive isolates (S), isogenic breakpoint (B), and resistant isolates (R) were sequenced. Single nucleotide variations (SNVs), and insertions or deletions (InDels) associated with the development of clarithromycin resistance were identified. Growth and biofilm production were also assessed.
RESULTS: The S isolates with A2143G mutation in the 23S rRNA gene were successfully induced to be resistant. According to the data, antibiotic exposure may alter the expression of certain genes, including those that code for the Cag4/Cag protein, the vacuolating cytotoxin domain-containing protein, the sel1 repeat family protein, and the rsmh gene, which may increase the risk of developing and enhances virulence in H. pylori. Enhanced biofilm formation was detected among R isolates compared to B and S isolates. Furthermore, high polymorphism was also detected among the genes associated with biofilm production.
CONCLUSIONS: Therefore, this study suggests that H. pylori may acquire virulence factors while also developing antibiotic resistance due to clarithromycin exposure.
Fulltext A qualitative study on self-regulated learning among high performing medical students

Foong CC, Bashir Ghouse NL, Lye AJ, Khairul Anhar Holder NA, Pallath V, Hong WH, et al.

BMC Med Educ, 2021 Jun 05;21(1):320.
PMID: 34090439 DOI: 10.1186/s12909-021-02712-w

BACKGROUND: Self-regulated learning (SRL) is an important contributing element to the academic success of students. Literature suggests that the understanding of SRL among medical students is obscure as there is still some uncertainty about whether high performing medical students use SRL. This study explored the characteristics of high performing medical students from the SRL perspective to gain a better understanding of the application of SRL for effective learning.
METHODS: Twenty-one students who scored at the 90th percentile in written knowledge-based assessment consented to participate in this study. Each student wrote a guided reflective journal and subsequently attended a semi-structured interview. Students were prompted to explain the rationales for their answers. The data were then analysed using thematic analysis to identify patterns among these students from the SRL perspective. Two coders analysed the data independently and discussed the codes to reach a consensus.
RESULTS: High performing students set goals, made plans, and motivated themselves to achieve the goals. They put consistent efforts into their studies and applied effective learning strategies. They also employed coping mechanisms to deal with challenges. High performing students regularly evaluated their performance and adopted new strategies.
CONCLUSIONS: This study reported that high performing students applied SRL and described the rationales of practice. Medical schools could design SRL-driven interventions to enhance the learning experiences of medical students. Recommendations are made for students on how to apply SRL.
Fulltext Antisecretory, gastroprotective, antioxidant and anti-Helicobcter pylori activity of zerumbone from Zingiber zerumbet (L.) Smith

Sidahmed HM, Hashim NM, Abdulla MA, Ali HM, Mohan S, Abdelwahab SI, et al.

PLoS One, 2015;10(3):e0121060.
PMID: 25798602 DOI: 10.1371/journal.pone.0121060

BACKGROUND: Zingiber zerumbet Smith is a perennial herb, broadly distributed in many tropical areas. In Malaysia, it's locally known among the Malay people as "lempoyang" and its rhizomes, particularly, is widely used in traditional medicine for the treatment of peptic ulcer disease beyond other gastric disorders.
AIM OF THE STUDY: The aim of the current study is to evaluate the gastroprotective effect of zerumbone, the main bioactive compound of Zingiber zerumbet rhizome, against ethanol-induced gastric ulcer model in rats.
MATERIALS AND METHODS: Rats were pre-treated with zerumbone and subsequently exposed to acute gastric ulcer induced by absolute ethanol administration. Following treatment, gastric juice acidity, ulcer index, mucus content, histological analysis (HE and PAS), immunohistochemical localization for HSP-70, prostaglandin E2 synthesis (PGE2), non-protein sulfhydryl gastric content (NP-SH), reduced glutathione level (GSH), and malondialdehyde level (MDA) were evaluated in ethanol-induced ulcer in vivo. Ferric reducing antioxidant power assay (FRAP) and anti-H. pylori activity were investigated in vitro.
RESULTS: The results showed that the intragastric administration of zerumbone protected the gastric mucosa from the aggressive effect of ethanol-induced gastric ulcer, coincided with reduced submucosal edema and leukocyte infiltration. This observed gastroprotective effect of zerumbone was accompanied with a significant (p <0.05) effect of the compound to restore the lowered NP-SH and GSH levels, and to reduce the elevated MDA level into the gastric homogenate. Moreover, the compound induced HSP-70 up-regulation into the gastric tissue. Furthermore, zerumbone significantly (p <0.05) enhanced mucus production, showed intense PAS stain and maintained PG content near to the normal level. The compound exhibited antisecretory activity and an interesting minimum inhibitory concentration (MIC) against H. pylori strain.
CONCLUSION: The results of the present study revealed that zerumbone promotes ulcer protection, which might be attributed to the maintenance of mucus integrity, antioxidant activity, and HSP-70 induction. Zerumbone also exhibited antibacterial action against H. pylori.
Fulltext Altered Proteome of Burkholderia pseudomallei Colony Variants Induced by Exposure to Human Lung Epithelial Cells

Al-Maleki AR, Mariappan V, Vellasamy KM, Tay ST, Vadivelu J

PLoS One, 2015;10(5):e0127398.
PMID: 25996927 DOI: 10.1371/journal.pone.0127398

Burkholderia pseudomallei primary diagnostic cultures demonstrate colony morphology variation associated with expression of virulence and adaptation proteins. This study aims to examine the ability of B. pseudomallei colony variants (wild type [WT] and small colony variant [SCV]) to survive and replicate intracellularly in A549 cells and to identify the alterations in the protein expression of these variants, post-exposure to the A549 cells. Intracellular survival and cytotoxicity assays were performed followed by proteomics analysis using two-dimensional gel electrophoresis. B. pseudomallei SCV survive longer than the WT. During post-exposure, among 259 and 260 protein spots of SCV and WT, respectively, 19 were differentially expressed. Among SCV post-exposure up-regulated proteins, glyceraldehyde 3-phosphate dehydrogenase, fructose-bisphosphate aldolase (CbbA) and betaine aldehyde dehydrogenase were associated with adhesion and virulence. Among the down-regulated proteins, enolase (Eno) is implicated in adhesion and virulence. Additionally, post-exposure expression profiles of both variants were compared with pre-exposure. In WT pre- vs post-exposure, 36 proteins were differentially expressed. Of the up-regulated proteins, translocator protein, Eno, nucleoside diphosphate kinase (Ndk), ferritin Dps-family DNA binding protein and peptidyl-prolyl cis-trans isomerase B were implicated in invasion and virulence. In SCV pre- vs post-exposure, 27 proteins were differentially expressed. Among the up-regulated proteins, flagellin, Eno, CbbA, Ndk and phenylacetate-coenzyme A ligase have similarly been implicated in adhesion, invasion. Protein profiles differences post-exposure provide insights into association between morphotypic and phenotypic characteristics of colony variants, strengthening the role of B. pseudomallei morphotypes in pathogenesis of melioidosis.

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