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Differential responses of lineages-committed hematopoietic progenitors and altered expression of self-renewal and differentiation-related genes in 1,4-benzoquinone (1,4-BQ) exposure

Chow PW, Rajab NF, Chua KH, Chan KM, Abd Hamid Z

Toxicol In Vitro, 2018 Feb;46:122-128.
PMID: 28986286 DOI: 10.1016/j.tiv.2017.10.001

Despite of reports on hematotoxic and leukemogenic evidences related to benzene exposure, the mechanism of benzene toxicity affecting the hematopoietic stem and progenitor cells (HSPCs) fate remains unclear. This study aims to elucidate the benzene's effect on the lineages-committed progenitors and genes-regulating self-renewal and differentiation of HSPCs. Isolated mouse bone marrow (BM) cells were exposed to the benzene metabolite, 1,4-benzoquinone (1,4-BQ) at 1.25, 2.5, and 5μM for 24h. The clonogenic potency of erythroid, myeloid, and Pre-B lymphoid progenitors was evaluated through colony-forming-cell assay. Quantitative real time-PCR was used to analyze the self-renewal (Bmi-1, HoxB4, and Wnt3) and differentiation (GATA1, GATA2, and GATA3)-related genes' expression levels. 1,4-BQ exposure significantly lowered the clonogenicity of the myeloid progenitor at 1.25 and 2.5μM (p<0.05), but affected neither the erythroid nor Pre-B lymphoid progenitors. Furthermore, significant upregulation of HoxB4 expression level was observed at all concentrations. GATA3 and Bmi-1 expressions were also significant upregulated at 2.5 and 5μM 1,4-BQ, respectively. In conclusion, 1,4-BQ could modulate the fate of HSPCs by altering the self-renewal and differentiation related genes. The definite role of lineages specificity and responsive genes in governing the hematotoxicity and leukemogenicity of 1,4-BQ should be further investigated.
Neuroimaging Functional Magnetic Resonance Imaging Task-Based Dorsolateral Prefrontal Cortex Activation Following 12 Weeks of Cosmos caudatus Supplementation Among Older Adults With Mild Cognitive Impairment

You YX, Shahar S, Mohamad M, Rajab NF, Haron H, Che Din N, et al.

J Magn Reson Imaging, 2021 12;54(6):1804-1818.
PMID: 34080265 DOI: 10.1002/jmri.27762

BACKGROUND: Cosmos caudatus (CC) is traditional Asian vegetable, commonly consumed among the Southeast Asian population. It has been reported to be high in flavonoids and might potentially improve brain activity among older adults with mild cognitive impairment (MCI). The effect of CC in brain activation improvement using neuroimaging is yet to be discovered.
PURPOSE: To investigate the effects of CC supplement on brain activity using functional magnetic resonance imaging (fMRI) among older adults with MCI.
STUDY TYPE: Prospective, randomized, double-blind, placebo-controlled trial.
POPULATION/SUBJECTS: Twenty older adults with mild cognitive impairment (60-75 years old), 14 of them (70%) were female subjects.
FIELD STRENGTH/SEQUENCE: A 3.0-T, T1-weighted anatomical images, T2*-weighted imaging data, A single shot, gradient echo-echo planar imaging (EPI) sequence.
ASSESSMENT: All subjects were asked to consume two 500 mg capsules of either CC supplement or placebo (maltodextrin) daily for 12 weeks. Cognitive function was measured using validated neuropsychological tests (i.e. Mini-mental State Examination and Digit Span) and task-based fMRI (N-back and Stroop Color Word Test) at baseline and 12th week. Brodmann's area 9, 46 and anterior cingulate cortex were selected as the regions of interest to define dorsolateral prefrontal cortex (DLPFC) in fMRI analysis.
STATISTICAL TESTS: Normality test was performed with the Shapiro-Wilk test. Two-way repeated ANOVA determined the intervention effects of the CC supplementation on brain activity after adjustments for covariates. Significance level at P
Fulltext Is There Any Relationship Between Biochemical Indices and Anthropometric Measurements With Dorsolateral Prefrontal Cortex Activation Among Older Adults With Mild Cognitive Impairment?

You YX, Shahar S, Mohamad M, Rajab NF, Che Din N, Lau HJ, et al.

Front Hum Neurosci, 2021;15:765451.
PMID: 35046782 DOI: 10.3389/fnhum.2021.765451

Working memory is developed in one region of the brain called the dorsolateral prefrontal cortex (DLPFC). The dysfunction of this region leads to synaptic neuroplasticity impairment. It has been reported that several biochemical parameters and anthropometric measurements play a vital role in cognition and brain health. This study aimed to investigate the relationships between cognitive function, serum biochemical profile, and anthropometric measurements using DLPFC activation. A cross-sectional study was conducted among 35 older adults (≥60 years) who experienced mild cognitive impairment (MCI). For this purpose, we distributed a comprehensive interview-based questionnaire for collecting sociodemographic information from the participants and conducting cognitive tests. Anthropometric values were measured, and fasting blood specimens were collected. We investigated their brain activation using the task-based functional MRI (fMRI; N-back), specifically in the DLPFC region. Positive relationships were observed between brain-derived neurotrophic factor (BDNF) (β = 0.494, p < 0.01) and Mini-Mental State Examination (MMSE) (β = 0.698, p < 0.01); however, negative relationships were observed between serum triglyceride (β = -0.402, p < 0.05) and serum malondialdehyde (MDA) (β = -0.326, p < 0.05) with right DLPFC activation (R 2 = 0.512) while the participants performed 1-back task after adjustments for age, gender, and years of education. In conclusion, higher serum triglycerides, higher oxidative stress, and lower neurotrophic factor were associated with lower right DLPFC activation among older adults with MCI. A further investigation needs to be carried out to understand the causal-effect mechanisms of the significant parameters and the DLPFC activation so that better intervention strategies can be developed for reducing the risk of irreversible neurodegenerative diseases among older adults with MCI.
Cell death induced by hydroxyapatite on L929 fibroblast cells

Inayat-Hussain SH, Rajab NF, Roslie H, Hussin AA, Ali AM, Annuar BO

Med J Malaysia, 2004 May;59 Suppl B:176-7.
PMID: 15468875

Biomaterials intended for end-use application as bone-graft substitutes have to undergo safety evaluation. In this study, we investigated the in vitro cytotoxic effects especially to determine the mode of death of two hydroxyapatite compounds (HA2, HA3) which were synthesized locally. The methods used for cytotoxicity was the standard MTT assay whereas AO/PI staining was performed to determine the mode of cell death in HA treated L929 fibroblasts. Our results demonstrated that both HA2 and HA3 were not significantly cytotoxic as more than 75% cells after 72 hours treatment were viable. Furthermore, we found that the major mode of cell death in HA treated cells was apoptosis. In conclusion, our results demonstrated that these hydroxyapatite compounds are not cytotoxic where the mode of death was primarily via apoptosis.
Fulltext Polygonumins A, a newly isolated compound from the stem of Polygonum minus Huds with potential medicinal activities

Ahmad R, Sahidin I, Taher M, Low C, Noor NM, Sillapachaiyaporn C, et al.

Sci Rep, 2018 03 09;8(1):4202.
PMID: 29523802 DOI: 10.1038/s41598-018-22485-5

Polygonumins A, a new compound, was isolated from the stem of Polygonum minus. Based on NMR results, the compound's structure is identical to that of vanicoside A, comprising four phenylpropanoid ester units and a sucrose unit. The structure differences were located at C-3″″'. The cytotoxic activity of polygonumins A was evaluated on several cancer cell lines by a cell viability assay using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The compound showed the highest antiproliferative (p
Fulltext Antiproliferative Activities of Acetone Extract From Canarium Odontophyllum (Dabai) Stem Bark Against Human Colorectal Cancer Cells

Ishak SF, Rajab NF, Basri DF

Dose Response, 2023;21(2):15593258221098980.
PMID: 37077718 DOI: 10.1177/15593258221098980

Colorectal cancer is the most common malignant cancer in developing countries. Canarium odontophyllum, also known as "Dabai" or "Borneo Olive" is among the natural plants that can potentially be used as an anticancer agent. This study aims to determine the antiproliferative activities and cytotoxicity effects of acetone extract from C. odontophyllum stem bark against human colorectal cancer cell lines HCT 116 and HT 29. Acetone extract of C. odontophyllum stem bark exerted a significant cytotoxic effect on HCT 116 and HT 29 cells determined by MTT assay at the concentration of 12.5 μg/mL to 200 μg/mL for 24, 48, and 72 hours treatment. It was found that acetone extract of C. odontophyllum stem bark inhibited proliferation of HCT 116 with an IC50 value of 184.93 ± .0 μg/mL, 61.24 ± .1 μg/mL, 79.98 ± .029 for 24, 48 and 72 hours respectively. The findings also showed that acetone extract of C. odontophyllum stem bark revealed a lower inhibitory effect against HT-29 with an IC50 value of more than 200 μg/mL for 24, 48 and 72 hours. However, acetone extract of C. odontophyllum stem bark at similar concentrations and time points did not show any cytotoxic effect to normal colorectal fibroblast cell CCD18-Co. In conclusion, the acetone extract of C. odontophyllum stem bark exhibited more sensitivity against HCT 116 than HT 29. Its antiproliferative ability towards HCT 116 and HT 29 cells provides insight that this extract may serve as an anticancer agent against colorectal cancer.
Fulltext Impact of diabetes mellitus on osteoarthritis: a scoping review on biomarkers

Seow SR, Mat S, Ahmad Azam A, Rajab NF, Safinar Ismail I, Singh DKA, et al.

Expert Rev Mol Med, 2024 Apr 12;26:e8.
PMID: 38606593 DOI: 10.1017/erm.2024.7

Osteoarthritis (OA) commonly affects the knee and hip joints and accounts for 19.3% of disability-adjusted life years and years lived with disability worldwide (Refs , ). Early management is important in order to avoid disability uphold quality of life (Ref. ). However, a lack of awareness of subclinical and early symptomatic stages of OA often hampers early management (Ref. ). Moreover, late diagnosis of OA among those with severe disease, at a stage when OA management becomes more complicated is common (Refs , , , ). Established risk factors for the development and progression of OA include increasing age, female, history of trauma and obesity (Ref. ). Recent studies have also drawn a link between OA and metabolic syndrome, which is characterized by insulin resistance, dyslipidaemia and hypertension (Refs , ).
Fulltext Bone Marrow Oxidative Stress and Acquired Lineage-Specific Genotoxicity in Hematopoietic Stem/Progenitor Cells Exposed to 1,4-Benzoquinone

Mathialagan RD, Abd Hamid Z, Ng QM, Rajab NF, Shuib S, Binti Abdul Razak SR

Int J Environ Res Public Health, 2020 08 13;17(16).
PMID: 32823552 DOI: 10.3390/ijerph17165865

Hematopoietic stem/progenitor cells (HSPCs) are susceptible to benzene-induced genotoxicity. However, little is known about the mechanism of DNA damage response affecting lineage-committed progenitors for myeloid, erythroid, and lymphoid. Here, we investigated the genotoxicity of a benzene metabolite, 1,4-benzoquinone (1,4-BQ), in HSPCs using oxidative stress and lineage-directed approaches. Mouse bone marrow cells (BMCs) were exposed to 1,4-BQ (1.25-12 μM) for 24 h, followed by oxidative stress and genotoxicity assessments. Then, the genotoxicity of 1,4-BQ in lineage-committed progenitors was evaluated using colony forming cell assay following 7-14 days of culture. 1,4-BQ exposure causes significant decreases (p < 0.05) in glutathione level and superoxide dismutase activity, along with significant increases (p < 0.05) in levels of malondialdehyde and protein carbonyls. 1,4-BQ exposure induces DNA damage in BMCs by significantly (p < 0.05) increased percentages of DNA in tail at 7 and 12 μM and tail moment at 12 μM. We found crucial differences in genotoxic susceptibility based on percentages of DNA in tail between lineage-committed progenitors. Myeloid and pre-B lymphoid progenitors appeared to acquire significant DNA damage as compared with the control starting from a low concentration of 1,4-BQ exposure (2.5 µM). In contrast, the erythroid progenitor showed significant damage as compared with the control starting at 5 µM 1,4-BQ. Meanwhile, a significant (p < 0.05) increase in tail moment was only notable at 7 µM and 12 µM 1,4-BQ exposure for all progenitors. Benzene could mediate hematological disorders by promoting bone marrow oxidative stress and lineage-specific genotoxicity targeting HSPCs.
Fulltext The role of Hibiscus sabdariffa L. (Roselle) in maintenance of ex vivo murine bone marrow-derived hematopoietic stem cells

Abdul Hamid Z, Lin Lin WH, Abdalla BJ, Bee Yuen O, Latif ES, Mohamed J, et al.

ScientificWorldJournal, 2014;2014:258192.
PMID: 25405216 DOI: 10.1155/2014/258192

Hematopoietic stem cells- (HSCs-) based therapy requires ex vivo expansion of HSCs prior to therapeutic use. However, ex vivo culture was reported to promote excessive production of reactive oxygen species (ROS), exposing HSCs to oxidative damage. Efforts to overcome this limitation include the use of antioxidants. In this study, the role of Hibiscus sabdariffa L. (Roselle) in maintenance of cultured murine bone marrow-derived HSCs was investigated. Aqueous extract of Roselle was added at varying concentrations (0-1000 ng/mL) for 24 hours to the freshly isolated murine bone marrow cells (BMCs) cultures. Effects of Roselle on cell viability, reactive oxygen species (ROS) production, glutathione (GSH) level, superoxide dismutase (SOD) activity, and DNA damage were investigated. Roselle enhanced the survival (P < 0.05) of BMCs at 500 and 1000 ng/mL, increased survival of Sca-1(+) cells (HSCs) at 500 ng/mL, and maintained HSCs phenotype as shown from nonremarkable changes of surface marker antigen (Sca-1) expression in all experimental groups. Roselle increased (P < 0.05) the GSH level and SOD activity but the level of reactive oxygen species (ROS) was unaffected. Moreover, Roselle showed significant cellular genoprotective potency against H2O2-induced DNA damage. Conclusively, Roselle shows novel property as potential supplement and genoprotectant against oxidative damage to cultured HSCs.
Fulltext Curcumin piperidone derivatives induce anti-proliferative and anti-migratory effects in LN-18 human glioblastoma cells

Razali NSC, Lam KW, Rajab NF, A Jamal AR, Kamaluddin NF, Chan KM

Sci Rep, 2022 07 30;12(1):13131.
PMID: 35907913 DOI: 10.1038/s41598-022-16274-4

Curcumin has demonstrated potential cytotoxicity across various cell lines despite its poor bioavailability and rapid metabolism. Therefore, our group have synthesized curcuminoid analogues with piperidone derivatives, FLDP-5 and FLDP-8 to overcome these limitations. In this study, the analogues were assessed on LN-18 human glioblastoma cells in comparison to curcumin. Results from cytotoxicity assessment showed that FLDP-5 and FLDP-8 curcuminoid analogues caused death in LN-18 cells in a concentration-dependent manner after 24-h treatment with much lower IC50 values of 2.5 µM and 4 µM respectively, which were more potent compared to curcumin with IC50 of 31 µM. Moreover, a significant increase (p
Fulltext Curcumin piperidone derivatives induce caspase-dependent apoptosis and suppress miRNA-21 expression in LN-18 human glioblastoma cells

Razali NSC, Lam KW, Rajab NF, Jamal ARA, Kamaludin NF, Chan KM

Genes Environ, 2024 Feb 01;46(1):4.
PMID: 38303058 DOI: 10.1186/s41021-023-00297-y

BACKGROUND: Previously, we have reported on the two curcuminoid analogues with piperidone derivatives, namely FLDP-5 and FLDP-8 have more potent anti-proliferative and anti-migration effects than curcumin. In this study, we further investigated the mode of cell death and the mechanism involved in the cell death process induced by these analogues on human glioblastoma LN-18 cells.
RESULTS: The FLDP-5 and FLDP-8 curcuminoid analogues induced LN-18 cell death through apoptosis in a concentration-dependent manner following 24 h of treatment. These analogues induced apoptosis in LN-18 cells through significant loss of mitochondrial mass and mitochondrial membrane potential (MMP) as early as 1-hour of treatment. Interestingly, N-acetyl-l-cysteine (NAC) pretreatment did not abolish the apoptosis induced by these analogues, further confirming the cell death process is independent of ROS. However, the apoptosis induced by the analogues is caspases-dependent, whereby pan-caspase pretreatment inhibited the curcuminoid analogues-induced apoptosis. The apoptotic cell death progressed with the activation of both caspase-8 and caspase-9, which eventually led to the activation of caspase-3, as confirmed by immunoblotting. Moreover, the existing over-expression of miRNA-21 in LN-18 cells was suppressed following treatment with both analogues, which suggested the down-regulation of the miRNA-21 facilitates the cell death process.
CONCLUSION: The FLDP-5 and FLDP-8 curcuminoid analogues downregulate the miRNA-21 expression and induce extrinsic and intrinsic apoptotic pathways in LN-18 cells.
Fulltext Effects of Eurycoma longifolia Jack standardised water extract (Physta) on well-being of perimenopausal and postmenopausal women: protocol for a randomised, double-blinded, placebo-controlled, parallel group study

Muniandy S, Yahya HM, Shahar S, Kamisan Atan I, Mahdy ZA, Rajab NF, et al.

BMJ Open, 2023 Nov 01;13(11):e073323.
PMID: 37914304 DOI: 10.1136/bmjopen-2023-073323

INTRODUCTION: Eurycoma longifolia Jack (EL), profoundly recognised as 'Tongkat Ali', is a medicinal herb originating from Southeast Asia. It is commonly used in traditional 'antiageing' treatments to address decreased energy, mood, libido and hormonal imbalances. While the benefits of EL have been extensively studied among the male population, less attention has been given to its effects on women. Menopause can impact the overall well-being of middle-aged women and incorporation of herbal supplements can aid them in managing the menopausal symptoms.
METHODS AND ANALYSIS: This 12-week randomised double-blind, placebo-controlled, parallel-group study aims to evaluate the efficacy of the standardised water extract of EL known as Physta in increasing the quality of life of perimenopausal and postmenopausal women. The study involves 150 women aged 40-55 years who score more than 61 on the Menopause-Specific Quality of Life (MENQOL) assessment. These participants will be randomised into three groups, receiving Physta at either 50 mg or 100 mg or a placebo. The outcomes measures include mood state, quality of life, fatigue, sleep quality, sexual function and pain score assessed using Profile of Mood State, MENQOL, Chalder Fatigue Scale, Pittsburgh Sleep Quality Index, Female Sexual Function Index and the Brief Pain Inventory questionnaires, respectively. The secondary outcome of the study includes full blood analysis, urine analysis, female reproductive hormone profiling, inflammatory and oxidative stress biomarkers analysis.
ETHICS AND DISSEMINATION: The research protocol of the study was reviewed and approved by the Research Ethics Committee of Universiti Kebangsaan Malaysia (UKM/PPI/111/8/JEP-2021-898). The findings will be disseminated to participants, healthcare professionals and researchers via conference presentations and peer-reviewed publications.
TRIAL REGISTRATION NUMBER: ACTRN12622001341718.
Safety and efficacy of dermal fibroblast conditioned medium (DFCM) fortified collagen hydrogel as acellular 3D skin patch

Maarof M, Mh Busra MF, Lokanathan Y, Bt Hj Idrus R, Rajab NF, Chowdhury SR

Drug Deliv Transl Res, 2019 02;9(1):144-161.
PMID: 30547385 DOI: 10.1007/s13346-018-00612-z

Skin substitutes are one of the main treatments for skin loss, and a skin substitute that is readily available would be the best treatment option. However, most cell-based skin substitutes require long production times, and therefore, patients endure long waiting times. The proteins secreted from the cells and tissues play vital roles in promoting wound healing. Thus, we aimed to develop an acellular three-dimensional (3D) skin patch with dermal fibroblast conditioned medium (DFCM) and collagen hydrogel for immediate treatment of skin loss. Fibroblasts from human skin samples were cultured using serum-free keratinocyte-specific media (KM1 or KM2) and serum-free fibroblast-specific medium (FM) to obtain DFCM-KM1, DFCM-KM2, and DFCM-FM, respectively. The acellular 3D skin patch was soft, semi-solid, and translucent. Collagen mixed with DFCM-KM1 and DFCM-KM2 showed higher protein release compared to collagen plus DFCM-FM. In vitro and in vivo testing revealed that DFCM and collagen hydrogel did not induce an immune response. The implantation of the 3D skin patch with or without DFCM on the dorsum of BALB/c mice demonstrated a significantly faster healing rate compared to the no-treatment group 7 days after implantation, and all groups had complete re-epithelialization at day 17. Histological analysis confirmed the structure and integrity of the regenerated skin, with positive expression of cytokeratin 14 and type I collagen in the epidermal and dermal layer, respectively. These findings highlight the possibility of using fibroblast secretory factors together with collagen hydrogel in an acellular 3D skin patch that can be used allogeneically for immediate treatment of full-thickness skin loss.
Rapid treatment of full-thickness skin loss using ovine tendon collagen type I scaffold with skin cells

Mh Busra F, Rajab NF, Tabata Y, Saim AB, B H Idrus R, Chowdhury SR

J Tissue Eng Regen Med, 2019 05;13(5):874-891.
PMID: 30811090 DOI: 10.1002/term.2842

The full-thickness skin wound is a common skin complication affecting millions of people worldwide. Delayed treatment of this condition causes the loss of skin function and integrity that could lead to the development of chronic wounds or even death. This study was aimed to develop a rapid wound treatment modality using ovine tendon collagen type I (OTC-I) bio-scaffold with or without noncultured skin cells. Genipin (GNP) and carbodiimide (EDC) were used to cross-link OTC-I scaffold to improve the mechanical strength of the bio-scaffold. The physicochemical, biomechanical, biodegradation, biocompatibility, and immunogenicity properties of OTC-I scaffolds were investigated. The efficacy of this treatment approach was evaluated in an in vivo skin wound model. The results demonstrated that GNP cross-linked OTC-I scaffold (OTC-I_GNP) had better physicochemical and mechanical properties compared with EDC cross-linked OTC-I scaffold (OTC-I_EDC) and noncross-link OTC-I scaffold (OTC-I_NC). OTC-I_GNP and OTC-I_NC demonstrated no toxic effect on cells as it promoted higher cell attachment and proliferation of both primary human epidermal keratinocytes and human dermal fibroblasts compared with OTC-I_EDC. Both OTC-I_GNP and OTC-I_NC exhibited spontaneous formation of bilayer structure in vitro. Immunogenic evaluation of OTC-I scaffolds, in vitro and in vivo, revealed no sign of immune response. Finally, implantation of OTC-I_NC and OTC-I_GNP scaffolds with noncultured skin cells demonstrated enhanced healing with superior skin maturity and microstructure features, resembling native skin in contrast to other treatment (without noncultured skin cells) and control group. The findings of this study, therefore, suggested that both OTC-I scaffolds with noncultured skin cells could be promising for the rapid treatment of full-thickness skin wound.
Fulltext Cytoprotection, Genoprotection, and Dermal Exposure Assessment of Chitosan-Based Agronanofungicides

Maluin FN, Hussein MZ, Yusof NA, Idris AS, Daim LDJ, Sarian MN, et al.

Pharmaceutics, 2020 May 29;12(6).
PMID: 32486034 DOI: 10.3390/pharmaceutics12060497

Health risks which result from exposure to pesticides have sparked awareness among researchers, triggering the idea of developing nanoencapsulation pesticides with the aim to enhance cytoprotection as well as genoprotection of the pesticides. In addition, nanocapsules of pesticides have slow release capability, high bioavailability, and site-specific delivery, which has attracted great interest from researchers. Hence, the objective of this work is to synthesize a nanoformulation of a fungicide of different sizes, namely, chitosan-hexaconazole nanoparticles (18 nm), chitosan-dazomet nanoparticles (7 nm), and chitosan-hexaconazole-dazomet nanoparticles (5 nm), which were then subjected to toxicological evaluations, including cytotoxicity, genotoxicity, cell death assay, and dermal irritation assays. Incubation of chitosan-based nanofungicides with V79-4 hamster lung cell did not reveal cytotoxicity or genotoxicity, potentially suggesting that encapsulation with chitosan reduces direct toxicity of the toxic fungicides. Meanwhile, pure fungicide revealed its high cytotoxic effect on V79-4 hamster lung cells. In addition, dermal exposure assessment on rabbits revealed that chitosan-hexaconazole nanoparticles are classified under corrosive subcategory 1C, while chitosan-dazomet nanoparticles are classified under corrosive subcategory 1B. Moreover, both chitosan-hexaconazole nanoparticles and chitosan-dazomet nanoparticles are classified as causing mild irritation.
Fulltext Biological Safety Assessments of High-Purified Ovine Collagen Type I Biomatrix for Future Therapeutic Product: International Organisation for Standardisation (ISO) and Good Laboratory Practice (GLP) Settings

Fadilah NIM, Ahmat N, Hao LQ, Maarof M, Rajab NF, Idrus RBH, et al.

Polymers (Basel), 2023 May 24;15(11).
PMID: 37299233 DOI: 10.3390/polym15112436

Wound care management is incredibly challenging for chronic injuries, despite the availability of various types of wound care products in the market. However, most current wound-healing products do not attempt to mimic the extracellular matrix (ECM) and simply provide a barrier function or wound covering. Collagen is a natural polymer that involves a major constituent of the ECM protein, thus making it attractive to be used in skin tissue regeneration during wound healing. This study aimed to validate the biological safety assessments of ovine tendon collagen type-I (OTC-I) in the accredited laboratory under ISO and GLP settings. It is important to ensure that the biomatrix will not stimulate the immune system to produce any adverse reaction. Therefore, we successfully extracted collagen type-I from the ovine tendon (OTC- I) using a method of low-concentration acetic acid. The three-dimensional (3D) skin patch of spongy OTC-I was a soft and white colour, being tested for safety and biocompatibility evaluations based on ISO 10993-5, ISO 10993-10, ISO 10993-11, ISO 10993-23, USP 40 <151>, and OECD 471. For the dermal sensitisation and acute irritation test, none of the tested animals displayed any erythema or oedema effects (p > 0.005). In addition, there were no abnormalities detected in the organ of the mice after being exposed to OTC-I; additionally, no morbidity and mortality were observed in the acute systemic test under the guideline of ISO 10993-11:2017. The grade 0 (non-reactive) based on ISO 10993-5:2009 was graded for the OTC-I at 100% concentration and the mean number of the revertant colonies did not exceed 2-fold of the 0.9% w/v sodium chloride compared to the tester strains of S. typhimurium (TA100, TA1535, TA98, TA1537), and E. coli (WP2 trp uvrA). Our study revealed that OTC-I biomatrix does not present any adverse effects or abnormalities in the present study's condition of induced skin sensitization effect, mutagenic and cytotoxic towards cells and animals. This biocompatibility assessment demonstrated a good agreement between in vitro and in vivo results regarding the absence of skin irritation and sensitization potential. Therefore, OTC-I biomatrix is a potential medical device candidate for future clinical trials focusing on wound care management.
Dietary Pattern, Genomic Stability and Relative Cancer Risk in Asian Food Landscape

Sharif R, Shahar S, Rajab NF, Fenech M

Nutr Cancer, 2021 Jul 20.
PMID: 34282666 DOI: 10.1080/01635581.2021.1952627

The incidence of cancer globally is increasing, partly due to lifestyle factors. Despite a better understanding of cancer biology and advancement in cancer management and therapies, current strategies in cancer treatment remain costly and cause socioeconomic burden especially in Asian countries. Hence, instead of putting more efforts in searches for new cancer cures, attention has now shifted to understanding how to mitigate cancer risk by modulating lifestyle factors. It has been established that carcinogenesis is multifactorial, and the important detrimental role of oxidative stress, chronic inflammation, and genomic instability is evident. To date, there is no study linking dietary pattern and genomic stability in cancer risk in the Asian food landscape. Thus, this present review article discusses recent literature on dietary pattern and genomic stability and its relationship with cancer risk in Asia.
Fulltext Relationships between dietary nutrients intake and lipid levels with functional MRI dorsolateral prefrontal cortex activation

Lau H, Shahar S, Mohamad M, Rajab NF, Yahya HM, Din NC, et al.

Clin Interv Aging, 2019;14:43-51.
PMID: 30613138 DOI: 10.2147/CIA.S183425

Background: Dorsolateral prefrontal cortex (DLPFC) is a key node in the cognitive control network that supports working memory. DLPFC dysfunction is related to cognitive impairment. It has been suggested that dietary components and high-density lipoprotein cholesterol (HDL-C) play a vital role in brain health and cognitive function.
Purpose: This study aimed to investigate the relationships between dietary nutrient intake and lipid levels with functional MRI (fMRI) brain activation in DLPFC among older adults with mild cognitive impairment.
Participants and methods: A total of 15 community-dwelling older adults with mild cognitive impairment, aged ≥60 years, participated in this cross-sectional study at selected senior citizen clubs in Klang Valley, Malaysia. The 7-day recall Diet History Questionnaire was used to assess participants' dietary nutrient intake. Fasting blood samples were also collected for lipid profile assessment. All participants performed N-back (0- and 1-back) working memory tasks during fMRI scanning. DLPFC (Brodmann's areas 9 and 46, and inferior, middle, and superior frontal gyrus) was identified as a region of interest for analysis.
Results: Positive associations were observed between dietary intake of energy, protein, cholesterol, vitamins B6 and B12, potassium, iron, phosphorus, magnesium, and HDL-C with DLPFC activation (P<0.05). Multivariate analysis showed that vitamin B6 intake, β=0.505, t (14)=3.29, P=0.023, and Digit Symbol score, β=0.413, t (14)=2.89, P=0.045; R2=0.748, were positively related to DLPFC activation.
Conclusion: Increased vitamin B6 intake and cognitive processing speed were related to greater activation in the DLPFC region, which was responsible for working memory, executive function, attention, planning, and decision making. Further studies are needed to elucidate the mechanisms underlying the association.
Fulltext The effects of six months Persicaria minor extract supplement among older adults with mild cognitive impairment: a double-blinded, randomized, and placebo-controlled trial

Lau H, Shahar S, Mohamad M, Rajab NF, Yahya HM, Din NC, et al.

BMC Complement Med Ther, 2020 Oct 19;20(1):315.
PMID: 33076878 DOI: 10.1186/s12906-020-03092-2

BACKGROUND: Persicaria minor extract exhibits antioxidant and anti-inflammatory properties and has potential effects on cognitive function and mood. However, the effects of P.minor on brain activation and biomarkers have not been studied among older adults. This multicentre, randomized, double-blinded, placebo-controlled study aimed to investigate the effect of 6 months P.minor extract supplement (Biokesum®) on cognition, mood, biomarkers, and brain activation among older adults with Mild Cognitive Impairment (MCI).
METHOD: A total of 36 Malaysian community-dwelling older adults with MCI (60-75-year-old) were randomized into Biokesum® (n = 18) and placebo group (n = 18). Each subject consumed one capsule of Biokesum® (250 mg/capsule) or placebo (maltodextrin, 280 mg/capsule) twice daily for 6 months. Cognitive function and mood were assessed at baseline, 3rd, and 6th-month using neuropsychological tests (MMSE, Digit Span, RAVLT, Digit Symbol, and Visual Reproduction) and Profile of Mood State (POMS) questionnaire. Blood lipid profile, fasting blood glucose, and biomarkers (MDA, LPO, COX-2, iNOS, and BDNF) were measured at baseline and 6th month. By the end of the intervention, there were 30 compliers (Biokesum®: N = 15; Placebo: N = 15) and 6 dropouts. For brain activation assessment, 15 subsamples (Biokesum®: N = 8; Placebo: N = 7) completed N-back and Stroop tasks during fMRI scanning at baseline and 6th month. The dorsolateral prefrontal cortex (Brodmann's area 9 and 46) was identified as a region of interest (ROI) for brain activation analysis using SPM software.
RESULTS: Two-way mixed ANOVA analysis showed significant improvements in Visual Reproduction II (p = 0.012, partial η2 = 0.470), tension (p = 0.042, partial η2 = 0.147), anger (p = 0.010, partial η2 = 0.207), confusion (p = 0.041, partial η2 = 0.148), total negative subscales (p = 0.043, partial η2 = 0.145), BDNF (p = 0.020, partial η2 = 0.179) and triglyceride (p = 0.029, partial η2 = 0.237) following 6 months of Biokesum® supplementation. Preliminary finding also demonstrated significant improvement at 0-back task-induced right DLPFC activation (p = 0.028, partial η2 = 0.652) among subsamples in Biokesum® group. No adverse events were reported at the end of the study.
CONCLUSION: Six months Biokesum® supplementation potentially improved visual memory, negative mood, BDNF, and triglyceride levels among older adults with MCI. Significant findings on brain activation at the right DPLFC must be considered as preliminary.
TRIAL REGISTRATION: Retrospectively registered on 30th August 2019 [ ISRC TN12417552 ].
Fulltext Cognitive frailty among Malaysian older adults: baseline findings from the LRGS TUA cohort study

Malek Rivan NF, Shahar S, Rajab NF, Singh DKA, Din NC, Hazlina M, et al.

Clin Interv Aging, 2019;14:1343-1352.
PMID: 31413555 DOI: 10.2147/CIA.S211027

PURPOSE: This study was aimed at determining the presence of cognitive frailty and its associated factors among community-dwelling older adults from the "LRGS-Towards Useful Aging (TUA)" longitudinal study.
PATIENTS AND METHODS: The available data related to cognitive frailty among a sub-sample of older adults aged 60 years and above (n=815) from two states in Malaysia were analysed. In the LRGS-TUA study, a comprehensive interview-based questionnaire was administered to obtain the socio-demographic information of the participants, followed by assessments to examine the cognitive function, functional status, dietary intake, lifestyle, psychosocial status and biomarkers associated with cognitive frailty. The factors associated with cognitive frailty were assessed using a bivariate logistic regression (BLR).
RESULTS: The majority of the older adults were categorized as robust (68.4%), followed by cognitively pre-frail (37.4%) and cognitively frail (2.2%). The data on the cognitively frail and pre-frail groups were combined for comparison with the robust group. A hierarchical BLR indicated that advancing age (OR=1.04, 95% CI:1.01-1.08, p<0.05) and depression (OR=1.49, 95% CI:1.34-1.65, p<0.001) scored lower on the Activity of Daily Living (ADL) scale (OR=0.98, 95% CI:0.96-0.99, p<0.05), while low social support (OR=0.98, 95% CI:0.97-0.99, p<0.05) and low niacin intake (OR=0.94, 95% CI:0.89-0.99, p<0.05) were found to be significant factors for cognitive frailty. Higher oxidative stress (MDA) and lower telomerase activity were also associated with cognitive frailty (p<0.05).
CONCLUSION: Older age, a lower niacin intake, lack of social support, depression and lower functional status were identified as significant factors associated with cognitive frailty among older Malaysian adults. MDA and telomerase activity can be used as potential biomarkers for the identification of cognitive frailty.

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