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Fulltext Sri Petaling COVID-19 cluster in Malaysia: challenges and the mitigation strategies

Safuan S, Edinur HA

Acta Biomed, 2020 11 10;91(4):e2020154.
PMID: 33525245 DOI: 10.23750/abm.v91i4.10345

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Fulltext Potential Effect of Polyphenolic-Rich Fractions of Corn Silk on Protecting Endothelial Cells against High Glucose Damage Using In Vitro and In Vivo Approaches

Hamzah N, Safuan S, Wan Ishak WR

Molecules, 2021 Jun 16;26(12).
PMID: 34208534 DOI: 10.3390/molecules26123665

Endothelial cell dysfunction is considered to be one of the major causes of vascular complications in diabetes. Polyphenols are known as potent antioxidants that can contribute to the prevention of diabetes. Corn silk has been reported to contain polyphenols and has been used in folk medicine in China for the treatment of diabetes. The present study aims to investigate the potential protective role of the phenolic-rich fraction of corn silk (PRF) against injuries to vascular endothelial cells under high glucose conditions in vitro and in vivo. The protective effect of PRF from high glucose toxicity was investigated using human umbilical vein endothelial cells (HUVECs). The protective effect of PRF was subsequently evaluated by using in vivo methods in streptozotocin (STZ)-induced diabetic rats. Results showed that the PRF significantly reduced the cytotoxicity of glucose by restoring cell viability in a dose-dependent manner. PRF was also able to prevent the histological changes in the aorta of STZ-induced diabetic rats. Results suggested that PRF might have a beneficial effect on diabetic patients and may help to prevent the development and progression of diabetic complications such as diabetic nephropathy and atherosclerosis.
Fulltext Peritumoral lymphatic vessel density and invasion detected with immunohistochemical marker D240 is strongly associated with distant metastasis in breast carcinoma

Norhisham NF, Chong CY, Safuan S

BMC Clin Pathol, 2017;17:2.
PMID: 28203117 DOI: 10.1186/s12907-017-0041-4

BACKGROUND: Detection of vascular invasion by hematoxylin and eosin staining is the current pathological assessment practice to diagnose breast carcinoma. However, conventional hematoxylin and eosin staining failed to distinguish between blood vessel invasion and lymphatic vessel invasion. Both are important prognostic criteria however with different outcomes. The aim of this study is to distinguish between blood vessel invasion and lymphatic vessel invasion using conventional assessment and immunohistochemical markers. The prognostic significance of both circulatory invasions in invasive breast carcinoma was also investigated.
METHODS: Consecutive sections of breast carcinoma samples from 58 patients were stained with CD34 and D240 to stain blood and lymphatic vessels respectively. Hematoxylin and eosin staining was carried out on another consecutive section as conventional staining.
RESULTS: Although blood vessel density is higher in the sections (median = 10.3 vessels) compared to lymphatic vessel density (median = 0.13), vessel invasion is predominantly lymphatic invasion (69.8 and 55.2% respectively). Interestingly, peritumoral lymphatic vessel density and peritumoral lymphatic invasion was significantly associated with distant metastasis (p = 0.049 and p = 0.05 respectively). The rate of false positive and false negative interpretation by hematoxylin and eosin was 46.7 and 53.3% respectively.
CONCLUSIONS: Lymphatic vessel invasion is a strong prognostic markers of breast carcinoma invasion and the use of immunohistochemical markers increase the rate and accuracy of detection.
Fulltext Mitigating the shadow economy through financial sector development in Indonesia: some empirical results

Safuan S, Habibullah MS, Sugandi EA

Heliyon, 2021 Dec;7(12):e08633.
PMID: 34988322 DOI: 10.1016/j.heliyon.2021.e08633

We examine the relationship between financial sector development and the shadow economy in Indonesia from 1980 to 2020. We estimate the size of Indonesia's shadow economy using the "Modified Cash to Deposits Ratio" approach. We then construct a long-term model using the size of Indonesia's shadow economy as the dependent variable. We set financial sector development as the main independent variable in our model. We use per capita real gross domestic product, the misery index, and foreign direct investment as control variables in our model. We find that financial sector development and the size of Indonesia's shadow economy have a nonlinear relationship that shows an inverted U-shape curve. The size of the shadow economy expands at the early stages of financial sector development to a turning point and decreases when financial sector development increases further. We also find that foreign direct investment curtails Indonesia's shadow economy. Additionally, increases in income expand Indonesia's shadow economy while misery index shows ambiguous results. We suggest the Indonesian authorities widen access for micro, small, and medium firms to the credit markets and enhance existing programs to reduce poverty and narrow the income gap in the country. These efforts help to narrow the size of Indonesia's shadow economy.
Aging of the cells: Insight into cellular senescence and detection Methods

Mohamad Kamal NS, Safuan S, Shamsuddin S, Foroozandeh P

Eur J Cell Biol, 2020 Aug;99(6):151108.
PMID: 32800277 DOI: 10.1016/j.ejcb.2020.151108

Cellular theory of aging states that human aging is the result of cellular aging, in which an increasing proportion of cells reach senescence. Senescence, from the Latin word senex, means "growing old," is an irreversible growth arrest which occurs in response to damaging stimuli, such as DNA damage, telomere shortening, telomere dysfunction and oncogenic stress leading to suppression of potentially dysfunctional, transformed, or aged cells. Cellular senescence is characterized by irreversible cell cycle arrest, flattened and enlarged morphology, resistance to apoptosis, alteration in gene expression and chromatin structure, expression of senescence associated- β-galactosidase (SA-β-gal) and acquisition of senescence associated secretory phenotype (SASP). In this review paper, different types of cellular senescence including replicative senescence (RS) which occurs due to telomere shortening and stress induced premature senescence (SIPS) which occurs in response to different types of stress in cells, are discussed. Biomarkers of cellular senescence and senescent assays including BrdU incorporation assay, senescence associated- β-galactosidase (SA-β-gal) and senescence-associated heterochromatin foci assays to detect senescent cells are also addressed.
Fulltext Subacute Toxicity Evaluation of Methanolic Extract of Syzygium polyanthum in Rats

Harun NH, Rasdi NA, Salleh RM, Safuan S, Ahmad WANW, Fuad WEM

Trop Life Sci Res, 2021 Jun;32(2):65-81.
PMID: 34367515 DOI: 10.21315/tlsr2021.32.2.5

Syzygium polyanthum (Wight) Walp. var. polyanthum (serai kayu) leaves is a popular herb and widely used in traditional medicine. Despite the ethnomedicinal benefits, very limited studies have researched on the toxicity of this plant. The aim of the present study was to investigate the potential effects of methanolic extract of Syzygium polyanthum (MESP) leaves via 28-day repeated oral dosing in Sprague Dawley rats. MESP leaves was administered at doses of 0 (control), 400, 1000 or 2000 mg/kg to an equal number of male and female rats (n = 10/group). Results obtained indicated that MESP did not affect the general conditions (body weight, feed intake and oestrous cycle) and apparent behavioural changes of the rats. Biochemical parameters revealed a slight significant variation in the aspartate aminotransferase (AST) level between the male rats treated with the lowest and highest doses of MESP, but these findings were both statistically insignificant when compared to the control group. The liver of the males (dose 1000 and 2000 mg/kg/day) also exhibited histoarchitectural defects on the hepatocytes and cytoplasm when compared to those of the control group. In contrast, female rats did not encounter any significant findings in all parameters tested. In conclusion, this study suggests that the MESP leaves might exhibit sex-based variation effects and thus, the use of this extract particularly at higher doses should be thoroughly considered.
Fulltext A single mass gathering resulted in massive transmission of COVID-19 infections in Malaysia with further international spread

Che Mat NF, Edinur HA, Abdul Razab MKA, Safuan S

J Travel Med, 2020 05 18;27(3).
PMID: 32307549 DOI: 10.1093/jtm/taaa059
Double-edged Swords: Diaryl pyrazoline thiazolidinediones synchronously targeting cancer epigenetics and angiogenesis

Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, et al.

Bioorg Chem, 2021 11;116:105350.
PMID: 34547645 DOI: 10.1016/j.bioorg.2021.105350

In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot.
Development and investigation of thiazolidinedione and pyrazoline compounds as antiangiogenic weapons targeting VEGFR-2

Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, et al.

Future Med Chem, 2021 11;13(22):1963-1986.
PMID: 34581188 DOI: 10.4155/fmc-2021-0139

Background: Angiogenesis deregulation is often linked to cancer and is thus an essential target. Materials & methods: Twenty-nine compounds were developed as VEGFR-2 inhibitors. Compounds were evaluated to determine their antiangiogenic activity. Results: B1, PB11 and PB16 showed HUVEC's IC50 scores in the submicromolar range. B1, B2 and PB16 reduced cellular migration and capillary tube formation of HUVECs. VEGFR-2 inhibitory activity was found in the nanomolar range: 200 nM of B1, 500 nM of B2 and 600 nM of PB16. B1 and PB16 suppressed the formation of new capillaries on growing CAMs. B1 and PB16 occupied the ATP site and allosteric pocket of VEGFR-2 in docking studies. Conclusion: These compounds can target VEGFR-2 and are endowed with in vitro and in vivo antiangiogenic activity.
Lignosus rhinocerotis extract ameliorates airway inflammation and remodelling via attenuation of TGF-β1 and Activin A in a prolonged induced allergic asthma model

Muhamad SA, Safuan S, Stanslas J, Wan Ahmad WAN, Bushra SM, Nurul AA

Sci Rep, 2023 Oct 27;13(1):18442.
PMID: 37891170 DOI: 10.1038/s41598-023-45640-z

Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. The sclerotium of Lignosus rhinocerotis (Cooke) Ryvarden (Tiger Milk mushroom) is used traditionally to treat various illnesses, including asthma in Southeast Asia. This study was carried out to evaluate the effect of L. rhinocerotis extract (LRE) on airway inflammation and remodelling in a chronic model of asthma. The present study investigated the therapeutic effects of LRE on airway inflammation and remodelling in prolonged allergen challenged model in allergic asthma. Female Balb/C mice were sensitised using ovalbumin (OVA) on day 0 and 7, followed by OVA-challenged (3 times/week) for 2, 6 and 10 weeks. LRE (125, 250, 500 mg/kg) were administered by oral gavage one hour after every challenge. One group of mice were left untreated after the final challenge for two weeks. LRE suppressed inflammatory cells and Th2 cytokines (IL-4, IL-5 and IL-13) in BALF and reduced IgE level in the serum. LRE also attenuated eosinophils infiltration and goblet cell hyperplasia in the lung tissues; as well as ameliorated airway remodelling by reducing smooth muscle thickness and reducing the expressions of TGF-β1 and Activin A positive cell in the lung tissues. LRE attenuated airway inflammation and remodelling in the prolonged allergen challenge of allergic asthma model. These findings suggest the therapeutic potential of LRE as an alternative for the management of allergic asthma.
Fulltext Intranasal administration of Lignosus rhinocerotis (Cooke) Ryvarden (Tiger Milk mushroom) extract attenuates airway inflammation in murine model of allergic asthma

Muhamad SA, Muhammad NS, Ismail NDA, Mohamud R, Safuan S, Nurul AA

Exp Ther Med, 2019 May;17(5):3867-3876.
PMID: 30988772 DOI: 10.3892/etm.2019.7416

Asthma is a chronic inflammatory disorder in the airways that involves the activation of cells and mediators. Lignosus rhinocerotis (Cooke) Ryvardan or Tiger Milk mushroom is a medicinal mushroom that is traditionally used to treat inflammatory diseases including asthma. In this study, the protective effects of intranasal administration of L. rhinocerotis extract (LRE) in ovalbumin (OVA)-induced airway inflammation mouse model were investigated. Mice were sensitized by intraperitoneal (i.p) injection on days 0 and 14, followed by a daily challenge with 1% OVA from days 21 to 27. Following OVA challenge, LRE and dexamethasone were administered via intranasal and i.p. injection respectively. On day 28, the level of serum immunoglobulin (Ig)E, differential cell counts and T-helper (Th) 2 cytokines in bronchoalveolar lavage fluid (BALF) fluid, cell subset population in lung-draining lymph nodes (LNs), leukocytes infiltration and mucus production in the lungs of the animals was measured. Results demonstrated that intranasal administration of LRE significantly suppressed the level of inflammatory cell counts in BALF as well as populations of CD4+ T-cells in lung draining LNs. Apart from that, LRE also significantly reduced the level of Th2 cytokines in BALF and IgE in the serum in OVA-induced asthma. Histological analysis also demonstrated the amelioration of leukocytes infiltration and mucus production in the lungs. Overall, these findings demonstrated the attenuation of airway inflammation in the LRE-treated mice therefore suggesting a promising alternative for the management of allergic airway inflammation.
Fulltext Multi-target weapons: diaryl-pyrazoline thiazolidinediones simultaneously targeting VEGFR-2 and HDAC cancer hallmarks

Upadhyay N, Tilekar K, Safuan S, Kumar AP, Schweipert M, Meyer-Almes FJ, et al.

RSC Med Chem, 2021 Sep 23;12(9):1540-1554.
PMID: 34671737 DOI: 10.1039/d1md00125f

In anticancer drug discovery, multi-targeting compounds have been beneficial due to their advantages over single-targeting compounds. For instance, VEGFR-2 has a crucial role in angiogenesis and cancer management, whereas HDACs are well-known regulators of epigenetics and have been known to contribute significantly to angiogenesis and carcinogenesis. Herein, we have reported nineteen novel VEGFR-2 and HDAC dual-targeting analogs containing diaryl-pyrazoline thiazolidinediones and their in vitro and in vivo biological evaluation. In particular, the most promising compound 14c has emerged as a dual inhibitor of VEGFR-2 and HDAC. It demonstrated anti-angiogenic activity by inhibiting in vitro HUVEC proliferation, migration, and tube formation. Moreover, an in vivo CAM assay showed that 14c repressed new capillary formation in CAMs. In particular, 14c exhibited cytotoxicity potential on different cancer cell lines such as MCF-7, K562, A549, and HT-29. Additionally, 14c demonstrated significant potency and selectivity against HDAC4 in the sub-micromolar range. To materialize the hypothesis, we also performed molecular docking on the crystal structures of both VEGFR-2 (PDB ID: 1YWN) and HDAC4 (PDB-ID: 4CBY), which corroborated the designing and biological activity. The results indicated that compound 14c could be a potential lead to develop more optimized multi-target analogs with enhanced potency and selectivity.
Fulltext Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro

Storr SJ, Safuan S, Ahmad N, El-Refaee M, Jackson AM, Martin SG

Cancer Immunol Immunother, 2017 Oct;66(10):1287-1294.
PMID: 28551814 DOI: 10.1007/s00262-017-2020-0

Lymphovascular invasion (LVI), encompassing blood and lymphatic vessel invasion, is an important event in tumourigenesis. Macrophages within the tumour microenvironment are linked to the presence of LVI and angiogenesis. This study investigates the role of macrophage-derived, caspase-1-dependent interleukin-1beta (IL-1β) in an in vitro model of LVI. IL-1β significantly augmented the adhesion and transmigration of breast cancer cell lines MCF7 and MDA-MB-231 across endothelial cell barriers. MDA-MB-231 and MCF7 showed a higher percentage of adhesion to lymphatic endothelial cells than blood endothelial cells following endothelial cell IL-1β stimulation (P
Human neutrophil antigen frequency data for Malays, Chinese and Indians

Hajar CGN, Zulkafli Z, Md Riffin NS, Tuan Mohammad TH, Safuan S, Nelson BR, et al.

Transfus Apher Sci, 2020 Apr;59(2):102651.
PMID: 31606336 DOI: 10.1016/j.transci.2019.09.004

BACKGROUND: Human neutrophil antigens (HNAs) are implicated in several clinical disorders and their allelic variations have been reported for many populations. This new study was aimed to report the genotype and alleles frequencies of HNA-1, -3, -4 and -5 loci in Malays, Chinese and Indians in Peninsular Malaysia.
METHODS: A total of 222 blood samples were collected from healthy, unrelated Malay, Chinese and Indian individuals. Their HNA-1, -3 and -4 and HNA-5 loci were genotyped using polymerase chain reaction-sequence specific primer (PCR-SSP) or PCR-restriction fragment length polymorphism (RFLP) assays.
RESULTS: All HNA loci are polymorphic, except for HNA -4. Geneotypes HNA-1a/1b, -3a/3b and -4a/4a were observed most frequently at these three loci in all three ethnic groups. In contrast, HNA-5a/5b and -5a/5a were observed as the predominant genotypes in Malays vs. Chinese and Indians, respectively. The Malays, Chinese and Indians shared HNA -3a (0.505-0.527), HNA -4a (1.000) and -5a (0.676-0.854) as the most frequent alleles. However, HNA-1a was found to be the most common in Malays (0.506) and Chinese (0.504) and HNA-1b for Indians (0.525).
CONCLUSION: Combined with HNA data that have been published for Malay subethnic and Orang Asli groups, this study provides the first fully comprehensive HNA dataset for populations to be found in Peninsular Malaysia. Overall, our findings provide further evidence of genetic complexity in the region. This now publicly available HNA dataset can be used as a reliable reference source for improving medical outcomes.

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