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Cytochrome P450 4B1 (CYP4B1) as a target in cancer treatment

Lim S, Alshagga M, Ong CE, Chieng JY, Pan Y

Hum Exp Toxicol, 2020 Jun;39(6):785-796.
PMID: 32054340 DOI: 10.1177/0960327120905959

Cytochrome P450 4B1 (CYP4B1) plays crucial roles in biotransforming of xenobiotics. Its predominant extrahepatic expression has been associated with certain tissue-specific toxicities. However, the expressions of CYP4B1 in various cancers and hence their potential roles in cancer development were inclusive. In this work, existing knowledge on expression and regulation of CYP4B1 gene and protein, catalysis of CYP4B1, association of CYP4B1 with cancers, contradicting findings about human CYP4B1 activities as well as the employing CYP4B1 in suicide gene approach for cancer treatment were reviewed. To date, it appears that there is a wide spectrum of tissue distribution of CYP4B1 with lungs as the predominant sites. Several nuclear receptors are possibly responsible for regulating its gene expression. The involvement of CYP4B1 in cancer was considered via activation of procarcinogens and neovascularization. However, human CYP4B1 was found to be inactive due to a substitution of proline with serine at position 427. Suicide gene approach combining reengineered CYP4B1 and prodrug 4-ipomeanol (4-IPO) has shown a promising potential for targeted cancer therapy. Further studies should focus on the verification of human CYP4B1 catalytic activities. More compounds with similar structure as 4-IPO should be tested to identify more alternative agents for the suicide gene approach in cancer treatment.
Fulltext The Effect of Nutritional Mobile Apps on Populations With Cancer: Systematic Review

Ng KLS, Munisamy M, Lim JBY, Alshagga M

JMIR Cancer, 2025 Feb 05;11:e50662.
PMID: 39908548 DOI: 10.2196/50662

BACKGROUND: Limited access to nutrition support among populations with cancer is a major barrier to sustainable and quality cancer care. Increasing use of mobile health in health care has raised concerns about its validity and health impacts.
OBJECTIVE: This systematic review aimed to determine the effectiveness of commercial or cancer-specific nutritional mobile apps among people living with cancer.
METHODS: A systematic search of the CENTRAL, Embase, PubMed (MEDLINE), and Scopus databases was carried out in May 2024. All types of intervention studies were included, except observational studies, gray literature, and reference lists of key systematic reviews. Studies were eligible for inclusion if they involved (1) patients with or survivors of cancer and (2) nutrition-related mobile apps. Studies were excluded if the nutrition intervention was not delivered via mobile app or the app intervention was accompanied by dietary counseling. The review process was conducted based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The Risk of Bias 2 and Risk of Bias in Nonrandomized Studies tools were used to assess the study quality. The Cochrane Review Manager (version 5.4) software was used to synthesize the results of the bias assessment.
RESULTS: A total of 13 interventions were included, comprising 783 adults or teenagers with cancer. Most studies focused on breast cancer (6/13, 46%), overweight (6/13, 46%), and survivors (9/13, 69%). Data on anthropometry and body composition (7/13, 54%; 387 participants), nutritional status (3/13, 23%; 249 participants), dietary intake (7/13, 54%; 352 participants), and quality of life (6/13, 46%; 384 participants) were gathered. Experimental groups were more likely to report significant improvements in body weight or composition, dietary compliance, nutritional status, and quality of life than control groups.
CONCLUSIONS: Although mobile app platforms are used to deliver nutrition interventions, the evidence for long-term efficacy, particularly in populations with cancer, remains elusive. More robust randomized controlled trials with larger sample sizes, as well as more homogeneous population characteristics and outcome measures, are warranted.
TRIAL REGISTRATION: PROSPERO CRD42023330575; https://tinyurl.com/55v56yaj.
Fulltext The Role of Psychosocial and Belief Factors in Self-Reported Cigarette Smoking Among University Students in Malaysia

Al-Dubai S, Ganasegeran K, Alshagga M, Hawash A, Wajih W, Kassim S

Health Psychol Res, 2014 Jan 13;2(1):1195.
PMID: 26973928 DOI: 10.4081/hpr.2014.1195

This study aimed to explore factors associated, specifically belief factors, with self-reported tobacco smoking status. A sample of 300 students was recruited from a private university in Malaysia. Data was collected using a pre-tested self-administrated questionnaire that investigated various factors including socio-demographics, socio-economic status, smoking behavior and beliefs on tobacco smoking. The main tobacco use in this study sample was cigarettes and the estimated prevalence of self-reported cigarette smoking was 10.3%. In bivariate analysis, self-reported cigarette smoking was significantly associated with socio-demographic, behavioral factors and faculty of study (P<0.05). In multivariate modeling, being male and a non-medical student, did not exercise, having a smoker father and brother or sister, suffering from financial difficulties and having the belief that smokers had more friends, all had statistically significant associations (P<0.05) with self-reported cigarette smoking. Social and interpersonal factors were associated with self-reported cigarette smoking status. A comprehensive health model focusing on changing the social norms of parent and sibling tobacco smoking and students' beliefs, alongside nurturing skills of dealing with stressful situations, warrant implementation.
CYP35 family in Caenorhabditis elegans biological processes: fatty acid synthesis, xenobiotic metabolism, and stress responses

Lim SYM, Alshagga M, Kong C, Alshawsh MA, Alshehade SA, Pan Y

Arch Toxicol, 2022 12;96(12):3163-3174.
PMID: 36175686 DOI: 10.1007/s00204-022-03382-3

With more than 80 cytochrome P450 (CYP) encoding genes found in the nematode Caenorhabditis elegans (C. elegans), the cyp35 genes are one of the important genes involved in many biological processes such as fatty acid synthesis and storage, xenobiotic stress response, dauer and eggshell formation, and xenobiotic metabolism. The C. elegans CYP35 subfamily consisted of A, B, C, and D, which have the closest homolog to human CYP2 family. C. elegans homologs could answer part of the hunt for human disease genes. This review aims to provide an overview of CYP35 in C. elegans and their human homologs, to explore the roles of CYP35 in various C. elegans biological processes, and how the genes of cyp35 upregulation or downregulation are influenced by biological processes, upon exposure to xenobiotics or changes in diet and environment. The C. elegans CYP35 gene expression could be upregulated by heavy metals, pesticides, anti-parasitic and anti-chemotherapeutic agents, polycyclic aromatic hydrocarbons (PAHs), nanoparticles, drugs, and organic chemical compounds. Among the cyp35 genes, cyp-35A2 is involved in most of the C. elegans biological processes regulation. Further venture of cyp35 genes, the closest homolog of CYP2 which is the largest family of human CYPs, may have the power to locate cyps gene targets, discovery of novel therapeutic strategies, and possibly a successful medical regime to combat obesity, cancers, and cyps gene-related diseases.
Fulltext In vitro and In silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP(1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5

Lim SYM, Loo JSE, Alshagga M, Alshawsh MA, Ong CE, Pan Y

Toxicol Rep, 2022;9:759-768.
PMID: 36518400 DOI: 10.1016/j.toxrep.2022.03.040

Cathinone is the psychostimulatory major active ingredient of khat (Catha edulis Forsk) and are often co-abused with alcohols and polydrugs. With the increased consumption of khat and cathinones on a global scale, efforts should be channelled into understanding and minimising the excruciating effects of possible khat-drug interactions. This study aimed to determine the in vitro inhibitory effects of cathinone on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 and the in silico identification of their type of interactions and residues involved. The activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 were examined by fluorescence based assays using recombinant cDNA-expressed human CYPs in Vivid® P450 screening kits. Cathinone reversibly inhibited CYP1A2, CYP2A6 and CYP3A5 via competitive, uncompetitive and noncompetitive modes with inhibition constant (Ki) values of 57.12, 13.75 and 23.57 µM respectively. Cathinone showed negligible inhibitory effects on CYP2B6, CYP2C8, CYP2C19, CYP2E1 and CYP2J2. Cathinone showed negligible time dependent inhibition on all 8 CYPs. Docking studies was performed on cathinone with CYP1A2, CYP2A6 and CYP3A5 following their inhibition in vitro. Cathinone is bound to a few key amino acid residues in the active sites while π-π interactions are formed in aromatic clusters of CYP1A2 and CYP3A5. These findings offer valuable reference for the use of cathinones and khat when combined with therapeutic drugs that are metabolised by CYP enzymes especially patients on medications metabolised by CYP1A2, CYP2A6 and CYP3A5.
Caenorhabditis elegans CYP33 Family in Eicosanoid Regulation, Xenobiotic Metabolism, Nanotoxicity and Spermatogenesis

Lim SYM, Lim W, Peter AP, Pan Y, Alshagga M, Alshawsh MA

J Appl Toxicol, 2024 Oct 04.
PMID: 39367649 DOI: 10.1002/jat.4707

The CYP33 family in Caenorhabditis elegans is integral to processes like xenobiotic detoxification, eicosanoid regulation, nanotoxicity response and spermatogenesis. Limited research on C. elegans CYP33 suggests its functions are similar to human CYP33, indicating conserved roles in metabolism and disease. This review examines C. elegans CYP33 enzymes, especially CYP-33E1 and CYP-33E2, and their human homologues, focusing on their roles in eicosanoid biosynthesis, xenobiotic metabolism, nanotoxicity and spermatogenesis. Understanding these enzymes enhances insights into cytochrome P450 biology, metabolism and cyp-associated diseases.
Fulltext Protein-Ligand Identification and In Vitro Inhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

Lim SYM, Loo JSE, Alshagga M, Alshawsh MA, Ong CE, Pan Y

Int J Toxicol, 2022;41(5):355-366.
PMID: 35658727 DOI: 10.1177/10915818221103790

Cathine is the stable form of cathinone, the major active compound found in khat (Catha edulis Forsk) plant. Khat was found to inhibit major phase I drug metabolizing cytochrome P450 (CYP) enzyme activities in vitro and in vivo. With the upsurge of khat consumption and the potential use of cathine to combat obesity, efforts should be channelled into understanding potential cathine-drug interactions, which have been rather limited. The present study aimed to assess CYPs activity and inhibition by cathine in a high-throughput in vitro fluorescence-based enzyme assay and molecular docking analysis to identify how cathine interacts within various CYPs' active sites. The half maximal inhibitory concentration (IC50) values of cathine determined for CYP2A6 and CYP3A4 were 80 and 90 μM, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in Ki analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with Ki value of 63 and 100 μM, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and π-stacking interactions and formed hydrophobic and hydrogen bonds with active site residues in CYP3A4. Both molecular docking prediction and in vitro outcome are in agreement, granting more detailed insights for predicting CYPs metabolism besides the possible cathine-drug interactions. Cathine-drug interactions may occur with concomitant consumption of khat or cathine-containing products with medications metabolized by CYP2A6 and CYP3A4.
CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan

Lim SYM, Pan Y, Alshagga M, Lim W, Cin K, Alshehade SA, et al.

J Appl Toxicol, 2024 Nov;44(11):1647-1656.
PMID: 38472099 DOI: 10.1002/jat.4597

CYP-14 members of the Caenorhabditis elegans (C. elegans) Cytochrome P450 (CYP) enzyme family, plays important roles in mitochondrial dysfunction, detoxification, lipid metabolism, defense and lifespan regulation. The review identifies CYP-14 members: cyp-14A1, cyp-14A2, cyp-14A3, cyp-14A4, cyp-14A5 and their homology with human CYP families. Despite limited studies on C. elegans cyp-14 members, the findings unraveled their complex crosstalk between mitochondrial stress, detoxification mechanisms, and lifespan regulation, emphasizing the complexity of these interconnected pathways as well as how their regulation depends on environmental cues changes including pH, nutrients, ROS and chemical stressors. The review underscores the translational relevance to human health, shedding light on potential human homologues and their implications in age-related, metabolic and respiratory diseases. Among other genes, cyp-14A2 and cyp-14A4 predominate the mitochondrial function, heat resistance, lipid metabolism, detoxification and lifespan pathways. In conclusion, these insights pave the way for future research, offering promising avenues for therapeutic interventions targeting CYP-14 activity to address age-related diseases and promote healthy aging.
Exploring the anti-obesity effects of Lactobacillus in C57BL/6 mice: mechanisms, interventions, and future directions

Lim SYM, Chong EJ, Mah WY, Pan Y, Fang CM, Murugaiah C, et al.

Lett Appl Microbiol, 2025 Mar 03;78(3).
PMID: 39965784 DOI: 10.1093/lambio/ovaf024

Lactobacillus species show strong potential in fighting obesity-related inflammation and metabolic issues. Obesity causes inflammation in adipose tissue, which harms insulin sensitivity and leads to fat buildup. Lactobacillus strains like Lactobacillus gasseri, Lactobacillus reuteri, and Lactobacillus plantarum help regulate lipid metabolism by boosting key genes, preventing fat cell formation, and encouraging fat breakdown. They also produce short-chain fatty acids (SCFAs) that improve gut health, activate metabolic pathways, and reduce inflammation. Studies in animals have shown that Lactobacillus can reduce body weight, fat, and inflammation, with Lactobacillus plantarum being especially effective in improving gut microbiota and liver function. When combined with other probiotics or prebiotics, these strains work even better, enhancing lipid metabolism and reducing inflammation. These results suggest that Lactobacillus could be an effective way to manage obesity and related health problems by influencing metabolism, gut health, and inflammation. However, more research, particularly human clinical trials, is needed to confirm its potential as a dietary treatment for obesity.