Dillenia suffruticosa dichloromethane root extract induced apoptosis towards MDA-MB-231 triple negative breast cancer cells

Ethnopharmacological Relevance: Dillenia suffruticosa is traditionally used for treatment of cancerous growth including breast cancer in Malaysia. Aim of The Study: Dillenia suffruticosa is a well-known medicinal plant in Malaysia for the treatment of cancer. Nevertheless, no study has been reported the cytotoxicity of this plant towards MDA-MB-231 triple-negative breast cancer cells. The present study was designed to investigate the mode of cell death and signalling pathways of MDA-MB-231 cells treated with dichloromethane Dillenia suffruticosa root extract (DCM-DS). Methods: Extraction of Dillenia suffruticosa root was performed by the use of sequential solvent procedure. The cytotoxicity of DCM-DS was determined by using MTT assay. The mode of cell death was evaluated by using an inverted light microscope and flow cytometry analysis using Annexin-V/PI. Cell cycle analysis and measurement of reactive oxygen species level were performed by using flow cytometry. The cells were treated with DCM-DS and antioxidants α-tocopherol or ascorbic acid to evaluate the involvement of ROS in the cytotoxicity of DCM-DS. Effect of DCM-DS on the expression of antioxidant, apoptotic, growth, survival genes and proteins were analysed by using GeXP-based multiplex system and Western blot, respectively. The cytotoxicity of compounds isolated from DCM-DS was evaluated towards MDA-MB-231 cells using MTT assay. Results: DCM-DS induced apoptosis, G2/M phase cell cycle arrest and oxidative stress in MDA-MB-231 cells. The induction of apoptosis in MDA-MB-231 cells by DCM-DS is possibly due to the activation of pro-apoptotic JNK1 and down-regulation of anti-apoptotic ERK1, which in turn down-regulates anti-apoptotic BCL-2 to increase the BAX/BCL-2 ratio to initiate the mitochondrial apoptotic pathway. The cell cycle arrest in DCM-DS-treated MDA-MB-231 cells is possibly via p53-independent but p21-dependent pathway. A total of 3 triterpene compounds were isolated from DCM-DS. Betulinic acid appears to be the most major and most cytotoxic compound in DCM-DS. Conclusion: The data suggest the potential application of DCM-DS in the treatment of triple-negative breast cancer

Antiulcer properties of Kelulut honey against ethanol-induced gastric ulcer

Ulcers in the gastrointestinal tract refer to any appreciable depth of break in the mucosa lining that may involve submucosa. Common types of ulcer include peptic, gastric and duodenal ulcer, which may lead to chronic inflammation. Ulcers may be caused by excessive alcohol intake or prolonged use of non-steroidal anti-inflammatory drugs (NSAID), in addition to several other factors. Conventional medication such as Omeprazole (proton pump inhibitor) and Ranitidine (H2 blockers) for management of ulcers may cause severe side effects such as myelosupression and abnormal heart rhythm. This has driven researchers to explore the potential of natural products for management of ulcers with reduced side effects. Kelulut honey (KH) is a type of honey that is produced by stingless bees from the Trigona species. It is believed to have a lot of medicinal properties such as being antimicrobial, antioxidant and antidiabetic. Yet, no scientific study has been carried out on its antiulcer properties. This study was carried out to determine the antiulcer properties of KH. Eighteen male Sprague dawley rats (5 to 6 weeks old, weighing between 200 and 300 g) were divided into three groups (n=6). The groups were 1) normal control group (without ulcer, without KH), 2) positive control group (with ulcer, without KH) and 3) treatment group (with ulcer, treated with KH). The treatment, KH (1183 mg/kg), was given twice daily for 30 consecutive days by oral administration. On Day 31, the rats were induced with absolute ethanol (5 mL/kg) via oral administration after being fasted for 24 h and were sacrificed 15 min after the induction. The stomach was collected for macroscopic and histopathological evaluation. Pretreatment with KH significantly reduced (p<0.05) both the total area of ulcer and the ulcer index compared to the positive control group. The percentage of ulcer inhibition in the KH pre-treated group was 65.56% compared with the positive control group. The treatment, KH, exhibited antiulcer properties against ethanol-induced gastric ulcer

Predictors of recurrence of major depressive disorder

A total of 201 patients with major depressive disorder from four hospitals in Malaysia were followed up for 5 years to determine the prognostic factors of recurrent major depressive disorder that could potentially contribute to improving the management of MDD patients. For each individual patient, at the time of recruitment as part of a case-control study, information was collected on recent threatening life events, personality and social and occupational functioning, while blood samples were collected to genotype single nucleotide polymorphisms of vitamin D receptor (VDR), zinc transporter-3 (ZnT3), dopamine transporter-1 (DAT1), brain-derived neurotropic factor (BDNF), serotonin receptor 1A (HT1A) and 2A (HT2A) genes. Kaplan-Meier and Cox-regression were used to estimate hazard functions for recurrence of major depressive disorder. Individuals with severe MDD in previous major depressive episodes had five and a half times higher hazard of developing recurrence compared to mild and moderate MDD (HR = 5.565, 95% CI = 1.631–18.994, p = 0.006). Individuals who scored higher on social avoidance had three and a half times higher hazard of recurrence of MDD (HR = 3.525, 95% CI = 1.349–9.209; p = 0.010). There was significant interaction between ApaI +64978C>A single nucleotide polymorphism and severity. The hazard ratio increased by 6.4 times from mild and moderate to severe MDD for A/A genotype while that for C/A genotype increased by 11.3 times. Social avoidance and severity of depression at first episode were prognostic of recurrence. Screening for personality factors at first encounter with MDD patients needs to be considered as part of the clinical practice. For those at risk of recurrence in relation to social avoidance, the psychological intervention prescribed should be customized to focus on this modifiable factor. Prompt and appropriate management of severe MDD is recommended to reduce risk of recurrence

Apoptotic-related signalling pathways in mcf-7 cells treated with ethyl acetate extract of dillenia suffruticosa, and isolation of its major compounds

Breast cancer is the most prevalent cancer among women worldwide. The trend for breast cancer treatment has shifted towards the use of natural product such as herbal medicine as an alternative and complementary medicine. Dillenia suffruticosa (Griff) Martelli that belongs to the family Dilleniaceae has been traditionally used to treat cancerous growth. In this study, the anti-cancer activity of ethyl acetate extract of D. suffruticosa (EADs) root was examined on breast cancer cells, MCF-7. EADs was prepared from the root of D. suffruticosa by using sequential solvent extraction. MTT assay was used to determine the cytotoxicity of EADs, which was demonstrated to be dose- and time-dependent, with IC50 of 39 ± 3.6 µg/mL at 72 hours. Flow cytometry cell cycle analysis displayed that EADs induced non-phase specific cell cycle arrest. EADs induced mainly apoptosis in MCF-7 cells in Annexin-FITC/PI analysis. The use of general caspase-inhibitor Z-VAD-FMK indicated that EADs-induced apoptosis was caspase-independent. EADs was found to promote oxidative stress that will lead to cell death because the pre-treatment with antioxidants α-tocopherol and ascorbic acid significantly reduced the cytotoxicity of the extract (P<0.05). DCFH-DA assay revealed that treatment with EADs attenuated the generation of intracellular ROS. The use of JC-1 dye reflected that EADs caused disruption in the mitochondrial membrane potential. Up-regulation of p53 and p21, is believed has led to EADs-induced nonphase specific cell cycle arrest (P<0.05). Elevation of Bax/Bcl-2 ratio and the depolarization of mitochondrial membrane potential indicated that EADs-induced apoptosis was mitochondrial-dependent.The expression of oxidative stress–related proteins AKT, p-AKT, ERK, and p-ERK was downregulated with upregulation of JNK and p-JNK suggesting that induction of apoptosis by EADs is mediated by inhibition of AKT and ERK, and activation of JNK. The major compounds of EADs were then isolated using column chromatography and elucidated using nuclear magnetic resonance analysis producing a total of 6 compounds. The cytotoxicity of the isolated compound was determined using MTT assay. Gallic acid was found to be most cytotoxic against MCF-7 cell line compared to others, with IC50 of 36 ± 1.7µg/mL (P<0.05). In summary, EADs induced cell cycle arrest, oxidative stress and apoptosis in MCF-7 cells Thus, EADs has the potential to be developed as an anti-cancer agent against breast cancer

The genetic landscape of CYP24A1 polymorphisms in cancer risk: evidence from a systematic review

Abstract Cancer remains a significant global health challenge, with a multifaceted etiology that includes genetic factors. Among these, CYP24A1 stands out for its pivotal role in vitamin D metabolism and regulates biological processes influencing cancer risk. Single nucleotide polymorphisms in CYP24A1 are associated with variations in vitamin D bioavailability, potentially impacting the initiation and progression of cancer. To date, no comprehensive review has been conducted on this topic. Therefore, this systematic review aims to investigate the association between common CYP24A1 polymorphisms and cancer susceptibility, by analyzing studies retrieved from PubMed, Scopus, Cochrane Library, and Web of Science databases up to January 2024. Using PRISMA guidelines and quality assessments with the Newcastle Ottawa Scale (NOS), 22 studies, with 28,132 participants (12,751 cases and 15,381 controls) were included. The reported odds ratio and p-value were used to assess the association between CYP24A1 SNPs (rs2296241, rs6068816, rs927650, rs2181874 and rs2585428) with various cancer risks. Key findings revealed that SNP rs2296241 was linked to increased risk of follicular thyroid cancer but lower risks in papillary thyroid cancer, esophageal squamous cell carcinoma, oral cancer, and prostate cancer. SNP rs6068816 correlated with reduced breast and lung cancer risks, while rs927650 and rs2181874 were associated with lower risks in papillary thyroid cancer and prostate cancer, respectively. SNP rs2585428 showed a lower risk in breast and prostate cancers suggesting a protective effect against these malignancies. These results highlight CYP24A1 polymorphisms as potential molecular markers for cancer susceptibility, underscoring their clinical relevance in risk assessment and personalized interventions

Anti-breast cancer properties and toxicity of Dillenia suffruticosa root aqueous extract in BALB/c mice

AbstractObjectiveTo determine the anti-breast cancer activities and the safety oral consumption of Dillenia suffruticosa root aqueous extract (DRAE) in BALB/c mice.MethodsIn the anti-breast cancer study, female BALB/c mice were divided into five groups (n = 12), which were (1) positive control (with breast cancer, untreated), (2) negative control (without breast cancer, untreated) and other three groups of mice with breast cancer treated with 1000, 500 and 250 mg/kg of DRAE, respectively, by oral gavage for 28 days. All mice except from the negative control group were injected into the mammary fat pad with 4T1 cells (1 × 105 4T1 cells/0.1 mL of phosphate buffer solution). DRAE was administered orally on Day 11 after the tumor has developed.ResultsThe tumor volume of the 1000 mg/kg of DRAE group reduced significantly compared to the positive control while treatment with 500 mg/kg of DRAE had significantly inhibited metastasis to the heart. In the acute toxicity study, treatment with up to 5000 mg/kg of DRAE was not toxic to the animals, indicating its safety when a large amount of this plant extract was ingested. Based on the sub-acute toxicity study, treatment of the highest dose of DRAE (1000 mg/kg) had mild liver toxicity indicated by mild focal hemorrhage.ConclusionsDRAE possesses anti-breast cancer properties but at the same time it shows mild toxicity to the liver. The non observable adverse effect dose for DRAE is 500 mg/kg