The Potential Chemopreventive Effect of Andrographis paniculata on 1,2-Dimethylhydrazine and High-Fat-Diet-Induced Colorectal Cancer in Sprague Dawley Rats.

Colorectal cancer (CRC) is responsible for a notable rise in the overall mortality rate. Obesity is found to be one of the main factors behind CRC development. Andrographis paniculata is a herbaceous plant famous for its medicinal properties, particularly in Southeast Asia for its anti-cancer properties. This study examines the chemopreventive impact of A. paniculata ethanolic extract (APEE) against a high-fat diet and 1,2-dimethylhydrazine-induced colon cancer in Sprague Dawley rats. Sprague Dawley rats were administered 1,2-dimethylhydrazine (40 mg/kg, i.p. once a week for 10 weeks) and a high-fat diet (HFD) for 20 weeks to induce colorectal cancer. APEE was administered at 125 mg/kg, 250 mg/kg, and 500 mg/kg for 20 weeks. At the end of the experiment, blood serum and organs were collected. DMH/HFD-induced rats had abnormal crypts and more aberrant crypt foci (ACF). APEE at a dose of 500 mg/kg improved the dysplastic state of the colon tissue and caused a 32% reduction in the total ACF. HFD increased adipocyte cell size, while 500 mg/kg APEE reduced it. HFD and DMH/HFD rats had elevated serum insulin and leptin levels. Moreover, UHPLC-QTOF-MS analysis revealed that APEE was rich in anti-cancer phytochemicals. This finding suggests that APEE has anti-cancer potential against HFD/DMH-induced CRC and anti-adipogenic and anti-obesity properties.

Dietary Patterns, Metabolomic Profile, and Nutritype Signatures Associated with Type 2 Diabetes in Women with Postgestational Diabetes Mellitus: MyNutritype Study Protocol.

Women with previous gestational diabetes mellitus (post-GDM) have an increased risk of cardiometabolic diseases including type 2 diabetes (T2D). Current diabetes screening is based on the oral glucose tolerance test without nutritional assessments, even though unhealthy dietary patterns were found to expedite disease progression in women post-GDM. While a healthful dietary pattern reduces T2D risk, limited data support a dietary pattern tailored to the Asian population, especially in the Malaysian context. Metabolomic profiles associated with dietary patterns in this population are also lacking. The proposed study aims to investigate both components of dietary patterns and metabolomic profile, known as nutritype signatures, and their association with T2D in women post-GDM. The comparative cross-sectional study will involve a minimum of 126 Malaysian women post-GDM aged 18-49 years. Dietary patterns will be analysed using principal component analysis. Plasma and urinary metabolites will be quantified using one-dimensional proton nuclear magnetic resonance (1H NMR) spectroscopy. The aim of the study is identifying the nutritype signatures associated with T2D. The findings will support the development of early prevention measures against T2D in women post-GDM.

An Interactive Review on the Role of Tocotrienols in the Neurodegenerative Disorders.

Neurodegenerative disorders, such as Parkinson's and Alzheimer's disease, are claimed to be of major concern causing a significant disease burden worldwide. Oxidative stress, mitochondrial dysfunction and nerve damage are the main reasons for the emergence of these diseases. The formation of reactive oxygen species (ROS) is the common chemical molecule that is formed from all these three interdependent mechanisms which is highly reactive toward the neuronal cells. For these reasons, the administration of tocotrienols (T3s), which is a potent antioxidant, is proven to cater to this problem, through in vitro and in vivo investigations. Interestingly, their therapeutic potentials are not only limited to antioxidant property but also to being able to reverse the neuronal damage and act as a shield for mitochondria dysfunction. Thereby, T3s prevents the damage to the neurons. In regards to this statement, in this review, we focused on summarizing and discussing the potential therapeutic role of T3s on Alzheimer's and Parkinson's diseases, and their protective mechanisms based on evidence from the in vitro and in vivo studies. However, there is no clinical trial conducted to prove the efficacy of T3s for Alzheimer's and Parkinson's subjects. As such, the therapeutic role of T3s for these neurodegenerative disorders is still under debate.

Functional food mixtures: Inhibition of lipid peroxidation, HMGCoA reductase, and ACAT2 in hypercholesterolemia-induced rats.

Mixtures of selected functional foods (MSFF) were composed of nattokinase (fermented soybean), red yeast rice extract, Ginkgo biloba, oat fiber, garlic, bee pollen, and propolis as anti-hypercholesterolemic were studied. The goal of this study was to determine the bioactive compounds in these mixtures and their cholesterol-lowering potential effects (biochemical profiles, lipid peroxidation, liver tissue histopathology, and enzymatic activity analysis; HMGCoA reductase and ACAT2. The LC-MS/MS analysis showed that bioactive compounds such as Monacolin K, naringin, tocopherol, and glutamate, which have potential as anti-hypercholesterolemic agents, were present in these functional food mixtures. MSFF supplementation at 50 mg/kg 100 mg/kg and 200 mg/kg showed substantial reductions in serum lipid profiles (TC and LDL) (p < .05). The serum liver profiles of AST (115.33 ± 8.69 U/L) and ALT (61.00 ± 1.00 U/L) were significantly reduced (p < .05) with MSFF supplementation at 200 mg/kg. MDA lipid peroxidation has also decreased significantly (p < .05) in serum (3.69 ± 0.42 µmol/L) and liver (15.04 ± 0.97 µmol/mg) tissues and has been shown to protect against hepatic steatosis. The significant (p < .05) inhibition activity of HMGCoA reductase (163.82 ± 3.50 pg/ml) and ACAT2 (348.35 ± 18.85 pg/ml) was also attributed by the supplementation of MSFF at 200 mg/kg.

Antiobesity Activity of Elateriospermum tapos Shell Extract in Obesity-Induced Sprague Dawley Rats.

Obesity is one of the risk factors associated with cardiovascular diseases, hypertension, abnormal liver function, diabetes, and cancers. Orlistat is currently available to treat obesity, but it is associated with adverse side effects. Natural resources are widely used for obesity treatment. Hence, this study aimed to investigate the anti-obesity activity of Elateriospermum tapos (E. tapos) shell extract in obesity induced Sprague Dawley rats. The rats' obesity was induced by a high-fat (HF) diet made up of 50% standard rat pellet, 20% milk powder, 6% corn starch, and 24% ghee and a cafeteria (CAF) diet such as chicken rolls, salty biscuits, cakes, and cheese snacks. A hot aqueous method for the extraction of E. tapos shells was applied by using 500 mL of distilled water for about 24 h. Various dosages of E. tapos shell extract (10 mg/kg, 100 mg/kg, and 200 mg/kg) were used. At the end of the study, body weight, caloric intake, organ weight, lipid profile, lipoprotein lipase (LPL) activity, and histopathology analysis were carried out. E. tapos shell extract treated groups showed a reduction in body weight, positive lipid-lowering effect, decrements in triglyceride accumulation and LPL activity, and positive improvement in histopathology analysis. A dose of 200 mg/kg showed the most effective result compared to 10 mg/kg and 100 mg/kg doses.

Mikania micrantha Extract Inhibits HMG-CoA Reductase and ACAT2 and Ameliorates Hypercholesterolemia and Lipid Peroxidation in High Cholesterol-Fed Rats.

The present study aimed to determine the effect of an ethyl acetate extract of Mikania micrantha stems (EAMMS) in hypercholesterolemia-induced rats. Rats were divided into a normal group (NC) and hypercholesterolemia induced groups: hypercholesterolemia control group (PC), simvastatin group (SV) (10 mg/kg) and EAMMS extract groups at different dosages of 50, 100 and 200 mg/kg, respectively. Blood serum and tissues were collected for haematological, biochemical, histopathological, and enzyme analysis. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, malondialdehyde (MDA) level, as well as enzymes of HMG-CoA reductase (HMGCR) and acetyl-CoA acetyltransferase 2 (ACAT2), were measured. Feeding rats with high cholesterol diet for eight weeks resulted in a significantly (p < 0.05) increased of TC, TG, LDL-C, AST, ALT and MDA levels. Meanwhile, the administration of EAMMS extract (50, 100 and 200 mg/kg) and simvastatin (10 mg/kg) significantly reduced (p < 0.05) the levels of TC, TG, LDL-C and MDA compared to rats in the PC group. Furthermore, all EAMMS and SV-treated groups showed a higher HDL-C level compared to both NC and PC groups. No significant difference was found in the level of ALT, AST, urea and creatinine between the different dosages in EAMMS extracts. Treatment with EAMMS also exhibited the highest inhibition activity of enzyme HMGCR and ACAT2 as compared to the control group. From the histopathological examination, liver tissues in the PC group showed severe steatosis than those fed with EAMMS and normal diet. Treatment with EAMMS extract ameliorated and reduced the pathological changes in the liver. No morphological changes showed in the kidney structure of both control and treated groups. In conclusion, these findings demonstrated that EAMMS extract has anti-hypercholesterolemia properties and could be used as an alternative treatment for this disorder.

Antioxidant and anti-obesity properties of local chilies varieties in Malaysia.

Obesity is a serious health concern as it may initiate common chronic diseases. Chili pepper is an important spice that brings spiciness and commonly used in cuisines. However, the antioxidant and anti-obesity properties of chili varieties in Malaysia has not yet been fully investigated. Therefore, this study aimed to determine the antioxidant (content and activity) and anti-obesity properties of five different varieties of local chili peppers. The antioxidant activities of the extracts were determined through ferric-reducing antioxidant power (FRAP) and 2, 2'azinobis-(3-ethyl-benzothiazoline-6-sulphonic acid (ABTS) assays. Cell cytotoxicity of the selected chili extracts was determined in 3T3-L1 pre adipocytes using cell viability assay (MTT) assay. Whereas the ability to inhibit oil accumulation in fully differentiated 3T3-L1 adipocytes of the selected chili pepper extracts was assayed using Oil Red O staining. The results showed that Kulai 568 pulp extract had the highest level of total phenolic content (TPC) (47.88 ± 0.220 mg GAE/g), whereas Centil pulp extract had the highest level of total flavonoid content (TFC) (26.60 ± 0.52 mg QE/g). In term of antioxidant activities, Bara pulp extract had the highest value in FRAP (3.058 ± 0.002 mM Fe2+/mg extract) and ABTS (IC50 = 12.411 ± 0.025). High performance liquid chromatography (HPLC) analysis, Bara pulp extract has the highest level of capsaicin (72.271 ± 0.957 µg/ml). In terms of inhibition of oil accumulation Centil seed extract presented the best result (69.09-92.20%), while Bara pulp extract inhibited the most pancreatic lipase activity (IC50 = 4.84 ± 0.57 µg/ml). Thus, it is suggested that Centil seed and Bara pulp extracts can be a potent antioxidant and anti-obesity agents.

Iron Chelation Properties of Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Analysis on Tfr/Fth Regulations and Molecular Docking.

In many studies, green tea epigallocatechin-3-gallate (EGCG) has already shown its therapeutic effects in colorectal cancer cells (CRC). However, its mechanism of actions in CRC is poorly elucidated. Hence, this study attempts to elucidate the mechanism of actions of green tea ECGG via iron chelation activity in CRC. In order to investigate this property, HT-29 cell lines (CRC) were treated with EGCG for 24 h, 48 h, and 72 h. From western blot analysis, EGCG had upregulated transferrin receptor (TfR) protein and downregulated Ferritin-H (FtH) protein indicating that iron chelation activity has occurred in CRC. Meanwhile, the molecular docking study demonstrated that EGCG is able to strongly interact the ferritin protein with a high binding affinity (-7.3 kcal/mol) via strong hydrogen bindings to glutamic acid 64 and lysine 71; two moderate hydrogen bindings to asparagine 74 and a hydrophobic interaction to the hydrophobic pocket of lysine 71. The strong interaction predicted between EGCG to ferritin may lead to inhibition of ferritin by EGCG, thus supporting the downregulation of FtH observed in in vitro studies. Molecular docking study of TfR to EGCG cannot be modulated based on the in vitro results. In conclusion, EGCG possesses iron chelator property in CRC and this potential could be further exploited for CRC treatment.

The Acute Effects of Oral Administration of Phytic Acid-Chitosan-Magnetic Iron Oxide Nanoparticles in Mice.

A nanocomposite, phytic acid-chitosan-magnetic iron oxide nanoparticles (IP6-CS-MNPs) has been used to treat colon cancer in vitro, previously. However, its potential toxicity in vivo has yet to be elucidated. Hence, the present study aimed to evaluate the acute effects of oral administration of IP6-CS-MNPs in mice. In this study, 1000 and 2000 mg/kg body weight (b.w) of IP6-CS-MNPs were orally administered to two different groups of BALB/c mice, once. Additionally, the mice in the control group were given only deionized water. After 14 days of post-IP6-CS-MNPs administration, in a similar way to the untreated mice, the treated mice showed no sign of mortality and abnormalities. However, the serum urea level of mice receiving 2000 mg/kg b.w of IP6-CS-MNPs was significantly higher than the control group (p < 0.05). The mice that received 1000 mg/kg IP6-CS-MNPs showed a significantly higher level of serum alkaline phosphatase (ALP) compared to the control group. However, there were no significant histopathological changes seen in the liver and kidneys of treated mice compared to the untreated group.

Induction of Endoplasmic Reticulum Stress Pathway by Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Activation of PERK/p-eIF2α/ATF4 and IRE1α.

Epigallocatechin-3-gallate (EGCG) is the most abundant bioactive polyphenolic compound among the green tea constituents and has been identified as a potential anticancer agent in colorectal cancer (CRC) studies. This study was aimed to determine the mechanism of actions of EGCG when targeting the endoplasmic reticulum (ER) stress pathway in CRC. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed on HT-29 cell line and normal cell line (3T3) to determine the EGCG toxicity. Next, western blot was done to observe the expression of the related proteins for the ER stress pathway. The Caspase 3/7 assay was performed to determine the apoptosis induced by EGCG. The results demonstrated that EGCG treatment was toxic to the HT-29 cell line. EGCG induced ER stress in HT-29 by upregulating immunoglobulin-binding (BiP), PKR-like endoplasmic reticulum kinase (PERK), phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2α), activating transcription 4 (ATF4), and inositol-requiring kinase 1 alpha (IRE1α). Apoptosis was induced in HT-29 cells after the EGCG treatment, as shown by the Caspase 3/7 activity. This study indicates that green tea EGCG has the potential to inhibit colorectal cancer cells through the induction of ER stress.

Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer.

Mitogen-activated protein kinases (MAPKs) are the main regulators of cellular proliferation, growth, and survival in physiological or pathological conditions. Aberrant MAPK signaling plays a pivotal role in carcinogenesis, which leads to development and progression of human cancer. Dual-specificity phosphatase 6 (DUSP6), a member of the MAPK phosphatase family, interacts with specifically targeted extracellular signal-regulated kinase 1/2 via negative feedback regulation in the MAPK pathway of mammalian cells. This phosphatase functions in a dual manner, pro-oncogenic or tumor-suppressive, depending on the type of cancer. To date, the tumor-suppressive role of DUSP6 has been demonstrated in pancreatic cancer, non-small cell lung cancer, esophageal squamous cell and nasopharyngeal carcinoma, and ovarian cancer. Its pro-oncogenic role has been observed in human glioblastoma, thyroid carcinoma, breast cancer, and acute myeloid carcinoma. Both roles of DUSP6 have been documented in malignant melanoma depending on the histological subtype of the cancer. Loss- or gain-of-function effects of DUSP6 in these cancers highlights the significance of this phosphatase in carcinogenesis. Development of methods that use the DUSP6 gene as a therapeutic target for cancer treatment or as a prognostic factor for diagnosis and evaluation of cancer treatment outcome has great potential. This review focuses on molecular characteristics of the DUSP6 gene and its role in cancers in the purview of development, progression, and cancer treatment outcome.

Pro-apoptotic effect of rice bran inositol hexaphosphate (IP6) on HT-29 colorectal cancer cells.

Inositol hexaphosphate (IP6), or phytic acid is a natural dietary ingredient and has been described as a "natural cancer fighter", being an essential component of nutritional diets. The marked anti-cancer effect of IP6 has resulted in our quest for an understanding of its mechanism of action. In particular, our data provided strong evidence for the induction of apoptotic cell death, which may be attributable to the up-regulation of Bax and down-regulation of Bcl-xl in favor of apoptosis. In addition, the up-regulation of caspase-3 and -8 expression and activation of both caspases may also contribute to the apoptotic cell death of human colorectal adenocarcinoma HT-29 cells when exposed to IP6. Collectively, this present study has shown that rice bran IP6 induces apoptosis, by regulating the pro- and anti-apoptotic markers; Bax and Bcl-xl and via the activation of caspase molecules (caspase-3 and -8).

Preventive inositol hexaphosphate extracted from rice bran inhibits colorectal cancer through involvement of Wnt/ß-catenin and COX-2 pathways.

Nutritional or dietary factors have drawn attention due to their potential as an effective chemopreventive agent, which is considered a more rational strategy in cancer treatment. This study was designed to evaluate the effect of IP6 extracted from rice bran on azoxymethane- (AOM-) induced colorectal cancer (CRC) in rats. Initially, male Sprague Dawley rats were divided into 5 groups, with 6 rats in each group. The rats received two intraperitoneal (i.p.) injections of AOM in saline (15 mg/kg body weight) over a 2-week period to induce CRC. IP6 was given in three concentrations, 0.2% (w/v), 0.5% (w/v), and 1.0% (w/v), via drinking water for 16 weeks. The deregulation of the Wnt/ß-catenin signaling pathway and the expression of cyclooxygenase (COX)-2 have been implicated in colorectal tumorigenesis. ß-Catenin and COX-2 expressions were analysed using the quantitative RT-PCR and Western blotting. Herein, we reported that the administration of IP6 markedly suppressed the incidence of tumors when compared to the control. Interestingly, the administration of IP6 had also markedly decreased ß-catenin and COX-2 in colon tumors. Thus, the downregulation of ß-catenin and COX-2 could play a role in inhibiting the CRC development induced by IP6 and thereby act as a potent anticancer agent.