Novel piperazine-1,2,3-triazole leads for the potential treatment of pancreatic cancer.

From lead 1, (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2-p53 protein-protein interaction inhibitor based on an in silico modelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against 16 human cancer cell lines including the pancreatic cell lines MiaPaCa2, BxPC3, AsPC-1, Capan-2, HPAC, PANC-1 and the drug resistant CFPAC1. Modification of 1's phenylacetamide moiety, gave Library 1 with only modest pancreatic cancer activity. Modification of the 3-OCH3Ph moiety (Library 2) gave 4-CH3 (26), 4-CH2CH3 (27), 4-CF3 (31) and 4-NO2 (32) with sterically bulky groups more active. A 4-CF3 acetamide replacement enhanced cytotoxicity (Library 3). The 4-C(CH3)336 resulted in a predicted steric clash in the S100A2-p53 binding groove, with a potency decrease. Alkyl moieties afforded more potent analogues, 34 (4-CH3) and 35 (CH2CH3), a trend evident against pancreatic cancer: GI50 3.7 (35; BxPC-3) to 18 (40; AsPC-1) µM. Library 4 analogues with a 2-CF3 and 3-CF3 benzenesulfonamide moiety were less active than the corresponding Library 3 analogues. Two additional analogues were designed: 51 (4-CF3; 4-OCH3) and 52 (4-CF3; 2-OCH3) revealed 52 to be 10-20 fold more active than 51, against the pancreatic cancer cell lines examined with sub-micromolar GI50 values 0.43 (HPAC) to 0.61 µM (PANC-1). MOE calculated binding scores for each pose are also consistent with the observed biological activity with 52. The obtained SAR data is consistent with the proposed interaction within the S100A2-p53 bonding groove.

Salt-Taste Polymorphism TRPV1-rs8065080 Is Associated with Increased Likelihood of Depression in an Elderly Cohort.

INTRODUCTION: Despite the prevalence of depression and anxiety worldwide, their aetiologies remain unclear, and they can be difficult to diagnose and treat. Changes in salt-taste perception have been found in both conditions. Single-nucleotide polymorphisms (SNPs) in the salt-taste-related gene, TRPV1, have been associated with alterations to salt-taste perception, preference, and sodium consumption. Diet quality is a known modifier of depression and anxiety and recently, sodium intake has been studied in mental health. However, the relationships between salt-taste genetics, depression, anxiety, and these dietary factors are yet to be elucidated. METHODS: Data from the well-characterized cross-sectional Retirement Health and Lifestyle Study (n = 536, ≥65 y) were used to explore the relationships between the salt-taste SNP TRPV1-rs8065080, levels of depression and anxiety (Hospital Anxiety and Depression Scale, HADS), estimated sodium intake, and diet quality in this secondary analysis. Standard least-squares regression and nominal logistic regression modelling were used to compare continuous and categorical variables, respectively, with analyses stratified by sex. RESULTS: Presence of the TRPV1-rs8065080 variant allele (C) was found to increase the likelihood of having depression (HADS) in the total population and in males. The associations remained significant after adjusting for sodium intake, three diet quality indices, and demographic variables, suggesting that TRPV1-rs8065080 genotype is driving the association with depression. DISCUSSION/CONCLUSION: Future studies should explore extra-oral functions of the SNP and salt-taste receptors in the brain and the roles of neurotransmitters common to both depression and salt taste to improve the management of this increasingly prevalent and difficult-to-treat condition.

Liking of salt is associated with depression, anxiety, and stress.

Early research has shown variations in salt taste qualities in depression, anxiety, and stress. These studies evaluated changes to salt taste intensity and liking (pleasantness) of salt solutions but not of salty foods. Therefore, an Australian population survey (n = 424) was conducted where participants rated recalled intensity and liking of salt index foods and completed the Depression, Anxiety, and Stress Scale (DASS-21) to measure these states. Standard least squares regression (post hoc Tukey's HSD) compared means between groups, and nominal logistic regression assessed differences in distributions between categories. Higher salt liking was found in participants with DASS-21 scores indicative of severe depression (68.3 vs. 60.0, P = 0.005) and severe anxiety (68.4 vs. 60.0, P = 0.001) in comparison to those with normal scores, in all models. Higher salt liking was found in participants with DASS-21 scores indicative of moderate stress (67.7 vs. 60.2, P = 0.009) in the unadjusted model only. Higher salt liking was found in females with DASS-21 scores indicative of anxiety and stress, and in males with indicative depression and anxiety. No relationships between salt taste intensity ratings and the mood states were found. Results indicate that liking salty foods is positively correlated with depression, anxiety, and stress scores. Further research on the relationships between salt liking and intake of salt and salty foods, and the biological mechanisms of these mood states are needed to direct the application of findings toward potential new risk assessment measures, dietary interventions, or therapeutics.

Characterisation of a High Fibre Flour Prepared from Soy Milk By-Product and Its Potential Use in White Wheat Bread.

The commercial production of soy milk renders a large quantity of wet soybean by-product (SMB), which is typically dumped, incinerated, or partially used as animal fodder. This wet SMB has a high moisture content that is rich in nutritional and biologically active compounds. This study aimed to characterise the composition and properties of a flour milled from SMB dried at 100 °C (SMB100) and assess its possible application as a fibre substitute in white bread. The results showed that SMB100 has high levels of dietary fibre (40.6%) and protein (26.5%). It also contains high levels of saponins (31.4 mg/g) and isoflavones (698.0 µg/g). SMB100 has a light-yellow colour with low moisture content and water activity (8.2% and 0.55, respectively). The results also indicated that replacement of wheat flour with SMB100 at 10 or 12.5% by flour weight negatively impacted the raising volume, density, and texture of white bread. Alternatively, substituting wheat flour with 5% of SMB100, did not significantly impact the physical properties of white bread, while significantly improving its dietary fibre content in comparison with the control, revealing that SMB100 is a potential substitute of wheat flour for improvement of dietary fibre in bread. Future studies are needed to optimise bread formulation and improve the processing condition which produces quality white bread with high dietary fibre using SMB100.

The Mechanistic Roles of Sirtuins in Breast and Prostate Cancer.

Mammalian sirtuins (SIRT1-7) are involved in a myriad of cellular processes, including apoptosis, proliferation, differentiation, epithelial-mesenchymal transition, aging, DNA repair, senescence, viability, survival, and stress response. In this review, we discuss the current information on the mechanistic roles of SIRT1-7 and their downstream effects (tumor promotion or suppression) in cancers of the breast and prostate. Specifically, we highlight the involvement of sirtuins in the regulation of various proteins implicated in proliferation, apoptosis, autophagy, chemoresistance, invasion, migration, and metastasis of breast and prostate cancer. Additionally, we highlight the available information regarding SIRT1-7 regulation by miRNAs, laying much emphasis on the consequences in the progression of breast and prostate cancer.

Determination of bioactive compounds, antioxidant and anticancer activities of Tuckeroo (Cupaniopsis anacardioides) fruits.

This study aimed to determine the phytochemical, antioxidant, and anticancer activities of the crude extract and its fractions of Cupaniopsis anacardioides. The results showed that total phenolic content (TPC), their secondary metabolites (flavonoids-TFC; proanthocyanidins-TPro), and antioxidant activity were significantly different between the crude extract and its fractions. The butanol fraction (F3) had the highest levels of TPC, TFC, and TPro, followed by the crude extract, aqueous fraction (F4), dichloromethyl fraction (F2), and hexane fraction (F1). High-Pressure Liquid Chromatography (HPLC) analysis revealed 14 major bioactive compounds were identified in the C. anacardioides extract. Further analysis showed F3 fraction contained the highest levels of the major bioactive compounds, while F1 fraction had the lowest. A similar pattern was observed for antioxidant activities. The crude extract, F3 and F4 fractions were further tested for cytotoxicity against 10 cancer cell lines, including HT29 (colon); U87, SJG2 (glioblastoma); MCF-7 (Breast); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); BE2-C (neuroblastoma); MIA PaCa-2 (pancreas); and one non-tumour-derived normal breast cell line (MCF10A). Except for Du145 (prostate), the crude extract, F3 and F4 fractions inhibited the cancer cell lines at 100 µg/mL, with F3 possessing greater activity against these cancer cell lines. Future studies are recommended to isolate and identify the major bioactive compounds of the F3 fraction, and further tested their impact against cancer cell lines. This could identify the potential of anticancer agents from C. anacardioides.

3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety.

Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 = 2.97 µM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total. Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 < 6 µM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI50 values ranged from 1.4 to 30 µM against cohort-1 and 1.4-30 µM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2-3.4 µM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.

Biophysical evidence to support and extend the vitamin D-folate hypothesis as a paradigm for the evolution of human skin pigmentation.

OBJECTIVE: To test the "vitamin D-folate hypothesis for the evolution of human skin pigmentation." METHODS: Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n = 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n = 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. RESULTS: Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). UV-wavelength exhibits a dose-response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. Three dietary antioxidants (vitamins C, E, and ß-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3 . CONCLUSION: New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.

Sour Taste SNP KCNJ2-rs236514 and Differences in Nutrient Intakes and Metabolic Health Markers in the Elderly.

Single nucleotide polymorphisms (SNPs) in taste receptors influence dietary choices that contribute to health and quality of life. Individual differences in sour taste perception and preference have been linked to heritable genetics, yet the impact of sour taste receptor SNPs on sour taste is under-researched, and studies on sour taste SNP associations to diet and health are lacking. Therefore, this study explored the relationships between the sour taste SNP KCNJ2-rs236514 and estimated macronutrient, vitamin and mineral intakes, and markers of metabolic health. Associations were explored in 523 participants aged 65 years and older with data analysed using standard least squares and nominal logistic regression modelling with post hoc student's t-tests and Tukey's HSD. Associations were found between the presence of the KCNJ2-rs236514 variant allele (A) and lower intakes of energy, total fat, monounsaturated fat and saturated fat. The lower fat intakes were significant in female carriers of the variant allele (A), along with lower water intake. Lower retinol, riboflavin, folate, calcium and sodium intakes were found in the KCNJ2-A allele carriers. In females, the variant allele was associated with lower sodium intake before and after Bonferroni adjustment. Higher body mass index, waist and waist-to-hip ratio measures were found in males carrying the variant allele. Lower levels of liver function biomarkers were associated with the presence of the KCNJ2-A allele. Overall and in males, the variant's association to lower gamma-glutamyl transferase (GGT) levels remained significant after Bonferroni adjustments. These novel findings suggest the sour taste SNP, KCNJ2-rs236514, may be modifying macronutrient, vitamin and mineral intakes, and markers of metabolic health. Research on the extra-oral functions of this SNP may improve health outcomes for those with overweight, obesity and liver disease.

Targeting the S100A2-p53 Interaction with a Series of 3,5-Bis(trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity.

In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (three libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal; the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N-methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad-spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2-p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.

Cytotoxic 1,2,3-Triazoles as Potential Leads Targeting the S100A2-p53 Complex: Synthesis and Cytotoxicity.

In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 µM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF3 Library 3 analogues the most active, with GI50 values of 0.91 (3-ClPh; 13 i; BxPC-3, Pancreas) to 9.0 µM (4-CH3 ; 13 d; PANC-1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 µM (4-C(CH3 )3 ; 13 e; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.

Assessment and comparison of phytochemicals and antioxidant properties from various parts of the Australian maroon bush (Scaevola spinescens).

Scaevola spinescens is endemic to Australia and traditionally used as a medicinal plant. While its bioactive compounds have been studied, their concentrations in different parts of the plant have not been reported. This study compared total phenolic content (TPC), flavonoids, saponins and antioxidant properties, as well as major individual phytochemical compounds in the whole root, root bark, root wood, whole stem, stem bark, stem wood, and leaf of S. spinescens. The results showed the leaf had significantly highest concentrations of TPC followed by the root bark and stem bark (47.34, 12.24 and 10.20 mg GAE/g, respectively). Flavonoids concentrations were also significantly higher in the leaf compared to the root bark and stem bark (20.95, 6.22 and 4.19 mg CE/g, respectively). For saponins, the root bark contained significantly highest concentrations (112.58 mg EE/g). Luteolin 7-glucoside was isolated and identified in the leaf of S. spinescens. Eight major compounds were identified with the leaf displaying the highest diversity of major compounds, and in higher concentrations, compared to the other plant constituents. As the leaf and root bark contained the highest concentrations of phytochemicals, these plant parts are recommended as starting material for future studies, to further isolate and identify the major compounds from S. spinescens and investigate their biological properties for use in pharmaceutical and food applications.

Ethnopharmacology, Biological Activity and Phytochemistry of Scaevola spinescens.

Scaevola spinescens is endemic to Australia and has traditionally been used by Aboriginal and Torres Strait Islander communities to treat a variety of conditions including colds, flu, fever, stomach pain, urinary disorders, sores, tinea, leprosy, and cancer. Extracts prepared from S. spinescens are non-toxic and have been linked with various medicinal properties including antiviral, antibacterial, anti-inflammatory, and anticancer activities. These studies support the ethnopharmacological use of S. spinescens by Indigenous peoples of Australia and highlight the need for further investigations on the plant for potential use in pharmaceutical and food applications. This review provides a comprehensive, up-to-date review of the literature on S. spinescens focusing on the traditional use, medicinal properties, phytochemicals, and factors that affect their composition during pre-treatment and extraction, as well as providing a framework for future studies of the plant.

Association between Sour Taste SNP KCNJ2-rs236514, Diet Quality and Mild Cognitive Impairment in an Elderly Cohort.

Differences in sour-taste thresholds have been identified in cognition-related diseases. Diet is a modulator of cognitive health, and taste perception influences dietary preferences and habits. Heritable genetics and polymorphisms in the KCNJ2 gene involved in the transduction of sour taste have been linked to variations in sour taste and non-gustatory functions. However, relationships between sour taste genetics, mild cognitive impairment, and diet quality are yet to be elucidated. This study investigated the associations between the presence of the KCNJ2-rs236514 variant (A) allele, diet quality indices, and mild cognitive impairment evaluated by the Mini-Mental State Examination (MMSE), in a secondary cross-sectional analysis of data from the Retirement Health & Lifestyle Study. Data from 524 elderly Australians (≥65y) were analyzed, using standard least squares regression and nominal logistic regression modeling, with demographic adjustments applied. Results showed that the presence of the KCNJ2-A allele is associated with increased proportions of participants scoring in the range indicative of mild or more severe cognitive impairment (MMSE score of ≤26) in the total cohort, and males. These associations remained statistically significant after adjusting for age, sex, and diet quality indices. The absence of association between the KCNJ2-A allele and cognitive impairment in women may be related to their higher diet quality scores in all indices. The potential link between sour taste genotype and cognitive impairment scores may be due to both oral and extra-oral functions of sour taste receptors. Further studies are required on the role and relationship of neurotransmitters, sour taste genotypes and sour taste receptors in the brain, and dietary implications, to identify potential risk groups or avenues for therapeutic or prophylactic interventions.

Genetic Variation in the Bitter Receptors Responsible for Epicatechin Detection Are Associated with BMI in an Elderly Cohort.

Globally, more than one-third of adults are overweight. Overweight and obesity are complex and multifaceted conditions, associated with an increased risk of chronic illness and early mortality. While there are known risk factors, these alone do not fully explain the varying outcomes between individuals. Recently, taste receptors have been proposed to have a role in the risk for obesity. These receptors are expressed throughout the gastrointestinal tract. In this system, they may be involved in modulating dietary intake and metabolic processes. The taste 2 family of receptors (T2Rs) detects bitter compounds. Receptors T2R4 and T2R5 detect (-)-epicatechin (epicatechin), an antioxidant polyphenol, which may have protective effects against obesity. However, the potential role for taste receptors in this association has not been explored. This study assessed whether polymorphisms in TAS2R4 (rs2233998 and rs2234001) and TAS2R5 (rs2227264) were associated with body mass index (BMI). Genotyping (Taqman qPCR assays) was performed on DNA extracted from blood samples (n = 563) from an elderly cohort. Homozygosity for the minor allele of all polymorphisms was significantly associated with a lower BMI in males. The TAS2R4-rs2233998 CC genotype, the TAS2R4-rs2234001 CC genotype and the TAS2R5-rs2227264 TT genotype were associated with lower BMI (2.1, 2.1 and 2.2 units; p = 0.002, 0.003 and 0.001, respectively). Epicatechin intake was not associated with BMI and genotype was not associated with epicatechin intake. This suggests that the association between TAS2R genotype and elevated BMI risk occurs through altered extra-oral responses and not directly via altered epicatechin intake.

Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

Intense Sweeteners, Taste Receptors and the Gut Microbiome: A Metabolic Health Perspective.

Intense sweeteners (IS) are often marketed as a healthier alternative to sugars, with the potential to aid in combating the worldwide rise of diabetes and obesity. However, their use has been counterintuitively associated with impaired glucose homeostasis, weight gain and altered gut microbiota. The nature of these associations, and the mechanisms responsible, are yet to be fully elucidated. Differences in their interaction with taste receptors may be a potential explanatory factor. Like sugars, IS stimulate sweet taste receptors, but due to their diverse structures, some are also able to stimulate bitter taste receptors. These receptors are expressed in the oral cavity and extra-orally, including throughout the gastrointestinal tract. They are involved in the modulation of appetite, glucose homeostasis and gut motility. Therefore, taste genotypes resulting in functional receptor changes and altered receptor expression levels may be associated with metabolic conditions. IS and taste receptors may both interact with the gastrointestinal microbiome, and their interactions may potentially explain the relationship between IS use, obesity and metabolic outcomes. While these elements are often studied in isolation, the potential interactions remain unexplored. Here, the current evidence of the relationship between IS use, obesity and metabolic outcomes is presented, and the potential roles for interactions with taste receptors and the gastrointestinal microbiota in modulating these relationships are explored.

Encapsulation of phenolic-rich extract from banana (Musa cavendish) peel.

Banana peel, a by-product rich in phenolics and other bioactive compounds, has great potentials as a natural preservative or healthy food ingredient. However, the instability of bioactive compounds derived from banana peel limits their applications, and as such encapsulation is necessary to improve their stability and widen their applications. This study investigated the impact of spray drying conditions and coating materials on the physical, phytochemical, and antioxidant properties of the peel extract to identify the most suitable encapsulation process. The results showed that inlet temperature (ranging from 140 to 180 °C) and feeding rate (3-15 mL/min) did not significantly affect the total phenolic content (TPC) and antioxidant capacity but influenced the moisture content and recovery yield of the powder. The ratio of dry matter in fresh extract-to-coating material (DM-to-CM) (1:1-1:7 (w/w)) did not affect the moisture content. However, it affected the TPC, antioxidant properties, and recovery yield of the powder. Finally, the type of coating materials did not significantly affect TPC and antioxidant properties, but other physical properties, dopamine levels and recovery yield. The most suitable encapsulation conditions were identified as an inlet drying temperature of 150 °C, a feeding rate of 9 mL/min, a ratio of DM-to-CM of 1:1 (w/w), and coating with a combination of maltodextrin M100 and gum acacia. Powder prepared under the most suitable conditions had a spherical shape with a rough surface and had stable TPC under storage conditions of 40 °C for 4 weeks. It also has ideal physical, phytochemical and antioxidant properties and is suitable for further applications.

Independent and Interactive Influences of Environmental UVR, Vitamin D Levels, and Folate Variant MTHFD1-rs2236225 on Homocysteine Levels.

Elevated homocysteine (Hcy) levels are a risk factor for vascular diseases. Recently, increases in ultraviolet radiation (UVR) have been linked to decreased Hcy levels. This relationship may be mediated by the status of UVR-responsive vitamins, vitamin D and folate, and/or genetic variants influencing their levels; however, this has yet to be examined. Therefore, the independent and interactive influences of environmental UVR, vitamin D and folate levels and related genetic variants on Hcy levels were examined in an elderly Australian cohort (n = 619). Red blood cell folate, 25-hydroxyvitamin D (25(OH)D), and plasma Hcy levels were determined, and genotyping for 21 folate and vitamin D-related variants was performed. Erythemal dose rate accumulated over six-weeks (6W-EDR) and four-months (4M-EDR) prior to clinics were calculated as a measure of environmental UVR. Multivariate analyses found interactions between 6W-EDR and 25(OH)D levels (pinteraction = 0.002), and 4M-EDR and MTHFD1-rs2236225 (pinteraction = 0.006) in predicting Hcy levels. The association between 6W-EDR and Hcy levels was found only in subjects within lower 25(OH)D quartiles (<33.26 ng/mL), with the association between 4M-EDR and Hcy occurring only in subjects carrying the MTHFD1-rs2236225 variant. 4M-EDR, 6W-EDR, and MTHFD1-rs2236225 were also independent predictors of Hcy. Findings highlight nutrient-environment and gene-environment interactions that could influence the risk of Hcy-related outcomes.

Tetraspanin CD9 is Regulated by miR-518f-5p and Functions in Breast Cell Migration and In Vivo Tumor Growth.

Breast cancer is the most commonly diagnosed and the second leading cause of cancer-related mortality among women worldwide. miR-518f-5p has been shown to modulate the expression of the metastasis suppressor CD9 in prostate cancer. However, the role of miR-518f-5p and CD9 in breast cancer is unknown. Therefore, this study aimed to elucidate the role of miR-518f-5p and the mechanisms responsible for decreased CD9 expression in breast cancer, as well as the role of CD9 in de novo tumor formation and metastasis. miR-518f-5p function was assessed using migration, adhesion, and proliferation assays. miR-518f-5p was overexpressed in breast cancer cell lines that displayed significantly lower CD9 expression as well as less endogenous CD9 3'UTR activity, as assessed using qPCR and dual luciferase assays. Transfection of miR-518f-5p significantly decreased CD9 protein expression and increased breast cell migration in vitro. Cd9 deletion in the MMTV/PyMT mouse model impaired tumor growth, but had no effect on tumor initiation or metastasis. Therefore, inhibition of miR-518f-5p may restore CD9 expression and aid in the treatment of breast cancer metastasis.