Human Metabolism and Excretion of Kawakawa (Piper excelsum) Leaf Chemicals.

SCOPE: Piper excelsum (kawakawa) has a history of therapeutic use by Maori in Aotearoa New Zealand. It is currently widely consumed as a beverage and included as an ingredient in "functional" food product. Leaves contain compounds that are also found in a wide range of other spices, foods, and medicinal plants. This study investigates the human metabolism and excretion of kawakawa leaf chemicals. METHODS AND RESULTS: Six healthy male volunteers in one study (Bioavailability of Kawakawa Tea metabolites in human volunteers [BOKA-T]) and 30 volunteers (15 male and 15 female) in a second study (Impact of acute Kawakawa Tea ingestion on postprandial glucose metabolism in healthy human volunteers [TOAST]) consume a hot water infusion of dried kawakawa leaves (kawakawa tea [KT]). Untargeted Liquid Chromatography-Tandem Mass spectrometry (LC-MS/MS) analyses of urine samples from BOKA-T identified 26 urinary metabolites that are significantly associated with KT consumption, confirmed by the analysis of samples from the independent TOAST study. Seven of the 26 metabolites are also detected in plasma. Thirteen of the 26 urinary compounds are provisionally identified as metabolites of specific compounds in KT, eight metabolites are identified as being derived from specific compounds in KT but without resolution of chemical structure, and five are of unknown origin. CONCLUSIONS: Several kawakawa compounds that are also widely found in other plants are bioavailable and are modified by phase 1 and 2 metabolism.

Exploring the Chemical Space of Kawakawa Leaf (Piper excelsum).

The chemical profiles of kawakawa (Piper excelsum) leaves were analysed through targeted and non-targeted LC-MS/MS. The phytochemical profile was obtained for both aqueous extracts representative of kawakawa tea and methanolic extracts. Sixty-four compounds were identified from eight leaf sources including phenylpropanoids, lignans, flavonoids, alkaloids and amides. Eight of these compounds were absolutely quantified. The chemical content varied significantly by leaf source, with two commercially available sources of dried kawakawa leaves being relatively high in phenylpropanoids and flavonoids compared with field-collected fresh samples that were richer in amides, alkaloids and lignans. The concentrations of pharmacologically active metabolites ingested from the traditional consumption of kawakawa leaf as an aqueous infusion, or from novel use as a seasoning, are well below documented toxicity thresholds.

The landscape of potential health benefits of carotenoids as natural supportive therapeutics in protecting against Coronavirus infection.

The Coronavirus Disease-2019 (COVID-19) pandemic urges researching possibilities for prevention and management of the effects of the virus. Carotenoids are natural phytochemicals of anti-oxidant, anti-inflammatory and immunomodulatory properties and may exert potential in aiding in combatting the pandemic. This review presents the direct and indirect evidence of the health benefits of carotenoids and derivatives based on in vitro and in vivo studies, human clinical trials and epidemiological studies and proposes possible mechanisms of action via which carotenoids may have the capacity to protect against COVID-19 effects. The current evidence provides a rationale for considering carotenoids as natural supportive nutrients via antioxidant activities, including scavenging lipid-soluble radicals, reducing hypoxia-associated superoxide by activating antioxidant enzymes, or suppressing enzymes that produce reactive oxygen species (ROS). Carotenoids may regulate COVID-19 induced over-production of pro-inflammatory cytokines, chemokines, pro-inflammatory enzymes and adhesion molecules by nuclear factor kappa B (NF-κB), renin-angiotensin-aldosterone system (RAS) and interleukins-6- Janus kinase-signal transducer and activator of transcription (IL-6-JAK/STAT) pathways and suppress the polarization of pro-inflammatory M1 macrophage. Moreover, carotenoids may modulate the peroxisome proliferator-activated receptors γ by acting as agonists to alleviate COVID-19 symptoms. They also may potentially block the cellular receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human angiotensin-converting enzyme 2 (ACE2). These activities may reduce the severity of COVID-19 and flu-like diseases. Thus, carotenoid supplementation may aid in combatting the pandemic, as well as seasonal flu. However, further in vitro, in vivo and in particular long-term clinical trials in COVID-19 patients are needed to evaluate this hypothesis.

Acute Effects of Kawakawa (Piper excelsum) Intake on Postprandial Glycemic and Insulinaemic Response in a Healthy Population.

Background: Piper excelsum (kawakawa) is an endemic shrub of Aotearoa, New Zealand, of cultural and medicinal importance to Maori. Its fruits and leaves are often consumed. These tissues contain several compounds that have been shown to be biologically active and which may underpin its putative health-promoting effects. The current study investigates whether kawakawa tea can modulate postprandial glucose metabolism. Methods: We report a pilot three-arm randomized crossover study to assess the bioavailability of kawakawa tea (BOKA-T) in six male participants with each arm having an acute intervention of kawakawa tea (4 g/250 mL water; 1 g/250 mL water; water) and a follow-up two-arm randomized crossover study to assess the impact of acute kawakawa tea ingestion on postprandial glucose metabolism in healthy human volunteers (TOAST) (4 g/250 mL water; and water; n = 30 (15 male and 15 female)). Participants consumed 250 mL of kawakawa tea or water control within each study prior to consuming a high-glycemic breakfast. Pre- and postprandial plasma glucose and insulin concentrations were measured, and the Matsuda index was calculated to measure insulin sensitivity. Results: In the BOKA-T study, lower plasma glucose (p < 0.01) and insulin (p < 0.01) concentrations at 60 min were observed after consumption of a high-dose kawakawa tea in comparison to low-dose or water. In the TOAST study, only plasma insulin (p = 0.01) was lower at 60 min in the high-dose kawakawa group compared to the control group. Both studies showed a trend towards higher insulin sensitivity in the high-dose kawakawa group compared to water only. Conclusions: Consuming kawakawa tea may modulate postprandial glucose metabolism. Further investigations with a longer-term intervention study are warranted.

Zinc-induced upregulation of metallothionein (MT)-2A is predicted by gene expression of zinc transporters in healthy adults.

The usefulness of zinc transporter and metallothionein (MT) gene expressions to detect changes in zinc intake remains unclear. This pilot study aimed to determine the effects of zinc supplementation on zinc transporter and MT gene expressions in humans. Healthy adults (n = 39) were randomised to zinc treatment (ZT), receiving 22 mg Zn/day (n = 19), or no treatment (NT) (n = 20). Blood samples were collected on Days 0, 2, 7, 14, and 21. Plasma zinc and serum C-reactive protein concentrations were analysed. Gene expression of zinc transporters and MT in peripheral blood mononuclear cells was analysed using real-time PCR. Using repeated-measures ANOVA, MT-2A gene expression and fold change were found to be higher in the ZT group (P = 0.025 and P = 0.016, respectively) compared to the NT group, specifically at Day 2 (40 ± 18 % increase from baseline, P = 0.011), despite no significant increase in plasma zinc concentration. In a multiple regression model exploring the changes in gene expressions between Days 0 and 21, the change in MT-2A gene expression was correlated with changes in all zinc transporter expressions (r (2) = 0.54, P = 0.029); the change in ZIP1 expression emerged as a univariate predictor (P = 0.003). Dietary zinc intake was predictive of zinc transporter and MT expressions (P = 0.030). Physical activity level was positively correlated with baseline ZIP7 expression (r = 0.36, P = 0.029). The present study shows that MT-2A expression is related to changing expression of zinc transporter genes, specifically ZIP1, in response to zinc supplementation. The current report adds to our understanding of MT in the coordinated nature of cellular zinc homeostasis.

TNF-α gene expression is increased following zinc supplementation in type 2 diabetes mellitus.

Chronic low-grade inflammation in type 2 diabetes mellitus (DM) can elicit changes in whole-body zinc metabolism. The interaction among the expression of inflammatory cytokines, zinc transporter and metallothionein (MT) genes in peripheral blood mononuclear cells in type 2 DM remains unclear. In a 12-week randomized controlled trial, the effects of zinc (40 mg/day) supplementation on the gene expression of cytokines, zinc transporters and MT in women with type 2 DM were examined. In the zinc-supplemented group, gene expression of tumour necrosis factor (TNF)-α tended to be upregulated by 27 ± 10 % at week 12 compared to baseline (P = 0.053). TNF-α fold change in the zinc-treated group was higher than in those without zinc supplementation (P < 0.05). No significant changes were observed in the expression or fold change of interleukin (IL)-1ß or IL-6. Numerous bivariate relationships were observed between the fold changes of cytokines and zinc transporters, including ZnT7 with IL-1ß (P < 0.01), IL-6 (P < 0.01) and TNF-α (P < 0.01). In multiple regression analysis, IL-1ß expression was predicted by the expression of all zinc transporters and MT measured at baseline (r (2) = 0.495, P < 0.05) and at week 12 (r (2) = 0.532, P < 0.03). The current study presents preliminary evidence that zinc supplementation increases cytokine gene expression in type 2 DM. The relationships found among zinc transporters, MT and cytokines suggest close  interactions between zinc homeostasis and inflammation.

Zinc transporter gene expression and glycemic control in post-menopausal women with Type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is associated often with underlying zinc deficiency and nutritional supplements such as zinc may be of therapeutic benefit in the disease. In a randomized, double-blind, placebo-controlled, 12-week trial in postmenopausal women (n=48) with Type 2 DM we investigated the effects of supplementation with zinc (40mg/d) and flaxseed oil (FSO; 2g/d) on the gene expression of zinc transporters (ZnT1, ZnT5, ZnT6, ZnT7, ZnT8, Zip1, Zip3, Zip7, and Zip10) and metallothionein (MT-1A, and MT-2A), and markers of glycemic control (glucose, insulin, glycosylated hemoglobin [HbA1c]). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. No significant effects of zinc or FSO supplementation were observed on glycemic marker concentrations, HOMA-IR or fold change over 12 weeks in zinc transporter and metallothionein gene expression. In multivariate analysis, the change over 12 weeks in serum glucose concentrations (P=0.001) and HOMA-IR (P=0.001) predicted the fold change in Zip10. In secondary analysis, marginal statistical significance was observed with the change in both serum glucose concentrations (P=0.003) and HOMA-IR (P=0.007) being predictive of the fold change in ZnT6. ZnT8 mRNA expression was variable; HbA1c levels were higher (P=0.006) in participants who exhibited ZnT8 expression compared to those who did not. The significant predictive relationships between Zip10, ZnT6, serum glucose and HOMA-IR are preliminary, as is the relationship between HbA1c and ZnT8; nevertheless the observations support an association between Type 2 DM and zinc homeostasis that requires further exploration.

Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus.

The pathology of type 2 diabetes mellitus (DM) often is associated with underlying states of conditioned zinc deficiency and chronic inflammation. Zinc and omega-3 polyunsaturated fatty acids each exhibit anti-inflammatory effects and may be of therapeutic benefit in the disease. The present randomized, double-blind, placebo-controlled, 12-week trial was designed to investigate the effects of zinc (40 mg/day) and α-linolenic acid (ALA; 2 g/day flaxseed oil) supplementation on markers of inflammation [interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP)] and zinc transporter and metallothionein gene expression in 48 postmenopausal women with type 2 DM. No significant effects of zinc or ALA supplementation were observed on inflammatory marker concentrations or fold change in zinc transporter and metallothionein gene expression. Significant increases in plasma zinc concentrations were observed over time in the groups supplemented with zinc alone or combined with ALA (P=.007 and P=.009, respectively). An impact of zinc treatment on zinc transporter gene expression was found; ZnT5 was positively correlated with Zip3 mRNA (P<.001) only in participants receiving zinc, while zinc supplementation abolished the relationship between ZnT5 and Zip10. IL-6 predicted the expression levels and CRP predicted the fold change of the ZnT5, ZnT7, Zip1, Zip7 and Zip10 mRNA cluster (P<.001 and P=.031, respectively). Fold change in the expression of metallothionein mRNA was predicted by TNF-α (P=.022). Associations among inflammatory cytokines and zinc transporter and metallothionein gene expression support an interrelationship between zinc homeostasis and inflammation in type 2 DM.

Effect of vegetarian diets on zinc status: a systematic review and meta-analysis of studies in humans.

Plant-based diets contain less saturated fat and cholesterol and more folate, fibre and phytochemicals than omnivorous diets, but some micronutrients, especially zinc, are poorly bioavailable. The findings of studies exploring the zinc intake and zinc status in populations that habitually consume vegetarian diets are inconsistent. This study aims to investigate the effects of plant-based diets on dietary zinc intake and status in humans using systematic review and meta-analysis techniques. Thirty-four studies were included in the systematic review. Of these, 26 studies (reporting 48 comparisons) compared males and/or females consuming vegetarian diets with non-vegetarian groups and were included in meta-analyses. Dietary zinc intakes and serum zinc concentrations were significantly lower (-0.88 ± 0.15 mg day(-1), P < 0.001 and -0.93 ± 0.27 µmol L(-1), P = 0.001 respectively; mean ± standard error) in populations that followed habitual vegetarian diets compared with non-vegetarians. Secondary analyses showed greater impact of vegetarian diets on the zinc intake and status of females, vegetarians from developing countries and vegans. Populations that habitually consume vegetarian diets have low zinc intakes and status. Not all vegetarian categories impact zinc status to the same extent, but a lack of consistency in defining vegetarian diets for research purposes makes dietary assessment difficult. Dietary practices that increase zinc bioavailability, the consumption of foods fortified with zinc or low-dose supplementation are strategies that should be considered for improving the zinc status of vegetarians with low zinc intakes or serum zinc concentrations at the lower end of the reference range.

Zinc and glycemic control: a meta-analysis of randomised placebo controlled supplementation trials in humans.

BACKGROUND: Impaired zinc metabolism is prominent in chronic disorders including cardiovascular disease and diabetes. Zinc has the potential to affect glucose homeostasis in animals and humans and hence impact the risk of type 2 diabetes mellitus. METHODS: A systematic review and meta-analysis of randomised placebo controlled trials was conducted to determine the effect of zinc supplementation on fasting blood glucose, HbA1c, serum insulin and serum zinc concentrations. Relevant studies for inclusion were identified from a literature search of electronic databases up to July 2011. RESULTS: Fourteen reports (n=3978 subjects) were included in the meta-analysis. In the overall analysis, a small but statistically significant reduction in fasting glucose concentrations was observed (-0.19±0.08mmol/L, P=0.013) after zinc supplementation. HbA1c tended to decrease in zinc-supplemented individuals (-0.64±0.36%, P=0.072). No significant effect was observed for serum insulin concentrations. Plasma zinc concentrations increased significantly following supplementation (+4.03±0.81µmol/L, P=0.001). In secondary analyses of participants with chronic metabolic disease (types 1 and 2 diabetes mellitus, metabolic syndrome and obesity), zinc supplementation produced a greater reduction in glucose concentrations (-0.49±0.11mmol/L, P=0.001) compared to the effect that was observed in healthy participants. CONCLUSION: The significant albeit modest reduction in glucose concentrations and tendency for a decrease in HbA1c following zinc supplementation suggest that zinc may contribute to the management of hyperglycemia in individuals with chronic metabolic disease.

Zinc and regulation of inflammatory cytokines: implications for cardiometabolic disease.

In atherosclerosis and diabetes mellitus, the concomitant presence of low-grade systemic inflammation and mild zinc deficiency highlights a role for zinc nutrition in the management of chronic disease. This review aims to evaluate the literature that reports on the interactions of zinc and cytokines. In humans, inflammatory cytokines have been shown both to up- and down-regulate the expression of specific cellular zinc transporters in response to an increased demand for zinc in inflammatory conditions. The acute phase response includes a rapid decline in the plasma zinc concentration as a result of the redistribution of zinc into cellular compartments. Zinc deficiency influences the generation of cytokines, including IL-1ß, IL-2, IL-6, and TNF-α, and in response to zinc supplementation plasma cytokines exhibit a dose-dependent response. The mechanism of action may reflect the ability of zinc to either induce or inhibit the activation of NF-κB. Confounders in understanding the zinc-cytokine relationship on the basis of in vitro experimentation include methodological issues such as the cell type and the means of activating cells in culture. Impaired zinc homeostasis and chronic inflammation feature prominently in a number of cardiometabolic diseases. Given the high prevalence of zinc deficiency and chronic disease globally, the interplay of zinc and inflammation warrants further examination.

Zinc and redox signaling: perturbations associated with cardiovascular disease and diabetes mellitus.

Cellular signal transduction pathways are influenced by the zinc and redox status of the cell. Numerous chronic diseases, including cardiovascular disease (CVD) and diabetes mellitus (DM), have been associated with impaired zinc utilization and increased oxidative stress. In humans, mutations in the MT-1A and ZnT8 genes, both of which are involved in the maintenance of zinc homeostasis, have been linked with DM development. Changes in levels of intracellular free zinc may exacerbate oxidative stress in CVD and DM by impacting glutathione homeostasis, nitric oxide signaling, and nuclear factor-kappa B-dependent cellular processes. Zinc ions have been shown to influence insulin and leptin signaling via the phosphoinositide 3'-kinase/Akt pathway, potentially linking an imbalance of zinc at the cellular level to insulin resistance and dyslipidemia. The oxidative modification of cysteine residues in zinc coordination sites in proteins has been implicated in cellular signaling and regulatory pathways. Despite the many interactions between zinc and cellular stress responses, studies investigating the potential therapeutic benefit of zinc supplementation in the prevention and treatment of oxidative stress-related chronic disease in humans are few and inconsistent. Further well-designed randomized controlled trials are needed to determine the effects of zinc supplementation in populations at various stages of CVD and DM progression.

Effects of zinc on plasma lipoprotein cholesterol concentrations in humans: a meta-analysis of randomised controlled trials.

BACKGROUND: Studies in humans and animals suggest that zinc has the potential to affect lipoprotein metabolism and hence impact cardiovascular disease risk. METHODS: A meta-analysis of controlled clinical trials was conducted to determine the effect of zinc supplementation on plasma cholesterol and triglyceride concentrations in humans. Potentially relevant studies were identified from a literature search covering the period 1980-2008 (inclusive), and additional citation searches. RESULTS: Thirty three interventions (n=14,238 subjects) were included in the random effects meta-analysis. No overall significant effects of zinc supplementation were observed for plasma cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol or plasma triglyceride concentrations. Plasma zinc concentrations increased significantly (+2.42+/-0.25 micromol/L, P<0.001; n=14,047). Secondary analyses in individuals classified as healthy revealed that zinc supplementation is associated with a significant decrease in plasma HDL cholesterol concentrations (-0.10+/-0.02 mmol/L, P<0.001; n=13,215), equivalent to a 7% decrease from baseline. CONCLUSION: No effect of zinc supplementation on plasma lipoproteins was detected in the overall analysis. In individuals classified as healthy, zinc supplementation is associated with a decrease in HDL cholesterol concentrations and thus contributes to an increased risk of coronary heart disease.