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Older adults, Zinc deficiency, Artemisia and Corona

August 19, 2020 - 19:57 -- Pierre Lutgen

submitted by Pierre Lutgen, Jerome Munyangi and Mutaz Akkawi

Zinc (Zn) plays an essential role in many biological processes including immune response. Impaired Zn status promotes immune dysfunction, and it has been associated with enhanced chronic inflammation during aging. Zinc has a pivotal role in the entire immune system fostering resistance to infections by virus, fungi and bacteria. The immune system is strongly impaired by zinc deficiency, predominantly the cell-mediated response by T-lymphocytes.

Hönscheid A, Rink L, Haase H. T-lymphocytes: a target for stimulatory and inhibitory effects of zinc ions. Endocr Metab Immune Disord Drug Targets. 2009 Jun;9(2):132-44. Review.

Approximately 300 enzymes require zinc for their activities. Zinc is an essential trace mineral for DNA synthesis, cell division, and protein synthesis, all necessary processes for tissue regeneration and repair. Zinc deficiency has been associated with poor wound healing, which can result from decreased protein and collagen synthesis during healing found in zinc-deficient animals.
Animal immunoglobulin, G including human, specifically bind zinc ions, probably through a zinc-binding site.

Yamanaka Y, Matsugano S, Yoshikawa Y, Orino K. Binding Analysis of Human Immunoglobulin G as a Zinc-Binding Protein. Antibodies (Basel). 2016;5(2):13. Published 2016 May 19.

Zinc supplementation improves the cellular immune status, raises CD4 and the CD4/CD8 ratio as it was found in a ramdomly set trial with 76 children in an Indian slum. Th1 activation stimulates macrophages, which have a pivotal role in phagocytosis of aggressors. A high CD4+/CD8+ ratio is indicative of improved immune activity.

Sazawal S, Bentley M, Black RE, Dhingra P, George S, Bhan MK. Effect of zinc supplementation on observed activity in low socioeconomic Indian preschool children. Pediatrics. 1996 Dec;98(6 Pt 1):1132-7.
Similar positive results were obtained in Burkina Faso. Malaria and fever attacks were 23% lower in a group supplemented with 10mg Zn/6d/ week. A significant increase in IgG was noticed.

T Zekiba, I Zongo Sorgho, N Rouamba. Impact of zinc and vitamin A supplementation on malaria among children under 5 year in Burkina Faso MIM16690268 MIM Conference Nairobi 2-6 Nov 2009, Nairobi

PHYTATES AND OTHER DIETARY FACTORS

Zinc deficiency is influenced by dietary factors. Phytate which is present in staple foods like cereals, corn and rice, has a strong negative effect on zinc absorption from composite meals. Corn (maize) is rich in phytates.

Bread phytate as percentage of weight
- Cornbread : 1.36
- Whole wheat bread : 0.75
- White bread : 0.15
- French bread : 0.03
Abdoulaye Coulibaly, Brou Kouakou and Jie Chen, 2011. Phytic Acid in Cereal Grains: Structure, Healthy or Harmful Ways to Reduce Phytic Acid in Cereal Grains and Their Effects on Nutritional Quality. American Journal of Plant Nutrition and Fertilization Technology, 1: 1-22.
The poor absorption of zinc from soy formulas has been found to be attributable to the phytate present in these formulas.
Lönnerdal B, Cederblad A, Davidsson L, Sandström B.The effect of individual components of soy formula and cows' milk formula on zinc bioavailability. Am J Clin Nutr. 1984 Nov;40(5):1064-70.

It was found that substitution of a low–phytic acid grain in a maize-based diet is associated with a substantial increase, even doubling, in zinc absorption.
Christina L Adams, Michael Hambidge Zinc absorption from a low–phytic acid maize. The American Journal of Clinical Nutrition, Volume 76, Issue 3, September 2002, Pages 556–559,

Polenta is a staple of Northern Italian cuisines (and, to a lesser extent, the Central Italian one, e.g. Tuscany).

According to a study published in 2009 Artemisia annua stems are very poor in phytates compared to leaves (10.6 vs 120.0 mg/100 g dry matter)
E Brisibe, P Magalhäes, Jorge F.S. Ferreira, Nutritional characterisation and antioxidant capacity of different tissues of Artemisia annua L.Food Chemistry, 2009, 115, 1240-1246.

This may explain why in several samples of Artemisia annua herba from China we found more than 50% stems. The objective probably is to increase zinc absorption

CHLOROGENIC AND CAFFEEOYLQUINIC ACIDS

We were surprised to find that several samples of Artemisia annua herba from China were basically free of chlorogenic acid when compared to Artemisia samples of different origins and species, in a thesis of the VUB
Vannitssen Silke. Identificatie van de belangrijkeste antioxidanti in Artemisia samples Masterproef voorgelegd tot het verkrijgen van de graad van Apotheker en Master in Farmaceutische Zorg. Academiejaar 2015-2016.

The Chinese produce is void of these molecules, probably because they have no known antimalarial effect. Chlorogenic acid does not inhibit beta-hematin (Mutaz Akkawi, personal communication).
Looking for an hypothesis we found that drying at 100°C of sweet potato leaves reduces the total content of chlorogenic acid by 80-90%, but produces other caffeoylquinic isomers.
Toong Long, Jenga Chia Chi, LaiaTing. Effects of drying on caffeoylquinic acid derivative content and antioxidant capacity of sweet potato leaves. Journal of Food and Drug Analysis. Volume 23, Issue 4, December 2015, Pages 701-708
A similar effect was noticed in coffee roasting. Chlorogenic acid is transformed into lactones.
Dawidowicz, A.L., Typek, R. Transformation of chlorogenic acids during the coffee beans roasting process. Eur Food Res Technol 243, 379–390 (2017). https://doi.org/10.1007/s00217-016-2751-8

LOW ZINC STATUS: A RISK FOR PNEUMONIA IN THE ELDERLY

Plasma Zn decrease is strongly related to age and may be a predictor of all-cause mortality in elderly population. In a study in Italy plasma zinc levels were measured in individuals having an age range of 10–93 years. No significant differences in plasma zinc concentrations were found between males and females. Up to the age of 50 years, the mean plasma zinc of normal individuals remained relatively constant at 70 ± 32µg/100 ml after which the levels decreased.
Chooi M.K. · Todd J.K. · Boyd N.D. Influence of Age and Sex on Plasma Zinc Levels in Normal and Diabetic Individuals. Nutr Metab 1976;20:135–142
E Mocchegiani, Zinc and ageing: third Zincage conference. Immunity & Ageing 2007; 4 5.
Malavolta M, Giacconi R, Piacenza F, et al. Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population. Biogerontology. 2010;11(3):309-319.

Aged individuals are significantly more susceptible to zinc deficiency, increasing the likelihood of acquiring life threatening viral infections.
A J Cabrera , Zinc, aging, and immunosenecence : an overview. Pathology of Aging& Age Related Diseases, 2014.

In an observational study on 379 elderly patients it was found that in the low serum zinc group the incidence of pneumonia (no.per person-year) was 0.66 vs 0.25 in the high serum zinc group. The duration of pneumonia (days per person-year) was 6.82 vs. 3.19. The overall death toll (no. per person-year) was 0.19 vs. 0.12
Barnett JB, Hamer DH, Meydani SN. Low zinc status: a new risk factor for pneumonia in the elderly?. Nutr Rev. 2010;68(1):30-37.

In a study on virus replication, the inhibitory effect of zinc salts was concentration dependant and was not observed with other salts containing divalent cations such as calcium, magnesium and manganese.
Suara RO, Crowe JE Jr. Effect of zinc salts on respiratory syncytial virus replication. Antimicrob Agents Chemother. 2004;48(3):783-790.

ARTEMISIA PLANTS AND ZINC

Artemisia plants are very rich in zinc, more than most vegetables, and are sometimes considered as hyperaccumulators. This could explain the prophylactic effect which has been noticed for regular consumption of infusions of these plants. ARTAVOL a prophylactic drug against malaria in Uganda is composed of three plants rich in zinc: artemisia, avocado and lemongrass. An analysis of a dozen of medicinal herbs in Romania showed that Artemisia absinthium is top ranking in Zn content.
D S Antal, V Vlaia, Zinc across medicinal plants from Romanian biodiversity and the implications for human health. Revista ce Cimie-Bucharest, February 2015.

In an analysis we run on Artemisia annua samples from Luxembourg and Cameroon we found that they contained much more zinc than several samples of Camellia sinensis (0,275 vs 0.145 mg/kg dry matter).
Traore Alassane, Diallo Mouhamadou, Lutgen Pierre. Characterization of element and mineral content in Artemisia annua and Camellia sinensis leaves by handheld X-ray fluorescence. African Journal of Biotechnology Vol. 12(26), pp. 4179-4186, 26 June, 2013

Plants from the Artemisia family increase the CD4 count.
Constant Kansango Tchandema, Pierre Lutgen, In vivo trials on the therapeutic effects of encapsulated Artemisia annua and Artemisia afra, GJRA, 2016 Vol 5-Iss 6 ISSN No 2277-8160

But the question remains open, if it is the divalent Zn ion alone which is active, or if it needs to be associated with an organic molecule. The University of Al Quds found that Zn alone does not inhibit hemozoin. It inhibits only when combined with arginine well present in Artemisia (Mutaz Akkawi, personal communication)

ZINC AND CYP3A4

Cytochrom CYP3A4 is known as a strong inhibitor of many metabolisms. Consequently it enhances the efficiency of a number of drugs
S S Kuznetsova, N V Azarkina, T V Vygodina, Zinc ions as cytochrome C oxidase inhibitors: two sites of action. Biochemistry (Mosc) 2005 Feb; 70(2):128-36.

The CYP3A4 activity of Artemisia was extensively described by a study on samples we submitted to the Vrije Universiteit Brussels ; samples of Artemisia annua, afra, absinthium, apiacea, pontica, alba, abrotanum. The results were varying from sample to sample, but on the average, significantly higher than for grapefruit, a well known CYP3A4 inhibitor.
Lazaridi Kristina. Invloed van de chemische samenstelling van Artemisia annua op CYP3A4-activiteit en antioxidant vermogen, Masterproef Geneesmiddelenontwikkeling. Academiejaar 2013-2014. VUB
This CYP3A4 inhibition by Artemisia annua was recently confirmed by the Worcester Polytecnic Institute.
Desrosiers MR, Mittelman A, Weathers PJ. Dried Leaf Artemisia Annua Improves Bioavailability of Artemisinin via Cytochrome P450 Inhibition and Enhances Artemisinin Efficacy Downstream. Biomolecules. 2020; 10(2):254.

And again the high concentration of zinc in Artemisia plants might play a key role.
Joon-Sik Kim , Chul-Ho Yun. Inhibition of human cytochrome P450 3A4 activity by zinc(II) ion. Toxicol Lett 2005 Apr 28;156(3):341-50.