How zinc supplementation prevents Viral replication in covid-19 patients

Covid-19 is a systemic disease that affects the lungs and multiple organs and tissues. It is transmitted, rapidly from one person to another in close proximity, through contact with virus laden aerosols discharged in coughs and sneezes. Most affected patients die as a result of acute respiratory distress syndrome.

There are several variants of Covid-19, but the Alpha, Delta, and Omicron variants are most widely spread with severe health breakdown.

 

Symptoms Of Covid-19

The symptoms of covid-19 are similar to those of normal cold and flu. They are:

  • High temperature or chills
  • Continuous cough
  • Change in the sense of smell and taste
  • Short breath
  • Feeling of tiredness
  • Headache and body pains

 

Viral Life Cycle And Cell Invasion Of Covid-19

Once the virus gained entrance into the host body, it binds to host receptors and enters the host cells through endocytosis or membrane fusion. The virus is made up of for structural proteins, which are the,

  • Spike (S) protein
  • Membrane (M) protein
  • Envelope (E) protein
  • Nucleocapsid (N) protein

The S protein protrudes from the viral surface and is the most important viral protein for host attachment and penetration. It is composed of two functional subunits (S1 and S2). The S1 is responsible for viral binding to the host cell receptor, angiotensin-converting enzyme 2 (ACE-2) and the S2 subunit plays a role in the fusion of viral and host cellular membranes.

 

Corona Virus Undergoes Two-step Protease Cleavage After Activation

After binding to the ACE-2, the S protein undergoes activation through a two-step protease cleavage. The first cleavage is for priming at the S1/S2 cleavage site. The second cleavage activation occurs at a position adjacent to a fusion peptide within S2 subunit. Thus, the initial cleavage is for stabilization of S2 subunit while the second cleavage is activates the S protein and causes a conformational change that leads to viral and host cell membrane fusion.

Once the virus has gained entrance into the host cell, it undergoes viral replication and formation of a negative strand RNA by the pre-existing single-stranded positive RNA through RNA polymerase activity. The negative stranded RNA newly formed starts to produce new strands of positive RNAs, which then synthesize new proteins in the cytoplasm.

The viral N protein now binds the new genomic RNA and the M protein facilitates its integration to the cellular endoplasmic reticulum (ER). The newly formed nucleocapsids are then enclosed in the ER membrane and transported to the lumen. From the lumen, it is transported through Golgi vesicles to the cell membrane and then, through exocytosis to the extracellular space. The new viral particles are now ready to infect the next epithelia cell.

 

How Does Zinc Protect The Body From Entering Of The Virus?

When an individual is infected with coronavirus, the virus first targets the epithelium and ciliary dyskinesia for damage, thereby impairing mucocilia clearance. But zinc supplementation increases ciliary beat frequencies and thereby improves ciliary clearance of viral particles. The improved ciliary clearance also reduces bacterial infection.

 

How Does Zinc Directly Inhibit Viral Replication?

At first, zinc prevents viral fusion with the host membrane, decreases the viral polymerase functions, impairs the protein translation and processing and blocks viral particle release. It also destabilizes the viral envelope. When supplemented with a small concentration of the zinc ionophores pyrithione or hinokitol, zinc decreases viral RNA synthesis by directly inhibiting the RNA-dependent RNA polymerase of the virus.

 

REFERENCES

Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients. (2017) 9:1286. doi: 10.3390/nu9121286

Gammoh NZ, Rink L. Zinc in infection and inflammation. Nutrients. (2017) 9:624. doi: 10.20944/preprints201705.0176.v1

Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; in press.

Benefits of Zinc in Sexual Functions

What is Zinc?

Zinc, though beneficial for men’s sexual health, is a chemical element with an atomic number 30 and represented by the symbol, Zn. It is slightly brittle at room temperature and has a silvery-grayish appearance when oxidation is removed.

In the periodic table, zinc is the first element in the 12th group and in the 4th period. It possesses similar characteristic with magnesium; both elements exhibit one normal oxidation state, only (+2) and are similar in size.

It should be noted that Zinc is the 24th most abundant element in Earth’s crust and has five stable isotopes. The common Zinc ore being Sphalerite, a zinc sulfide mineral. Despite being the 24th most abundant element, Zinc is still a trace element in our body. meaning that our body require only a small amount of it in our circulatory systems.

What Are The Sources Of Zinc?

Zinc can be sourced from several foods such as meats, fishes, fruits, seeds, vegetables, nuts and some times, from the leaves and roots of certain herbal plants. Some of the plant sources of Zinc includes:

Meats and Fishes

meats are excellent sources of zinc. But red meat are in particular, great sources of Zinc. An ample amount of zinc can be found, however, several other kinds of meat and fishes, most especially from sea foods.

Legumes

Legumes like groundnut, cowpea, pigeon pea, beans, and several others, are great source of zinc. When you eats meat, fish or legumes, you are sue going to enrich your body with increased amount of zinc.

Eggs

Eggs are another great source of zinc, Though they contain moderate amount of zinc, they sure would help you meet your daily zinc requirements. When you consume one egg, you are supplied with 5% f your daily dietary value of zinc.

Fruits and Seeds

Most plant fruits and seed such as Avocado peer, black sunflower seeds, apple, star apple, garden eggs and several others possess ample amount of zinc which your body would need to maintain daily functions. when you think of the added antioxidants in fruits and seeds, and consider the benefits they and zinc offer sexually, you would want to eat fruits every passing day for a good health and reproductive functions.

What  Are The Benefits Of Zinc, Sexually?

According to studies, male infertility is responsible for approximately 30-55% of infertility cases. The commonest cause of male infertility is sperm dysfunction. And this may be due to some risk factors like

  • Varicocele
  • Obstructive lesions
  • Cryptorchidism
  • Cystic fibrosis
  • Trauma
  • Genitourinary infections
  • Environmental factors and
  • Nutritional deficiency of trace elements, especially zinc, selenium, and vitamins.

During ejaculation, the sexual accessory glands secrete serminal plasma which contains some elements that protect spermatozoa. Some of the serminal contents include,

  • Acid phosphatase
  • Alanine transaminase
  • Alkaline phosphatase
  • Aspartate transaminase
  • Lipids and

Zinc plays important role in male fertility by enhancing germinal cell proliferation, cell division, immune system and gene expression. And a dietary zinc deficiency is a risk factor low quality of sperm and idiopathic male infertility.

Zinc Enhances Testosterone Production

Low sperm zinc levels have a negative effect on serum testosterone concentration. It also affects the normal function of the hypothalamus-pituitary-gonadal axis. Zinc helps the body maintain proper thyroid function by producing hormones called thyroid-releasing hormones in the brain.

Thyroid hormones have several important roles in the body including metabolism, development and even body temperature. Whenever men are low in Zn, they
may fail to produce enough of these hormones. That can also affect testosterone levels.

According to a clinical study, adult males who denied themselves Zinc supplementation showed a disorder of testosterone synthesis in the Leydig cell. This is because zinc has a main role in the 5α reductase enzyme that is necessary for the transformation of testosterone into biologically active form, 5α dihydro testosterone.

How Does Zinc Enhances Testosterone production?

Zinc boosts male fertility via enhancing testosterone production by modulating the balance between testosterone and 5α dihydro testosterone (DHT). This is done by regulating the activity of 5α-reductase, which converts testosterone to DHT. It is important for the Leydig cells and play important role in the physiology of spermatozoa.

Benefits of Zinc Sexually in Sperm Count and Motility

During initiation of spermatogenesis, zinc participates in the ribonuclease activity as well as involves in spermatozoa maturation, maintains germinal epithelium and seminiferous tubule. It also enhances sperm motility and concentration during ejaculation.

Several studies have demonstrated that oral Zinc supplementation improves sperm motility in subfertile men with idiopathic asthenozoospermia and/oroligozoospermia. The negative correlation between seminal plasma Zn and sperm viability is a good sign of the importance of Zn in spermatogenesis.

Zn therapy improves sperm quality with increases in sperm density, progressive motility and improved conception and pregnancy outcome. Zn plays an important role in membrane-stabilizing and antioxidant activity and maintains sperm viability by inhibiting DNases.

Zinc Antibacterial Activities Enhances Sperm Health

One of the risk factors of sperm dysfunction is genitourinary infection. The antibacterial activity of zinc improves sperm health and sperm count by clearing bacterial infections. The oxide of zinc, ZnO has antimicrobial activities against both gram negative and gram positive bacteria as well as against spores. But the mechanism of action of ZnO against antimicrobial activity is yet to be elucidated.

Zinc Is Beneficial For Men’s Prostate Function

Apart from the Being Beneficial men’s sexual health, zinc also helps the prostate. It has been found that zinc inhibits the growth and invasion of prostate cancer cells. One of the ways zinc suppresses prostate cancer growth is through the suppressing the activity of mitochondrial aconitase and inhibition of the terminal oxidation in the electron transport chain. But that’s not all there is about Zinc; it also imposes apoptogenic effect and suppresses progression while protecting DNA integrity in the prostate cell.

 

REFERENCES

Aditya, A., Chattopadhyay, S., Jha, D., Gautam, H. K., Maiti, S., and Ganguli, M. (2018). Zinc oxide nanoparticles dispersed in ionic liquids show high antimicrobial efficacy to skin-specific bacteria. ACS Appl. Mater. Interfaces 10, 15401–15411. doi: 10.1021/acsami.8b01463.

Ali H, Ahmed M, Baig M, Ali M. Relationship of zinc concentrations in blood and seminal plasma with various semen parameters in infertile subjects. Pak J Med Sci. 2007;23(1):111-4.

Akinloye O, Abbiyesuku FM, Oguntibeju OO, Arowojolu AO, Truter EJ. The impact of blood and seminal plasma zinc and copper concentrations on spermogram and hormonal changes in infertile Nigerian men. Reprod Biol. 2011;11(2):83-98.

Brown, A. N., Smith, K., Samuels, T. A., Lu, J., Obare, S. O., and Scott, M. E. (2012). Nanoparticles functionalized with ampicillin destroy multiple-antibiotic-resistant isolates of Pseudomonas aeruginosa and Enterobacter aerogenes and methicillin-resistant Staphylococcus aureusAppl. Environ. Microbiol. 78, 2768–2774. doi: 10.1128/AEM.06513-11

Henkel R, Bittner J, Weber R, Hüther F, Miska W. Relevance of zinc in human sperm flagella and its relation to motility. Fertil Steril. 1999;71(6):1138-43.

Ho, E., & Song, Y. (2009). Zinc and prostatic cancer. Current opinion in clinical nutrition and metabolic care12(6), 640–645. https://doi.org/10.1097/MCO.0b013e32833106ee

Hunt CD, Johnson PE, Herbel J, Mullen LK. Effects of dietary zinc depletion on seminal volume and zinc loss, serum testosterone concentrations, and sperm morphology in young men. Am J Clin Nutr. 1992;56(1):148-57.

Khosronezhad N, Hosseinzadeh Colagar A, Mortazavi SM. The Nsun7 (A11337)-deletion mutation, causes reduction of its protein rate and associated with sperm motility defect in infertile men. J Assist Reprod Genet. 2015;32(5):807–15.

Omu A, Al-Azemi MK, Kehinde EO, Anim JT, Oriowo MA, Mathew TC. Indications of the mechanisms involved in improved sperm parameters by zinc therapy. Med Princ Pract. 2008;17(2):108-16.

Yuyan L, Junqing W, Wei Y, Weijin Z, Ersheng G. Are serum zinc and copper levels related to semen quality? Fertil Steril. 2008;89(4):1008–11.

Khan MS, Zaman S, Sajjad M, Shoaib M, Gilani G. Assessment of the level of trace element zinc in seminal plasma of males and evaluation of its role in male infertility. Int J Appl Basic Med Res. 2011;1 (2):93–6.

The Functions of Zinc in Immune System

Zinc is an essential macronutrient, which play a crucial role in multiple cellular functions, including immune cell signaling. In zinc dyshomeostasis, which includes zinc deficiency, there are impairments in several cellular and organ function including overall immune function and increased susceptibility to infection. This shows that zinc cannot be overlooked in immune system and other cellular processes.

Some of the problems associated with zinc deficiency are growth retardation, neurological disorder, immune dysfunction and Acrodermatitis enteropathica, a metabolic disorder.

 

Zinc Transporters

Zinc coordinates its signaling through two families of zinc transporters and metallothiones. The two families of zinc transporters are:

The Solute-linked carrier 39 (SLC39A or ZIP) family of zinc transporters, which transport zinc into the cytosol and out of the intracellular organelles and,

The Solute-liked carrier 30 (SLC30A or ZnT) family of zinc transporters, which transport zinc out of the cytosol and into the intracellular organelles.

Both ZIP and ZnT transporters are expressed in a cell- or tissue-specific manner.

Metallothione (MT)

Metallothione is a zinc-binding protein that functions as a reservoir of intracellular zinc. It has the ability to bind up to seven zinc ions per MT molecule. It also plays a crucial role in the distribution, transport and maintenance of intracellular zinc ions.

The Function of Zinc in Pathogen Invasion

Zinc regulates complex signaling pathways in immune cells. As a result, when an invasion by a pathogen occurs, the pathogen creates a conflict in which Zn becomes a shared resource.

In this battle-like state, the pathogen strives to utilize Zn for its biological functions at the expense o the host, while the host cells seek to reserve Zn and render it inaccessible for pathogen uptake. This strategy of the host cell curtails the growth of some pathogens, but there are some pathogen which resist this cellular mechanism by possessing strong Zn acquisition machineries that effectively compete with the host for Zn.

Excess zinc however, can exert toxic effects on microbial survival. And the immune cells have taken advantage of this to localize and fuel excessive Zn concentrations that intoxicate the pathogen without impacting host cells.

 

Zinc Signals in Monocytes and Macrophages.

The immune system provides two layers of defense against pathogens; they are innate and adaptive immunity. Innate immunity, which is the frontier of host defense, involves the recognition of pathogen-associated molecular patterns (PAMPs), conserved structures of invading pathogens, and the immediate initiation of immune responses.

During invasion, mononuclear phagocytes of innate immunity immediately recognize invading pathogens through the sensing of PAMPs by pathogen-recognition receptors (PRR), including Toll-like receptors (TLRs). Upon PAMP engagement, individual TLRs differentially recruit adaptor molecules such as MyD88, TRIF, TIRAP-dependent NF-kB, MARK, PI3K, and the TRIF/TRAM-dependent IRF3 pathway, and elicits a variety of monocyte and macrophage effectors’ functions.

 

TRIF/TRAM-dependent pathway

Signaling through TRIF activates several transcription factors, including NF-kB, IRF3, and AP-1. This leads to the production of cytokines and type-1 IFN, as well as maturation of myeloid dendric cells. Biological responses from TRIF-dependent signaling depends on both the type of cell responding and the particular TLR that is activated.

In TLR4 signaling, the TLR4 TIR domain use TRAM to recruit TRIF to the signaling complex, either by operating from the plasma membrane or from the endosomes. Localization of TRAM to the endosomes is necessary for IRF3 activation in the TRIF-dependent pathway.

When a lipopolysaccharide binds to TLR4, it leads to rapid zinc influx into the cytoplasm of monocytes and macrophages, which triggers zinc-mediated regulation of major signaling pathways, including TRIF/TRAM pathway.

 

MyD88/TIRAP-dependent NF-kB pathway.

The NF-kB transcription factor is a central regulator of proinflammatory gene induction and functions in a variety of immune responses. It influences the expression of proinflammatory cytokines, Chemokines, acute phase proteins, matrix metalloproteinase, adhesion molecules, growth factors, and other factors involved in inflammatory responses.

Zinc regulates the NF-kB activity by suppressing LPS-induced activation of IKKB. This is through a mechanism that is initiated by the inhibition of cyclic nucleotide phosphodiesterase (PDE), and subsequent elevation of cGMP, cross-activation of protein kinase A (PKA), and inhibitory phosphorylation of protein kinase Raf-1.

Another mechanism which involves direct inhibition of IKK upstream of NF-kB is mediated by ZIP8, which increase intracellular zinc, and involves a direct binding of Zn to IKKB.

 

 

Zinc (Zn)

Zinc (Zn) is a chemical element, which is an essential macronutrient for basic cell activities such as cell growth, cell differentiation and survival. It is found in high concentration in the red blood cells as an essential part of the enzyme, carbonic anhydrase, which promotes many reactions relating to carbon dioxide metabolism. In the pancreas, Zn aid in the production, secretion and storage of insulin.

The cellular functions of zinc can be found in the regulation, activation and expression of biological molecules such as transcription factors, enzymes, adapters, channels and growth factors, along with their receptors. When Zn is deficient or excessively absorbed, it disrupts Zn homeostasis and growth, morphogenesis and immune response, as well as neurosensory and endocrine functions.

Biological functions of Zinc

  • Zinc is required for the functions of many proteins, including enzymes and transcription factors.
  • It acts as a neuromodulator in synaptic transmissions.
  • Zinc behaves as a signal transducer to regulate cellular functions in which Zn transporters are involved.
  • Zinc is pivotal for mammalian oogenesis.
  • In plants and rats, Zn is essential for growth and development.
  • Zinc influences insulin production and secretion, and thereby influences blood glucose transport into cells and reduces hyperglycemia.
  • In diabetic patients, Zn supplementation lowers oxidative stress.

 

Zinc transporters

Zinc transporters are transmembrane proteins that control the movement of zinc across cellular membrane, distribution and storage. They belong to two major gene families, namely, The ZnT proteins (Solute-linked carrier 30, SLC30) and the ZIP ( Zrt/Irt-linked solute-linked carrier 39, SLC39).

ZIP Proteins

The ZIP proteins transport Zn into the cell through the plasma membrane or out of the subcellular organelles when cytosolic zinc is low or depleted. In mammals, there are fourteen members o the ZIP family. They have eight predicted transmembrane domains (TMDs) with an extracytosolic N- and C- terminals. Between TMD3 and TMD4, a long histidine-rich loop region is located.

ZIP family is expressed in a wide range of tissues and cells, and their proteins are located at distinct cellular compartments.

ZnT Proteins

Unlike ZIP, ZnT proteins transport Zn out of the cell through the plasma membrane or into the subcellular organelles when Zn cytosolic concentrations are high. They have a topology of six predicted transmembrane domains and a histidine-rich loop region between TMD4 and TMD5 with their N- and C- terminals located on the cytosolic side of the membrane. They are also expressed in a wide range of tissues and cells, and have distinct subcellular locations.

 

Zinc, Zn transporters, and Cell signaling

The process of cell signaling is complex and the role of Zn and Zinc transporters in cellular signaling is less defined.

Zinc mimics the actions of hormones, growth factors, and cytokines. It is actually taking precedence as a leading cell signaling molecule analogous to Calcium.

Modes of Zinc (Zn) signaling

There are two modes of Zn signaling, which are “early zinc signaling” (EZS) and “later Zinc signaling” (LZS).

Early Zinc Signaling: EZS involves a rapid change in intracellular levels of free Zn that occurs in minutes due to an extracellular stimulus that is transcription dependent. This rapid change in the intracellular free Zn is called “Zinc wave” and is dependent on both Calcium and MEK signaling.

Late Zinc Signaling: LZS is also triggered by an extracellular signal and involves transcription-dependent changes in expression of proteins involved in Zn homeostasis, such as storage proteins or transporters.

 

Role of Zinc (Zn) in Insulin Regulation

Zinc plays an integral role in the processing, storage and secretion of insulin by the pancreas, which subsequently increases glucose absorption. Whenever the plasma level of Zinc becomes low, it adversely affects the ability of the beta islet cells to produce and secrete insulin. By increasing the secretion of insulin, Zn promotes the phosphorylation of Akt (Also known as protein kinase B) and Glycogen synthase kinase 3B (GSK3B), which increase glucose uptake and reduces hyperglycemia.

Zinc deficiency and malabsorption has been linked to diabetes mellitus. This shows that Zn enhances insulin secretion and glucose uptake, thereby decreasing hyperglycemia, cellular apoptosis and excess glucose in kidney.

 

Zinc (Zn) Supplementation in Decreases Oxidative Stress

Hyperglycemia increases oxidative stress in diabetes mellitus. By decreasing blood glucose level, Zn reduces oxidative stress and protects the cells from oxidative injury. When combined with Chromium, Zn decreases thiobarbituric acid reactive substances’ (TBARS) levels. Zinc supplementation also increases glutathione levels, whereas lipid peroxidation is decreased.