Conservapedia - User contributions [en]

Zinc & Hinokitiol Synergism

2020-08-06T03:00:25Z

Amugune: category editing

[[Hinokitiol]] is one of the [[Zinc Ionophores]], which means they can attach themselves to Zinc molecules and transport them across the cell membranes hence increasing the intracellular zinc concentrations; therefore many studies revealed this capability has the potential to inhibit viral replication. The advantage of Zinc’s antiviral properties can be accelerated by using it in combination with Hinokitiol.[https://www.sciencedirect.com/topics/neuroscience/ionophores]

'''Zinc Inhibits Viral Replication'''

According to a recent article on Nutritional Immunology, Zinc ionophore such as hinokitiol hindered the RNA synthesis by inhibiting the RNA dependent polymerase in picornavirus, poliovirus, and influenza. [https://www.frontiersin.org/articles/10.3389/fimmu.2020.01712/full [2<nowiki>]</nowiki>]
[[Category:Dietary Supplements]] Furthermore, another study revealed that Hinokitiol also exhibits antiviral activity against [[rhinovirus]], [[coxsackievirus]], and [[megnovirus]] replication. When hinokitiol is combined with zinc it increases the intracellular Zinc ions which in return causes puncture to the cell as well as mitochondria.[https://jvi.asm.org/content/83/1/58 [3<nowiki>]</nowiki>]
== Antiviral Activities of Zinc + Hinoktiol ==
The antiviral properties of Zinc are virus-specific; however, the presence of zinc ions play an important role in causing zinc antiviral efficacy.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628855/#:~:text=In%20summary%2C%20it%20is%20evident,and%20uncoating%20(Figure%201).</ref><ref>https://pubmed.ncbi.nlm.nih.gov/9372416/</ref> In vitro, doses of Zinc of above 2 μM impede the multiplication of SARS-CoV through the inhibition of RNA-reliant RNA polymerase of the virus.<ref>https://publicnews18.com/2020/07/09/dr-zinx-exploits-the-hinokitiol-zinc/</ref><ref>https://www.frontiersin.org/articles/10.3389/fimmu.2020.01712/full</ref> Besides, Zinc has direct antiviral actions, which include the stimulation of various antiviral signaling activities.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628855/</ref> For instance, Zinc levels are linked with the impeding of IFN-l3 signaling, events that can moderate cytokine storm, which is linked to a worse condition in persons that are affected by SARS-CoV.<ref>https://publicnews18.com/2020/07/09/dr-zinx-exploits-the-hinokitiol-zinc/</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283076/ </ref>
== Role of Zinc + Hinokitiol ==
Hinokitiol (HK) is an example of a Zinc ionophore, and it is known for its capacity to bind on Zinc ions and transfer them into the cell.<ref>https://www.sciencedirect.com/topics/neuroscience/ionophores</ref> The transport of Zn2+ ions in the cells causes an increase in the intracellular Zinc concentration, which is effective for the protection of the body against viral infection.<ref>https://biomedgrid.com/fulltext/volume2/review-on-the-role-of-zn2+-ions-in-viral-pathogenesis-and-the-effect-of-zn2+-ions-for-host-cell-virus-growth-inhibition.000566.php</ref> Thus, the continuous need for Zinc ionophores like hinokitiol is essential for Zn2+ ions to retain antiviral activities. At a dose of 200μM, hinokitiol has major cytotoxic and antimicrobial actions against oral squamous cell carcinoma cell lines and oral pathogens, respectively.<ref>https://www.researchgate.net/publication/234121978_In_vitro_antimicrobial_and_anticancer_potential_of_hinokitiol_against_oral_pathogens_and_oral_cancer_cell_lines</ref> Also, 200μM HK has lower cytotoxic impacts for the usual human being oral keratinocytes, showing that hinokitiol exhibits a high possibility for effective and safe use within oral health care.<ref>https://www.researchgate.net/publication/234121978_In_vitro_antimicrobial_and_anticancer_potential_of_hinokitiol_against_oral_pathogens_and_oral_cancer_cell_lines</ref> Additionally, a >0.2 μg/ml dose of hinokitiol directly impedes bacterial activities, and a coronavirus sanitizer patent stated that an amount of 0.02 to 0.2% by mass HK was effective for antiviral purposes.<ref>https://publicnews18.com/2020/07/09/dr-zinx-exploits-the-hinokitiol-zinc/</ref> Therefore, it is evident that an amalgamation of Hinokitiol and Zinc is synergistic in hindering the replication of viruses such as SARS-COV.<ref>https://publicnews18.com/2020/07/09/dr-zinx-exploits-the-hinokitiol-zinc/</ref>

Hinokitiol

2020-07-27T03:36:55Z

Amugune: Promising Future; Additional Citations

Hinokitiol (β-thujaplicin) is a naturally occurring [https://en.wikipedia.org/wiki/Hinokitiol monoterpenoid] found in the wooden part of trees in the family [https://en.wikipedia.org/wiki/Hinokitiol Cupressaceae]. It is a tropolone derivative and is extensively used in oral care and treatment products for its potent broad-spectrum antiviral,[https://pubmed.ncbi.nlm.nih.gov/18922875/ [1]] antimicrobial[https://pubmed.ncbi.nlm.nih.gov/10513629/ [2]] and anti-inflammatory [https://pubmed.ncbi.nlm.nih.gov/25952949/ [3]] properties. Hinokitiol is a Zinc, and Iron Ionophore additionally approved as a food additive.[https://www.jstage.jst.go.jp/article/jhep/43/2/43_299/_article/-char/ja/ [4]]

It was first isolated in Taiwanese hinoki in 1936, signifying the origin of the name Hinokitiol. It is almost absent in Japanese hinoki now. At the same time, it is still contained in high concentration (about 0.04% of heartwood mass) in Juniperus Cedrus, Hiba cedarwood (Thujopsis dolabrata) and Western red cedar (Thuja plicata). It can be easily extracted from the cedarwood with solvent and ultrasonication.[https://onlinelibrary.wiley.com/doi/full/10.1002/tcr.201200024 [5<nowiki>]</nowiki>] [https://www.degruyter.com/view/journals/hfsg/61/2/article-p190.xml [6<nowiki>]</nowiki>]

Hinokitiol is similar to a tropolone in structure, which lacks the isopropyl substituent. Tropolones are active chelating agents.<ref>https://pubmed.ncbi.nlm.nih.gov/17055455/</ref>

'''Antimicrobial activity'''

Hinokitiol has a wide range of biological activities, many of which have been discovered and specified in the literature. The first, and most famous, is the potent antimicrobial activity against many bacteria and fungi, regardless of antibiotic resistance. [https://www.sciencedirect.com/science/article/pii/S0944501312001462?via%3Dihub [7<nowiki>]</nowiki>][https://www.jstage.jst.go.jp/article/bio1996/12/3/12_3_101/_article [8<nowiki>]</nowiki>] To be precise, Hinokitiol has shown to be effective against Streptococcus pneumonia, Streptococcus mutans, and Staphylococcus Aureus, common human pathogens. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040402/ [9<nowiki>]</nowiki>][https://onlinelibrary.wiley.com/doi/abs/10.1111/1348-0421.12688 [10<nowiki>]</nowiki>] Additionally, Hinokitiol has been demonstrated to have inhibitory effects on Chlamydia trachomatis and may be clinically beneficial as a topical drug. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140513/ [11<nowiki>]</nowiki>][https://en.wikipedia.org/wiki/Special:BookSources/978-3-8383-4661-8 [12<nowiki>]</nowiki>]

'''Antiviral activity'''

Some recent studies have shown that Hinokitiol also demonstrates antiviral action when used in combination with a zinc compound against several human viruses, including rhinovirus, coxsackievirus, and mengovirus.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [13<nowiki>]</nowiki>] Curing viral infections has the potential to reap the mass economic benefit and must be of dire importance to global institutions such as the World Health Organisation. By impairing viral polyprotein processing, Hinokitiol inhibits viral replication - however, this capability is dependent upon the availability of divalent metal ions, as Hinokitiol is a chelator thereof.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [14<nowiki>]</nowiki>] The presence of zinc, combined with Hinokitiol, supports these capabilities and is discussed further as follows.

'''Anti-Inflammatory'''

Hinokitiol revealed a modulatory effect on the production of tumor necrosis factor (TNF)-alpha, a factor that influences skin inflammation and hair follicle apoptosis. This is achieved at the transcription level by disrupting the mRNA synthesis of TNF-alpha. Additionally, it suppresses phosphorylation of PDK1, Akt/PKB, and ERK, as a result diminishing the nuclear factor (NF)-kappaB activation, hence restoring hair loss.[[(https://www.sigmaaldrich.com/catalog/papers/18537078)|[15]]] In a recent study, Hinokitiol also revealed notable protection against ocular surface inflammation in dry eye syndrome (DES by inhibiting the NF-κB pathway [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506343/ [16<nowiki>]</nowiki>].

'''Other activities'''

In addition to antimicrobial activity, anti-inflammatory, and anti-tumor activities, characterized in several in vitro cell studies and in vivo animal studies. Hinokitiol determined to exert cytotoxicity on several prominent cancer cell lines by inducing autophagic processes.[http://www.kjcls.org/journal/view.html?doi=10.15324/kjcls.2019.51.2.221 [17<nowiki>]</nowiki>][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979393/ [18<nowiki>]</nowiki>]
= History =
== Discovery ==
In 1936, [http://Dr.%20Tetsui%20Nozoe Dr. Tetsui Nozoe] discovered the presence of Hinokitiol from the Taiwan cypress essential oil. the element has a heptagonal molecular structure that is believed to be non-existent within nature.<ref>https://pubmed.ncbi.nlm.nih.gov/25346458/</ref>

=== Modern research ===

'''Anti-Cancer'''

This study indicates the inhibitory effect of hinokitiol on the migration of human adenocarcinoma A549 cells. The anticancer properties of hinokitiol are supported by the evaluation of results in the present study, including an increase of Bax/p53 and cytochrome c, and further activation of caspases-9/-3 and antioxidant enzymes CAT and SOD. Moreover, we discovered the inhibitory impact of hinokitiol on the A549 cell migration was accompanied through the downregulation of MMPs-9 and MMP-2. These outcomes can also illustrate a new therapeutic value of hinokitiol in anticancer therapy.

Furthermore, another research showed strong anticancer characteristics of Hinokitiol by increasing the cytotoxicity against cervical cancer cells and non-small cell lung cancer (NSCLC) cells. Most cancers cell deaths are medicated through caspase-3 in apoptosis and consequently enlarged lysosomes which are regarded as the possession of anticancer compounds and that can possibly result in lysosomal injury and increased autophagy followed by severe cell death. The choice of therapeutic to hinokitiol, a herbal product derivative, can be concluded to have a mechanism of action against NSCLC with minimum cytotoxic and maximized therapeutic effects.[http://www.kjcls.org/journal/view.html?doi=10.15324/kjcls.2019.51.2.221 [19<nowiki>]</nowiki>]

'''Further Cancer research'''

Hinokitiol has shown an established mechanism to antagonize epidermal growth factor receptor (EGFR) protein expression in mammosphere production breast cancer stem/progenitor cells (BCSCs) without altering the messenger RNA expression. Hinokitiol also decreased the stability of EGFR in BCSCs. The stable protein expression of EGFR and vasculogenic mimicry (VM) production capability of hinokitiol treated BCSCs were restored by combination treatment with a proteasome antagonist, MG132. It can be concluded that hinokitiol may antagonize the VM activity of BCSCs by stimulating proteasome-mediated EGFR break-down. Hinokitiol may be considered as a novel breast cancer therapeutic agent, by acting as an anti-VM. [https://www.spandidos-publications.com/10.3892/ol.2016.4300#:~:text=Hinokitiol%20dose%2Ddependently%20inhibits%20VM,anti%2Dinflammatory%20and%20antitumor%20activity [20<nowiki>]</nowiki>]

Further study demonstrated Hinokitiol regulates estrogen receptor signaling and also antagonizes the proliferation of breast cancer cells in humans. Hence, it can be considered as a promising agent against the treatment of hormone-sensitive mammary tumorigenesis.[https://www.tandfonline.com/doi/full/10.1080/09168451.2015.1008978 [21<nowiki>]</nowiki>]

'''Hinokitiol with Curcumin'''

A potent effect was observed against NSCLC and gefitinib resistant NSCLC cells when Hinokitiol was used in combination with Curcumin. This treatment indicated minimal cytotoxicity to healthy cells. [https://journals.sagepub.com/doi/10.1177/1934578X1801301223 [22<nowiki>]</nowiki>]

'''Coronavirus research'''

Potential antiviral effects of Hinokitiol arise from its action as a zinc ionophore. Hinokitiol enables the influx of zinc ions into cells, which inhibit the replication machinery of RNA viruses, and subsequently hindering the replication of the virus.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [23<nowiki>]</nowiki>] Some notable RNA viruses include the human influenza virus, SARS. Zinc ions were able to inhibit viral replication within cells significantly and proved that the action was dependent on zinc influx. This study was done with the zinc ionophore pyrithione, which functions very similarly to Hinokitiol.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973827/ [24<nowiki>]</nowiki>] In cell cultures, hinokitiol inhibit human rhinovirus, coxsackievirus, and mengovirus multiplication. Hinokitiol interferes with the processing of viral polyproteins, thus inhibiting picornavirus replication. Hinokitiol inhibits the replication of picornaviruses by impairing the viral polyprotein processing and that the antiviral activity of hinokitiol is dependent on the availability of zinc ions.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [25<nowiki>]</nowiki>]

'''Iron ionophore'''

Hinokitiol has been shown to restore hemoglobin production in rodents. Hinokitiol acts as an iron ionophore to channel iron into cells,[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470741/ [26<nowiki>]</nowiki>][https://www.sciencemag.org/news/2017/05/iron-man-molecule-restores-balance-cells [27<nowiki>]</nowiki>] increasing intracellular iron levels. Approximately 70% of the iron in humans is contained within red blood cells and specifically the hemoglobin protein. Iron is essential to almost all living organisms, and it is a critical element of several anatomical functions such as the oxygen transport system, deoxyribonucleic acid (DNA) synthesis, and electron transport and an iron deficiency can lead to blood disorders such as Anemia which, can be significantly detrimental to both physical and mental performance.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999603 [28<nowiki>]</nowiki>]

'''Zinc synergism'''

Hinokitiol is a Zinc ionophore, and this capability is believed to inhibit viral replication. In brief, as a zinc ionophore, Hinokitiol aids in the transport molecules into cells through a plasma membrane or intracellular membrane, thus increasing the intracellular concentration of the specified molecule (ex. Zinc). Hence, by taking advantage of Zinc’s antiviral properties, in combination with Hinokitiol, Zinc uptake can be accelerated.[https://www.sciencedirect.com/topics/neuroscience/ionophores]

'''Zinc Deficiency'''

Zinc deficiency has been demonstrated in some cancer cells, and returning optimum intra-cellular zinc levels can lead to suppression of tumor growth. Hinokitiol is a documented Zinc Ionophore; however, more research is required to establish effective concentrations of delivery methods for Hinokitiol and Zinc.

· “Effects of dietary zinc on melanoma growth and experimental metastasis...” [https://www.sciencedirect.com/science/article/abs/pii/0304383583902069]

· “Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature...” [https://www.nature.com/articles/onc2011592]

· “Zinc levels were relatively lower in patients with lung cancer as compared to a control group: a meta-analysis of observational studies...” [https://wjso.biomedcentral.com/articles/10.1186/s12957-019-1617-5]

· “Research progress on the relationship between zinc deficiency, related microRNA s, and esophageal carcinoma...” [https://onlinelibrary.wiley.com/doi/full/10.1111/1759-7714.12493]

Products containing Hinokitiol include toothpaste, oral sprays, sunscreen, and other cosmetics.

'''EWG Scoring Scale'''

Hinokitiol is also used in a wide range of consumer products, including cosmetics, toothpaste, oral sprays, sunscreens & hair-growth. One of the leading brands in the sale of consumer hinokitiol products is Hinoki Clinical. Hinoki Clinical (est. 1956) was established shortly after the first ‘industrial extraction of hinokitiol’ began in 1955.[https://www.hinoki.co.jp/products/hinokitiol/] Hinoki currently has over 18 different product ranges with hinokitiol as an ingredient. Another brand, namely, ‘Relief Life,’[https://www.anshin-tsuuhan.com/item/propogreen.html] , has boasted over a million sales with their ‘Dental Series’ toothpaste containing hinokitiol.[https://item.rakuten.co.jp/anshintsuuhan/10000015/] Other notable producers of hinokitiol based products include Otsuka Pharmaceuticals, Kobayashi Pharmaceuticals, Taisho Pharmaceuticals, SS Pharmaceuticals. Besides Asia, companies such as Swanson Vitamins®️ are commencing the utilization of hinokitiol in consumer products in markets such as the U.S.A.[https://www.swansonvitamins.com/now-foods-coq10-antioxidant-serum-1-fl-oz-liquid] and Australia [https://www.swansonaustralia.com/en/home/1033-now-foods-solutions-hyaluronic-acid-firming-serum-1-fl-oz-30ml.html] as an anti-oxidant serum and in other endeavors. In 2006, hinokitiol was categorized under the Domestic Substances List in Canada as non-persistent, non-bioaccumulative & non-toxic to aquatic organisms.[https://open.canada.ca/data/en/dataset/1d946396-cf9a-4fa1-8942-4541063bfba4] The Environmental Working Group (EWG), an American activist group, has dedicated a page to the ingredient hinokitiol indicating that it is ‘low hazard’ in areas such as “Allergies & Immunotoxicity,” “Cancer” & “Developmental & Reproductive Toxicity” [https://www.ewg.org/skindeep/ingredients/702859-HINOKITIOL/] giving Hinokitiol a score of 1-2. In contrast to Hinokitiol’s score, Propylparaben, an ingredient still sold in various mouthwashes, exhibits vast toxicity and hazardous concerns. Propylparaben has been deemed by the European Commission on Hormone Disruption to be a Human endocrine disruptor, among other concerns [https://www.ewg.org/skindeep/ingredients/705335-PROPYLPARABEN/] leaving it at a rating of 4-6 on the EWG website.

'''Dr. ZinX'''

On 2 April 2020, Advance Nanotek,[https://www.advancenanotek.com/] an Australian producer of zinc oxide, filed a joint patent application with AstiVita Limited,[https://www.astivita.com.au/] for an antiviral composition that included various oral care products [http://pericles.ipaustralia.gov.au/ols/auspat/applicationDetails.do?applicationNo=2020900820] containing hinokitiol as a vital component. The brand that is now incorporating this new invention is called Dr. ZinX and is likely to release its Zinc + Hinokitiol combination products in 2020.[https://www.asx.com.au/asxpdf/20200520/pdf/44hzh0v8bqgvlx.pdf][https://www.drzinx.com/] On 18 May 2020, Dr. ZinX published test results for a “Quantitative suspension test for the evaluation of hinokitol's virucidal properties in the medical area” [https://www.asx.com.au/asxpdf/20200520/pdf/44hzh0v8bqgvlx.pdf][https://www.drzinx.com/testresults] declaring a ‘3.25 log’ reduction (99.9% reduction) for a neat concentration in 5 minutes against COVID-19 surrogate Feline Coronavirus.[https://www.tga.gov.au/surrogate-viruses-use-disinfectant-efficacy-tests-justify-claims-against-covid-19] Zinc is considered to be an essential dietary supplement and trace element in the body. Globally it is estimated that 17.3% of the population has inadequate Zinc intake.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510072/][https://academic.oup.com/jn/article/132/11/3422/4687273]

'''A Promising Future'''

Beginning in the 2000s, researchers considered that hinokitiol could be of value as a pharmaceutical ingredient, notably for its inhibitory effect on the bacterium ''Chlamydia trachomatis''.<ref>https://www.researchgate.net/publication/7823344_In_Vitro_Inhibitory_Effects_of_Hinokitiol_on_Proliferation_of_Chlamydia_trachomatis</ref>
Chemist Martin Burke and colleagues at the University of Illinois at Urbana–Champaign and other institutions discovered the significance of hinokitiol in the medical field.<ref>https://news.illinois.edu/view/6367/499712</ref> Burke’s goal was to overcome the imbalance of iron transport in animals. Deficiencies of several proteins can lead to iron deficiency in cells (anemia) or the opposite effect, Hemochromatosis.[https://www.acs.org/content/acs/en/molecule-of-the-week/archive/h/hinokitiol.html] Using gene-depleted yeast cultures as surrogates, the researchers screened a library of small biomolecules for iron transport signs and, therefore, cell growth. Hinokitiol was identified to be the one that rejuvenate cell's functionality.<ref>https://www.sciencemag.org/news/2017/05/iron-man-molecule-restores-balance-cells </ref> Further study by the team established the mechanism by which hinokitiol balances cell iron.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470741/] They then diverted their study to mammals and found that when rodents that had been engineered to lack “iron proteins” were fed hinokitiol, they regained iron uptake by increasing the absorption in the gut. In a similar study on zebrafish, hinokitiol revealed to restore Hemoglobin production.[https://www.sciencemag.org/news/2017/05/iron-man-molecule-restores-balance-cells] A commentary on the work of Burke et al. nicknamed hinokitiol the “Iron Man molecule”.<ref>https://www.acs.org/content/acs/en/molecule-of-the-week/archive/h/hinokitiol.html </ref> This is fitting/ironic because discoverer Nozoe’s first name can be translated into English as “iron man”.<ref>https://www.acs.org/content/acs/en/molecule-of-the-week/archive/h/hinokitiol.html </ref>

Significant research has also been conducted into the oral applications of Hinokitiol, given the increased demand for Hinokitiol based oral products. One such study, affiliated with eight different institutions in Japan, titled: “Antibacterial Activity of Hinokitiol Against Both Antibiotic-Resistant and -Susceptible Pathogenic Bacteria That Predominate in the Oral Cavity and Upper Airways” concluded that “hinokitiol demonstrates antibacterial activity against a broad spectrum of pathogenic bacteria and has low cytotoxicity towards human epithelial cells.” [https://onlinelibrary.wiley.com/doi/abs/10.1111/1348-0421.12688]

Zinc Ionophores

2020-07-23T04:58:23Z

Amugune: category editing

Zinc ionophores are compounds that bind on zinc, and transport the extracellular Zn2+ ions across the cell membrane, and are researched for their anticancer and antiviral tendencies.<ref>https://pubmed.ncbi.nlm.nih.gov/19859983/</ref><ref>https://biomedgrid.com/fulltext/volume2/review-on-the-role-of-zn2+-ions-in-viral-pathogenesis-and-the-effect-of-zn2+-ions-for-host-cell-virus-growth-inhibition.000566.php</ref> Examples of Zinc Ionophores are [[Hinokitiol]] (HK) and [http://Pyrithione Pyrithione] (PT) and have been found to inhibit human [http://mengovirus mengovirus], [http://rhinovirus rhinovirus], and [http://coxsackievirus coxsackievirus] multiplication effectively.<ref>https://jvi.asm.org/content/83/1/58</ref> [http://Chloroquine Chloroquine] has also been identified as a Zinc Ionophore that portrays its anticancer capability, and it has been considered as a potential anticancer agent.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/</ref>
== Antiviral Activity ==
Zinc Ionophores, Hinokitiol, and Pyrithione are useful in the inhibition of Picornavirus replication through the interference with the viral polyprotein proper processing.<ref>https://pubmed.ncbi.nlm.nih.gov/18922875/</ref> Hinokitiol and Pyrithione also result in a swift importation of extracellular Zn2+ ions into the cells, which increases the inhibition against Picornavirus infection.<ref>https://jvi.asm.org/content/83/1/58</ref>
== Anticancer Activity ==
The ability to bind on Zinc ions allows Zinc ionophores to cause apoptosis within cancer cells.<ref>https://pubmed.ncbi.nlm.nih.gov/19859983/</ref> Zinc Ionophores kill cancer cells via ways such as proteasome inhibition and lysosomal disruption, and thus, have proven to be potential anticancer agents.<ref>https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.253</ref>
= References =

Zinc Ionophores

2020-07-23T04:55:49Z

Amugune: This is a new page called Zinc Ionophores

Hinokitiol

2020-07-21T03:26:27Z

Amugune: category editing, History, additional citations

Hinokitiol (β-thujaplicin) is a naturally occurring [https://en.wikipedia.org/wiki/Hinokitiol monoterpenoid] found in the wooden part of trees in the family [https://en.wikipedia.org/wiki/Hinokitiol Cupressaceae]. It is a tropolone derivative and is extensively used in oral care and treatment products for its potent broad-spectrum antiviral,[https://pubmed.ncbi.nlm.nih.gov/18922875/ [1]] antimicrobial[https://pubmed.ncbi.nlm.nih.gov/10513629/ [2]] and anti-inflammatory [https://pubmed.ncbi.nlm.nih.gov/25952949/ [3]] properties. Hinokitiol is a Zinc, and Iron Ionophore additionally approved as a food additive.[https://www.jstage.jst.go.jp/article/jhep/43/2/43_299/_article/-char/ja/ [4]]

It was first isolated in Taiwanese hinoki in 1936, signifying the origin of the name Hinokitiol. It is almost absent in Japanese hinoki now. At the same time, it is still contained in high concentration (about 0.04% of heartwood mass) in Juniperus Cedrus, Hiba cedarwood (Thujopsis dolabrata) and Western red cedar (Thuja plicata). It can be easily extracted from the cedarwood with solvent and ultrasonication.[https://onlinelibrary.wiley.com/doi/full/10.1002/tcr.201200024 [5<nowiki>]</nowiki>] [https://www.degruyter.com/view/journals/hfsg/61/2/article-p190.xml [6<nowiki>]</nowiki>]

Hinokitiol is similar to a tropolone in structure, which lacks the isopropyl substituent. Tropolones are active chelating agents.<ref>https://pubmed.ncbi.nlm.nih.gov/17055455/</ref>

'''Antimicrobial activity'''

Hinokitiol has a wide range of biological activities, many of which have been discovered and specified in the literature. The first, and most famous, is the potent antimicrobial activity against many bacteria and fungi, regardless of antibiotic resistance. [https://www.sciencedirect.com/science/article/pii/S0944501312001462?via%3Dihub [7<nowiki>]</nowiki>][https://www.jstage.jst.go.jp/article/bio1996/12/3/12_3_101/_article [8<nowiki>]</nowiki>] To be precise, Hinokitiol has shown to be effective against Streptococcus pneumonia, Streptococcus mutans, and Staphylococcus Aureus, common human pathogens. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040402/ [9<nowiki>]</nowiki>][https://onlinelibrary.wiley.com/doi/abs/10.1111/1348-0421.12688 [10<nowiki>]</nowiki>] Additionally, Hinokitiol has been demonstrated to have inhibitory effects on Chlamydia trachomatis and may be clinically beneficial as a topical drug. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140513/ [11<nowiki>]</nowiki>][https://en.wikipedia.org/wiki/Special:BookSources/978-3-8383-4661-8 [12<nowiki>]</nowiki>]

'''Antiviral activity'''

Some recent studies have shown that Hinokitiol also demonstrates antiviral action when used in combination with a zinc compound against several human viruses, including rhinovirus, coxsackievirus, and mengovirus.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [13<nowiki>]</nowiki>] Curing viral infections has the potential to reap the mass economic benefit and must be of dire importance to global institutions such as the World Health Organisation. By impairing viral polyprotein processing, Hinokitiol inhibits viral replication - however, this capability is dependent upon the availability of divalent metal ions, as Hinokitiol is a chelator thereof.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [14<nowiki>]</nowiki>] The presence of zinc, combined with Hinokitiol, supports these capabilities and is discussed further as follows.

'''Anti-Inflammatory'''

Hinokitiol revealed a modulatory effect on the production of tumor necrosis factor (TNF)-alpha, a factor that influences skin inflammation and hair follicle apoptosis. This is achieved at the transcription level by disrupting the mRNA synthesis of TNF-alpha. Additionally, it suppresses phosphorylation of PDK1, Akt/PKB, and ERK, as a result diminishing the nuclear factor (NF)-kappaB activation, hence restoring hair loss.[[(https://www.sigmaaldrich.com/catalog/papers/18537078)|[15]]] In a recent study, Hinokitiol also revealed notable protection against ocular surface inflammation in dry eye syndrome (DES by inhibiting the NF-κB pathway [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506343/ [16<nowiki>]</nowiki>].

'''Other activities'''

In addition to antimicrobial activity, anti-inflammatory, and anti-tumor activities, characterized in several in vitro cell studies and in vivo animal studies. Hinokitiol determined to exert cytotoxicity on several prominent cancer cell lines by inducing autophagic processes.[http://www.kjcls.org/journal/view.html?doi=10.15324/kjcls.2019.51.2.221 [17<nowiki>]</nowiki>][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979393/ [18<nowiki>]</nowiki>]
= History =
== Discovery ==
In 1936, [http://Dr.%20Tetsui%20Nozoe Dr. Tetsui Nozoe] discovered the presence of Hinokitiol from the Taiwan cypress essential oil. the element has a heptagonal molecular structure that is believed to be non-existent within nature.<ref>https://pubmed.ncbi.nlm.nih.gov/25346458/</ref>

=== Modern research ===

'''Anti-Cancer'''

This study indicates the inhibitory effect of hinokitiol on the migration of human adenocarcinoma A549 cells. The anticancer properties of hinokitiol are supported by the evaluation of results in the present study, including an increase of Bax/p53 and cytochrome c, and further activation of caspases-9/-3 and antioxidant enzymes CAT and SOD. Moreover, we discovered the inhibitory impact of hinokitiol on the A549 cell migration was accompanied through the downregulation of MMPs-9 and MMP-2. These outcomes can also illustrate a new therapeutic value of hinokitiol in anticancer therapy.

Furthermore, another research showed strong anticancer characteristics of Hinokitiol by increasing the cytotoxicity against cervical cancer cells and non-small cell lung cancer (NSCLC) cells. Most cancers cell deaths are medicated through caspase-3 in apoptosis and consequently enlarged lysosomes which are regarded as the possession of anticancer compounds and that can possibly result in lysosomal injury and increased autophagy followed by severe cell death. The choice of therapeutic to hinokitiol, a herbal product derivative, can be concluded to have a mechanism of action against NSCLC with minimum cytotoxic and maximized therapeutic effects.[http://www.kjcls.org/journal/view.html?doi=10.15324/kjcls.2019.51.2.221 [19<nowiki>]</nowiki>]

'''Further Cancer research'''

Hinokitiol has shown an established mechanism to antagonize epidermal growth factor receptor (EGFR) protein expression in mammosphere production breast cancer stem/progenitor cells (BCSCs) without altering the messenger RNA expression. Hinokitiol also decreased the stability of EGFR in BCSCs. The stable protein expression of EGFR and vasculogenic mimicry (VM) production capability of hinokitiol treated BCSCs were restored by combination treatment with a proteasome antagonist, MG132. It can be concluded that hinokitiol may antagonize the VM activity of BCSCs by stimulating proteasome-mediated EGFR break-down. Hinokitiol may be considered as a novel breast cancer therapeutic agent, by acting as an anti-VM. [https://www.spandidos-publications.com/10.3892/ol.2016.4300#:~:text=Hinokitiol%20dose%2Ddependently%20inhibits%20VM,anti%2Dinflammatory%20and%20antitumor%20activity [20<nowiki>]</nowiki>]

Further study demonstrated Hinokitiol regulates estrogen receptor signaling and also antagonizes the proliferation of breast cancer cells in humans. Hence, it can be considered as a promising agent against the treatment of hormone-sensitive mammary tumorigenesis.[https://www.tandfonline.com/doi/full/10.1080/09168451.2015.1008978 [21<nowiki>]</nowiki>]

'''Hinokitiol with Curcumin'''

A potent effect was observed against NSCLC and gefitinib resistant NSCLC cells when Hinokitiol was used in combination with Curcumin. This treatment indicated minimal cytotoxicity to healthy cells. [https://journals.sagepub.com/doi/10.1177/1934578X1801301223 [22<nowiki>]</nowiki>]

'''Coronavirus research'''

Potential antiviral effects of Hinokitiol arise from its action as a zinc ionophore. Hinokitiol enables the influx of zinc ions into cells, which inhibit the replication machinery of RNA viruses, and subsequently hindering the replication of the virus.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [23<nowiki>]</nowiki>] Some notable RNA viruses include the human influenza virus, SARS. Zinc ions were able to inhibit viral replication within cells significantly and proved that the action was dependent on zinc influx. This study was done with the zinc ionophore pyrithione, which functions very similarly to Hinokitiol.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973827/ [24<nowiki>]</nowiki>] In cell cultures, hinokitiol inhibit human rhinovirus, coxsackievirus, and mengovirus multiplication. Hinokitiol interferes with the processing of viral polyproteins, thus inhibiting picornavirus replication. Hinokitiol inhibits the replication of picornaviruses by impairing the viral polyprotein processing and that the antiviral activity of hinokitiol is dependent on the availability of zinc ions.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612303/ [25<nowiki>]</nowiki>]

'''Iron ionophore'''

Hinokitiol has been shown to restore hemoglobin production in rodents. Hinokitiol acts as an iron ionophore to channel iron into cells,[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470741/ [26<nowiki>]</nowiki>][https://www.sciencemag.org/news/2017/05/iron-man-molecule-restores-balance-cells [27<nowiki>]</nowiki>] increasing intracellular iron levels. Approximately 70% of the iron in humans is contained within red blood cells and specifically the hemoglobin protein. Iron is essential to almost all living organisms, and it is a critical element of several anatomical functions such as the oxygen transport system, deoxyribonucleic acid (DNA) synthesis, and electron transport and an iron deficiency can lead to blood disorders such as Anemia which, can be significantly detrimental to both physical and mental performance.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999603 [28<nowiki>]</nowiki>]

'''Zinc synergism'''

Hinokitiol is a Zinc ionophore, and this capability is believed to inhibit viral replication. In brief, as a zinc ionophore, Hinokitiol aids in the transport molecules into cells through a plasma membrane or intracellular membrane, thus increasing the intracellular concentration of the specified molecule (ex. Zinc). Hence, by taking advantage of Zinc’s antiviral properties, in combination with Hinokitiol, Zinc uptake can be accelerated.[https://www.sciencedirect.com/topics/neuroscience/ionophores]

'''Zinc Deficiency'''

Zinc deficiency has been demonstrated in some cancer cells, and returning optimum intra-cellular zinc levels can lead to suppression of tumor growth. Hinokitiol is a documented Zinc Ionophore; however, more research is required to establish effective concentrations of delivery methods for Hinokitiol and Zinc.

· “Effects of dietary zinc on melanoma growth and experimental metastasis...” [https://www.sciencedirect.com/science/article/abs/pii/0304383583902069]

· “Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature...” [https://www.nature.com/articles/onc2011592]

· “Zinc levels were relatively lower in patients with lung cancer as compared to a control group: a meta-analysis of observational studies...” [https://wjso.biomedcentral.com/articles/10.1186/s12957-019-1617-5]

· “Research progress on the relationship between zinc deficiency, related microRNA s, and esophageal carcinoma...” [https://onlinelibrary.wiley.com/doi/full/10.1111/1759-7714.12493]

Products containing Hinokitiol include toothpaste, oral sprays, sunscreen, and other cosmetics.

'''EWG Scoring Scale'''

Hinokitiol is also used in a wide range of consumer products, including cosmetics, toothpaste, oral sprays, sunscreens & hair-growth. One of the leading brands in the sale of consumer hinokitiol products is Hinoki Clinical. Hinoki Clinical (est. 1956) was established shortly after the first ‘industrial extraction of hinokitiol’ began in 1955.[https://www.hinoki.co.jp/products/hinokitiol/] Hinoki currently has over 18 different product ranges with hinokitiol as an ingredient. Another brand, namely, ‘Relief Life,’[https://www.anshin-tsuuhan.com/item/propogreen.html] , has boasted over a million sales with their ‘Dental Series’ toothpaste containing hinokitiol.[https://item.rakuten.co.jp/anshintsuuhan/10000015/] Other notable producers of hinokitiol based products include Otsuka Pharmaceuticals, Kobayashi Pharmaceuticals, Taisho Pharmaceuticals, SS Pharmaceuticals. Besides Asia, companies such as Swanson Vitamins®️ are commencing the utilization of hinokitiol in consumer products in markets such as the U.S.A.[https://www.swansonvitamins.com/now-foods-coq10-antioxidant-serum-1-fl-oz-liquid] and Australia [https://www.swansonaustralia.com/en/home/1033-now-foods-solutions-hyaluronic-acid-firming-serum-1-fl-oz-30ml.html] as an anti-oxidant serum and in other endeavors. In 2006, hinokitiol was categorized under the Domestic Substances List in Canada as non-persistent, non-bioaccumulative & non-toxic to aquatic organisms.[https://open.canada.ca/data/en/dataset/1d946396-cf9a-4fa1-8942-4541063bfba4] The Environmental Working Group (EWG), an American activist group, has dedicated a page to the ingredient hinokitiol indicating that it is ‘low hazard’ in areas such as “Allergies & Immunotoxicity,” “Cancer” & “Developmental & Reproductive Toxicity” [https://www.ewg.org/skindeep/ingredients/702859-HINOKITIOL/] giving Hinokitiol a score of 1-2. In contrast to Hinokitiol’s score, Propylparaben, an ingredient still sold in various mouthwashes, exhibits vast toxicity and hazardous concerns. Propylparaben has been deemed by the European Commission on Hormone Disruption to be a Human endocrine disruptor, among other concerns [https://www.ewg.org/skindeep/ingredients/705335-PROPYLPARABEN/] leaving it at a rating of 4-6 on the EWG website.

'''Dr. ZinX'''

On 2 April 2020, Advance Nanotek,[https://www.advancenanotek.com/] an Australian producer of zinc oxide, filed a joint patent application with AstiVita Limited,[https://www.astivita.com.au/] for an antiviral composition that included various oral care products [http://pericles.ipaustralia.gov.au/ols/auspat/applicationDetails.do?applicationNo=2020900820] containing hinokitiol as a vital component. The brand that is now incorporating this new invention is called Dr. ZinX and is likely to release its Zinc + Hinokitiol combination products in 2020.[https://www.asx.com.au/asxpdf/20200520/pdf/44hzh0v8bqgvlx.pdf][https://www.drzinx.com/] On 18 May 2020, Dr. ZinX published test results for a “Quantitative suspension test for the evaluation of hinokitol's virucidal properties in the medical area” [https://www.asx.com.au/asxpdf/20200520/pdf/44hzh0v8bqgvlx.pdf][https://www.drzinx.com/testresults] declaring a ‘3.25 log’ reduction (99.9% reduction) for a neat concentration in 5 minutes against COVID-19 surrogate Feline Coronavirus.[https://www.tga.gov.au/surrogate-viruses-use-disinfectant-efficacy-tests-justify-claims-against-covid-19] Zinc is considered to be an essential dietary supplement and trace element in the body. Globally it is estimated that 17.3% of the population has inadequate Zinc intake.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510072/][https://academic.oup.com/jn/article/132/11/3422/4687273]

'''A Promising Future'''

Beginning in the 2000s, researchers considered that hinokitiol could be of value as a pharmaceutical ingredient, notably for its inhibitory effect on the bacterium ''Chlamydia trachomatis''.<ref>https://www.researchgate.net/publication/7823344_In_Vitro_Inhibitory_Effects_of_Hinokitiol_on_Proliferation_of_Chlamydia_trachomatis</ref>

Chemist Martin Burke and colleagues at the University of Illinois at Urbana–Champaign and other institutions discovered the significance of hinokitiol in the medical field. Burke’s goal was to overcome the imbalance of iron transport in animals. Deficiencies of several proteins can lead to iron deficiency in cells (anemia) or the opposite effect, Hemochromatosis.[https://www.acs.org/content/acs/en/molecule-of-the-week/archive/h/hinokitiol.html] Using gene-depleted yeast cultures as surrogates, the researchers screened a library of small biomolecules for iron transport signs and, therefore, cell growth. Hinokitiol was identified to be the one that rejuvenate cell's functionality. Further study by the team established the mechanism by which hinokitiol balances cell iron.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470741/] They then diverted their study to mammals and found that when rodents that had been engineered to lack “iron proteins” were fed hinokitiol, they regained iron uptake by increasing the absorption in the gut. In a similar study on zebrafish, hinokitiol revealed to restore Hemoglobin production.[https://www.sciencemag.org/news/2017/05/iron-man-molecule-restores-balance-cells] A commentary on the work of Burke et al. nicknamed hinokitiol the “Iron Man molecule”. This is fitting/ironic because discoverer Nozoe’s first name can be translated into English as “iron man”.

Significant research has also been conducted into the oral applications of Hinokitiol, given the increased demand for Hinokitiol based oral products. One such study, affiliated with eight different institutions in Japan, titled: “Antibacterial Activity of Hinokitiol Against Both Antibiotic-Resistant and -Susceptible Pathogenic Bacteria That Predominate in the Oral Cavity and Upper Airways” concluded that “hinokitiol demonstrates antibacterial activity against a broad spectrum of pathogenic bacteria and has low cytotoxicity towards human epithelial cells.” [https://onlinelibrary.wiley.com/doi/abs/10.1111/1348-0421.12688]