In the earlier stages of the existence of the Earth, the conditions on the planet were quite different from those of today. The appearance of organic molecules including amino acids and small peptides was possible; however, organization from such a mixture of distinct simple living organisms with the ability to reproduction is an incorrect hypothesis. Then, as today, the blueprints for reproduction, i.e., nucleotide and nucleoside molecules, were needed as the organizers. These stable molecules with a ring structure with tri- and pentavalent nitrogen are most suitable for elevated temperatures (Brondz, 2021). The first building blocks of life were these thermodynamically stable tri- and pentavalent nitrogen ring structures (Brondz, 2021). They were the primary manifestation of life, which organized peptides into simple proteins, and simple proteins into simple living, self-reproducing organisms—viruses (Brondz, 2020). It is difficult to imagine that any living, self-reproducing organisms had appeared before the appearance of the genetic and ribosomal material comprising viruses. Viruses are quite simple organisms that today are intracellular parasites, which often cause the death of the infected cells. However, parasitism was not the primary aim of viruses; at the beginning, they were possibly predators for other types of viruses or even cannibalized each other. Once cells appeared, viruses started to use the cells as their prey and later became intracellular parasites. As occurs for all parasites over long-term evolution, they underwent simplification and adaptation to parasitism. Thus, viruses were transformed into simpler organized structures and lost many of their organelles and even parts of their genetic material.
Not all cells that are infected by viruses die. Some nontarget cells infected by virions stay alive after infection and even after the viral particles have left those cells.
Rubella is a contagious disease caused by infection with the rubella virus (Lambert et al., 2015), (Carlson et al., 2016). Infection with this virus may result in a child being born with congenital rubella syndrome (CRS) (Lambert et al., 2015) , the symptoms of which include coryza (which may convert to pneumonia (Michael, 1908)) and CRS can manifest as effects on the heart and brain (Lambert et al., 2015). Cytomegalovirus is a common virus that affects most humans. Its host organisms are humans and monkeys. Those who have been infected by cytomegalovirus have it for life. There is no curative treatment to eliminate this virus, although therapies exist (Mattes et al., 2000). For young and healthy individuals with a good immune system, the infection is a minimal problem, however, during pregnancy or in immunocompromised humans it can threaten health. Many viruses are retained in infected organisms for their lifetime, others can remain a part of their genome incorporated into the genome of the host when they leave the nontarget cell.
The target cells of the common flu virus are mucosal cells, but it also infects other cell types, including ovaries, and spermatozoids. Not all these cells die; some remain alive and are capable of performing their functions. Thus, fertilization can proceed normally, and the resulting babies may even be without defects. However, in some cases, the following generation is defective. Part of the viral genetic material can remain attached to the original genetic material of infected subjects (human, animal, plant, bacteria, or other). In these cases, the defects can be negative (i.e., they result in illnesses or even death), or positive (i.e., they result in additional capabilities). These defects are mutations. If part of the viral genome remains incorporated in these cells it can affect the next generation or be transmitted along through generations and affect newborns of the third, fourth, or many generations afterward, as in the case of hemophilia (a mostly inherited genetic disorder that impairs the body’s ability to make blood clots).
2. Role of Virus in the Environment
Charles Darwin described the appearance of species in “On the Origin of Species” (Darvin, 1859), (Freeman, 2002) in 1859 at a time when its genetic basis was unknown. His theory was based mainly on observation of natural selection without any understanding of the role of genetic’ mutation in the appearance of changes in a species. This theory is incorrect. Without mutation, the appearance of a new species is not possible. Gregor Johann Mendel (Czech: Řehoř Jan Mendel) is recognized as the founder of the modern science of genetics (Klein & Klein, 2013), who formulated the laws of Mendelian inheritance (Schacherer, 2016). These laws were originally proposed by Gregor Mendel in 1865 and 1866, and rediscovered in 1900. The principles of the initially controversial Mendelian theories were integrated with the Boveri-Sutton chromosome theory of inheritance by Thomas Hunt Morgan in 1915, and the combined theory became the core of classical genetics. The role of viruses in generating positive mutations resulting in the dominance of strong mutants and the disappearance of weak mutants was underestimated by Charles Darwin, although it was unknown to him. Mutations resulting from chemical or radioactive causes are usually rare and lead to defects or weak mutants. Mutations are more frequently caused by the involvement of viruses, which are the driving force in the appearance of both negative and positive mutations. Thus, viruses are the driving force behind the appearance of new species by inducing mutation and subsequent selection of strong mutants.
3. Comparative Situation
In a previous paper (Brondz, 2020), I presented the dangers of agricultural customs such as using the manure from pigs, which is a source of a range of infections including coronaviruses. Some pesticides and insecticides deactivate lysozyme, thus jeopardizing host immunity. In another paper (Brondz, 2017c), I warned strongly against the custom of using “fire farming” or “fire-stick farming” in agriculture and the blind eye turned by authorities to annual forest fires that are started deliberately. The accumulation of dioxins in the environment as a result of “fire farming” and “fire-stick farming” has led to disease in countries such as India, and dioxins can lead to mutations in viruses, which is a possible cause of the different dynamics of the epidemic in India and China (in India “fire farming” is a common custom, but in China, it is virtually unknown). However, the use in China and elsewhere in Asia of “gutter oil” by street kitchens. (The Making of “Gutter Oil” (https://www.youtube.com/watch?v=zrv78nG9R04)) can lead to the same problems as “fire farming” in India because the oil contains several different carcinogens. In both cases, the presence of carcinogens and dioxins is a fact. Dioxins, most pesticides, insecticides, radiation, heavy metal elements, all carcinogens, and many other environmental pollutants are jeopardizing human immunity and the immunity of other living creatures including even plants. Immunocompromised animals are a significant reservoir of dangerous infections (including viral infections) for humans. The substances listed above can trigger mutations in fungi, molds, bacteria, and viruses. The appearance of a new mutant COVID-19 in India could be predicted because of contamination of the environment by dioxins and is not surprising. In a previous paper (Brondz, 2017c), I provided an alert that “fire farming” is a significant crime against the population in these countries and against consumers worldwide who consume the contaminated products. In another paper (Brondz & Brondz, 2011), I presented clear evidence that some chlorinated pesticides can deactivate lysozyme. Lysozyme is a part of the humoral immune system that is present in all mucosal tissues and protects humans from the first minute of life (Minami et al., 2015). Lysozyme exhibits activity against viral infections (Oderinde et al., 2017; Cisani et al., 1984; Lee-Huang et al., 1999). Deactivation of lysozyme by chemicals and pesticides jeopardizes the immune system.
3.1. Anti-COVID-19 Medication: Chloroquine
In China, immediately after the outbreak of COVID infection in 2019, it was proposed to use chloroquine as a treatment. Chloroquine is a 4-aminoquinoline antimalarial drug.
Chloroquine Figure 1 was the first synthetic antimalarial drug (Brondz, 2011a); however, it is quite toxic. Other synthetic antimalarial drugs (primaquine, pamaquine, quinocide, and tafenoquine) are less toxic but have similar pharmacological and biochemical mechanisms to chloroquine. Figure 2 shows the structures of (a) primaquine, (b) quinocide, and (c) pamaquine. Their efficacy against COVID-19 may be based on their overall effects, in particular the arrest or inhibition of proton pumps.
3.2. Anti-COVID-19 Medication: Primaquine, Quinocide, and Pamaquine
The effects of contamination with quinocide in primaquine were studied using chromatography and mass spectrometry, and some of its biochemical toxicity analyzed in vitro. The toxicity (in vitro) was first presented as a poster see Figure 3 (Brondz et al., 2003) (below) and later published as a complete paper (Brondz et al., 2004a) . A new gas chromatography-mass spectrometry (GC-MS) method of analysis of the toxic contaminant quinocide in primaquine was developed and presented in (Brondz et al., 2004a, 2004b) (see Figure 4), and later
Figure 1. Structure of chloroquine, a 4-aminoquinoline.
Figure 2. (a) Primaquine, (b) quinocide, and (c) pamaquine. Primaquine, quinocide, and pamaquine are 8-aminoquinolines.
published as a complete paper (Brondz et al., 2005a). A subsequent series of papers supported the findings (Brondz et al., 2004a), (Brondz et al., 2005a), (Brondz et al., 2005b), (Brondz & Klein, 2005), (Brondz et al., 2005c), (Brondz & Klein, 2006), (Brondz et al., 2007), (Brondz et al., 2009), (Brondz, 2009a), (Brondz, 2009b), (Brondz, 2010), (Brondz, 2011b), (Brondz & Brondz, 2012a), (Brondz, 2014), (Brondz, 2011c). In references (Brondz et al., 2003) and (Brondz et al., 2004a), algicidal activity on Chlamydomonas reinhardtii strain CC124 was used as a measure of biological toxicity. The details of biological toxicity were presented at (Brondz, 2011b).
The effects of contamination with quinocide were studied using chromatography and mass spectrometry, and some of its biochemical toxicity analyzed in vitro. The toxicity (in vitro) was first presented as a poster see Figure 3 (Brondz et al., 2003) (below) and later published as a complete paper (Brondz et al., 2004a, 2004b). A new chromatography-mass spectrometry method of analysis of the toxic contaminant quinocide in primaquine was developed and presented in (Brondz et al., 2003) (see Figure 4), and later published as a complete paper
(Brondz et al., 2005a). A subsequent series of papers supported the findings (Brondz et al., 2004a, 2004b), (Brondz et al., 2005a), (Brondz et al., 2005b), (Brondz & Klein, 2005), (Brondz et al., 2005c), (Brondz & Klein, 2006), (Brondz et al., 2007), (Brondz et al., 2009), (Brondz, 2009a), (Brondz, 2009b), (Brondz, 2010), (Brondz, 2011b), (Brondz & Brondz, 2012a), (Brondz, 2014), (Brondz, 2011c). In references (Brondz et al., 2003) and (Brondz et al., 2004a), algicidal activity on Chlamydomonas reinhardtii strain CC124 was used as a measure of biological toxicity. The details of biological toxicity were presented at (Brondz, 2011b). The table of toxic effects is shown in Figure 5 [https://www.researchgate.net/publication/264346815_In_vitro_techniques_in_analysis_of_antimalarial_drug_primaquine_Historical_Overview_of_Chromatography_and_Related_Techniques_in_Analysis_of_Antimalarial_Drug_Primaquine].
C. reinhardtii is a well-studied biological model organism (Figure 6). Several effects of primaquine on C. reinhardtii have been described (Brondz et al., 2003). However, the immobilization by toxic actions of primaquine and quinocide of movements of this motile alga was only partly studied (Brondz et al., 2003). The main contaminant of the anti-malaria drug primaquine is its positional isomer (Brondz et al., 2004a; Brondz, 2011b).
Figure 6 scheme of the Chlamydomonas reinhardtii cell; schematically redrawn, based on this TEM micrograph: http://cellimagelibrary.org/images/CIL_37252 1) flagellum 2) mitochondrion 3) contractile vacuole 4) eyespot (stigma) 5) chloroplast 6) Golgi apparatus 7) starch granules 8) pyrenoid 9) vacuole 10) nucleus 11) endoplasmic reticulum 12) cell membrane 13) cell wall. (Image corresponds to Figure 2 in J. Cell Biol. 1967, 35, 3, 521-552. Image made available by James D. Jamieson and the Department of Cell Biology, Yale University School of Medicine. (The Public Domain Mark is for works that are no longer restricted by copyright and can be freely used by others).
Every cell of C. reinhardtii possesses two flagella which it uses for swimming (movement). C. reinhardtii has a unique ability to turn on hydrogen production only to induce anaerobiosis in response to a metabolic stress. Aminoquinolines have a variety of biological properties including antimalarial, antileishmanial, antitrypanosomally, anticancer, antibacterial, antifungal, antialgal (possibly due to triggering of anaerobiosis), and antiviral (recently reported) (Ray et al., 2020), (Gao et al., 2020), (Liu et al., 2020) effects. Primaquine may bind to DNA and alter its properties. Effects on glycolysis (suboptimal doses of primaquine have been used in critically ill obese patients) (Santos et al., 2010), (Brian et al., 2020), influences on intracellular pH, interference with the uptake of oxygen in the dark (respiration) and production of oxygen in light (photosynthesis) and interference with the electron transport chain in chloroplasts and mitochondria (Brondz et al., 2003), (Brondz et al., 2004a), (Brondz, 2011b).In vitro techniques in analysis of antimalarial drug primaquine (Historical Overview of Chromatography and Related Techniques in Analysis of Antimalarial Drug Primaquine) 7th Annual BioMalPar Conference on the Biology and Pathology of the Malaria Parasite, 16-18 May 2011, (Heidelberg) Germany, abstr. 54, p. 80, have all been
Figure 5. The table of toxic effects of primaquine and quinocide (reproduced from Brondz, 2011b [https://www.researchgate.net/publication/264346815_In_vitro_techniques_in_analysis_of_antimalarial_drug_primaquine_Historical_Overview_of_Chromatography_and_Related_Techniques_in_Analysis_of_Antimalarial_Drug_Primaquine]).
Figure 6. The scheme of the Chlamydomonas reinhardtii redroawn from TEM micrograph: http://cellimagelibrary.org/images/CIL_37252.
reported. Aminoquinolines can impair the overall bioenergetic metabolism of cells, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. By this mechanism, they induce mitochondrial dysfunction through the inhibition of cytochrome C reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential.
C. reinhardtii is a motile flagellated microalga. Flagellated movements are usually mediated by a hydrogen-proton motor. The arrest of C. reinhardtii movement by primaquine and quinocide may suggest the deactivation of this hydrogen-proton motor (Brondz et al., 2003), (Brondz et al., 2004a), (Brondz, 2011a), (Brondz, 2011b). Disruption of the hydrogen-proton motor suggests proton-pump inhibition. By this mechanism, the 8-aminoquinolines primaquine and quinocide and other 4-aminoquinolines may be candidates for selective targeting of COVID-19 replication (Watanabe et al., 2020), (Shin et al., 2004).
4. Hypericumperforatum L.
The content and biological activities of H. perforatum L. were studied at Oslo University by Brondz and reported in his thesis for the degree of Candidatus of Pharmaceutical sciences: (Brondz, I. In: Antibiotikumet “Hyperforin” ogandreinnholdsstoffer i drogen Hypericum perforatum L., (1979) Thesis (Cand. Pharm.) University of Oslo, Oslo Norway (in Norwegian)) (Brondz, 1979) (text is available from the University library). The content of H. perforatum L. was described and published in (Brondz et al., 1983a), (Brondz et al., 1983b). The n-alkenes were isolated from H. perforatum L. by truping (clathrating) using urea crystals (Figure 7) and identified using chromatography (Figure 8) (Brondz, 1979).
Special attention was directed to the study of the stereochemistry and antimicrobial activities of hyperforin. Hyperforin was isolated, its molecular mass was first established using MS with chemical ionization (Figure 9), and its antimicrobial activity against penicillin-resistant bacteria was demonstrated (Brondz, 1979).
The correct stereochemistry of this biologically active molecule is especially important for its pharmacological effects on enzymes and on the immune system. The relative and absolute stereochemistry of hyperforin was published previously by the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) in 1975 (Bystrov et al., 1976), (Bystrov et al., 1975). In another study (Brondz et al., 1982) the relative stereochemistry was supported by Brondz et al., X-ray diffraction measurements, however, the absolute configuration of hyperforin as determined at the USSR Academy of Sciences in Moscow (Bystrov et al., 1976), (Bystrov et al., 1975) was incorrect. The correct absolute configuration of hyperforin was reported based on the crystal structure determination of hyperforin p-bromobenzoate ester based on X-ray diffraction measurements (Brondz et al., 1983a) , (Brondz, 2016a). Other studies (Brondz, 2017a), (Brondz, 2017b), (Brondz, 2018) compared this version of the absolute configuration of hyperforin with that reported in (Bystrov et al., 1976) and (Bystrov et al., 1975) (Figure 10) and found that the correct absolute configuration of hyperforin was that first described in (Brondz et al., 1983a) and was supported in (Brondz, 2017b).
4.1. Hyperforin’s Antimicrobial and Immunomodulating Properties
The antimicrobial spectrum of hyperforin (is including that against penicillin-resistant bacteria) was described in (Brondz, 1979); later, it was reported that hyperforin had antimicrobial activity against multiresistant Staphylococcus and Neisseria meningitidis. The possibility of immunomodulatory effects of the drug was first suggested by Brondz in a lecture at the Symposium: Norlændska infektionssjkdomar, Sweden (1986), entitled “The influence of hyperforin on phagocytosis of E. coli by human polymorphonuclear neutrophils in vitro.” However, data about the phagocytosis of E. coli by human polymorphonuclear neutrophils (in vitro) was reported by Brondz et al. as early as 1984 (Brondz et al., 1984) . Later developments of the research were reported in (Brondz, 1987).
4.2. Enhancement of Immunity
The antimicrobial and immunomodulatory properties of hyperforin are especially important in meningococcal diseases, syphilis, and gonorrhea. Hyperforin, a substance from the herb H. perforatum L. (Brondz, 1979) is an immunomodulator (Brondz, 2016a), (Brondz, 1987), (Brondz, 2012), (Brondz & Brondz, 2012b), (Brondz, 2016b) (without suppressing the immune system). Its importance in curing the meningococcal diseases, syphilis, and gonorrhea difficult overestimate.
4.3. Lysozyme and Hyperforin Enhancement of Immunity and Activity against Viruses
Most antibiotics, antimycotics, cytostatic drugs, and antivirals have negative effects on the immune system. Commercially available treatments with exogenous and endogenous lysozyme can enhance the immune system and have antiviral effects (Oderinde et al., 2017), (Cisani et al., 1984), (Lee-Huang et al., 1999). Hyperforin has antimicrobial (Brondz, 1979) and immunostimulating effects (Brondz, 2016a), (Brondz, 1987). Influence of hyperforin upon phagocytic functions in human polymorphonuclear leucocytes was presented at Fourth International Conference on Chemistry and Biotechnology of Biological Active Natural Products, (Budapest) Hungary (1987) abstr. B-15, p. 119 (Brondz, 1987). Enhancement of the immunity in AIDS and other immunocompromised patients by hyperforin an antibiotic from Hypericumperforatum L. was also presented at 2nd ARIP European Conference on Antimicrobial Resistance & Infection Prevention, Vilnius, Lithuania, 4-5 October 2012, P12, p. 60. In: (Brondz, 2012) OFICIALUS LIETUVOS BENDROSIOS PRAKTIKOS GYDYTOJŲ KOLEGIJOS LEIDINYS, No. 7, ISSN, pp. 1392-3218. Hyperforin penetrates the BTB and the BBB (Brondz, 2016b), and accumulates in vital tissues including the liver, lungs, kidney, skin, testis, and brain (Brondz, 2016b). Hyperforin has activity against plant viruses (Brondz, 1979). However, more important is the discovery that it has antiviral activity against animal viruses (Verotta et al., 2007), (Huijie et al., 2019) and is active against the causative agent of COVID-19, SARS-CoV-2.
The use of harmful practices in the agriculture, farming of livestock, poultry, and fish, and in food processing must be avoided. Forest arsonists as well as the users of “fire farming” and the manufacturers of food with added toxic substances must be punished because they are jeopardizing the health of the global population. The reasons why medication with known antiviral (anti-COVID-19) drugs including 4-aminoquinolines, 8-aminoquinolines, lysozyme, hyperforin (Bajrai, et al., 2021), and other drugs has been not used during the wait for suspicious, incompletely developed, and not clinically tested vaccines should be investigated and questioned. Why wait for an illusory vaccine when several millions of humans have died globally, and not use the same medications that were used to treat former President Donald Trump, who was healthy two days after COVID-19 infection [https://www.youtube.com/watch?v=BqeNqEAE3R0]? The proposal and prediction that vaccination against COVID-19 infection must be repeated every six months for the majority of the population rather than using antiviral drugs show that vaccination is not sustainable, and it is most likely directed to aims other than protecting the global population from illness.
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