Tutankhamun's Antimalarial Drug for Covid-19.

Drug repositioning is a strategy that identifies new uses of approved drugs to treat conditions different from their original purpose. Current efforts to treat Covid-19 are based on this strategy. The first drugs used in patients infected with SARS-CoV-2 were antimalarial drugs. It is their mechanism of action, i. e., rise in endosomal pH, which recommends them against the new coronavirus. Disregarding their side effects, the study of their antiviral activity provides valuable hints for the choice and design of drugs against SARS-CoV-2. One prominent drug candidate is thymoquinone, an antimalarial substance contained in Nigella sativa - most likely one of the first antimalarial drugs in human history. Since the outbreak of the pandemic, the number of articles relating thymoquinone to Covid-19 continuously increases. Here, we use it as an exemplary model drug, compare its antiviral mechanism with that of conventional antimalarial drugs and establish an irreducible parametric scheme for the identification of drugs with a potential in Covid-19.Translation into the laboratory is simple. Starting with the discovery of Nigella sativa seeds in the tomb of Pharaoh Tutankhamun, we establish a physicochemical model for the interaction of thymoquinone with both coronavirus and cells. Exploiting the predictive capability of the model, we provide a generalizable scheme for the systematic choice and design of drugs for Covid-19. An unexpected offshoot of our research is that Tutankhamun could not have died of malaria, a finding contrary to the mainstream theory.

Quantum biology in low level light therapy: death of a dogma.

BACKGROUND: It is shown that despite exponential increase in the number of clinically exciting results in low level light therapy (LLLT), scientific progress in the field is retarded by a wrong fundamental model employed to explain the photon-cell interaction as well as by an inadequate terminology. This is reflected by a methodological stagnation in LLLT, persisting since 1985. The choice of the topics is, by necessity, somewhat arbitrary. Obviously, we are writing more about the fields we know more about. In some cases, there are obvious objective reasons for the choice. Progress in LLLT is currently realized by a trial and error process, as opposed to a systematic approach based on a valid photon-cell interaction model. METHODS: The strategy to overcome the current problem consists in a comprehensive analysis of the theoretical foundation of LLLT, and if necessary, by introducing new interaction models and checking their validity on the basis of the two pillars of scientific advance (I) agreement with experiment and (II) predictive capability. The list of references used in this work, does contain a representative part of what has been done in the photon-cell interaction theory in recent years, considered as ascertained by the scientific community. RESULTS: Despite the immense literature on the involvement of cytochrome c oxidase (COX) in LLLT, the assumption that COX is the main mitochondrial photoacceptor for R-NIR photons no longer can be counted as part of the theoretical framework proper, at least not after we have addressed the misleading points in the literature. Here, we report the discovery of a coupled system in mitochondria whose working principle corresponds to that of field-effect transistor (FET). The functional interplay of cytochrome c (emitter) and COX (drain) with a nanoscopic interfacial water layer (gate) between the two enzymes forms a biological FET in which the gate is controlled by R-NIR photons. By reducing the viscosity of the nanoscopic interfacial water layers within and around the mitochondrial rotary motor in oxidatively stressed cells R-NIR light promotes the synthesis of extra adenosine triphosphate (ATP). CONCLUSIONS: Based on the results of our own work and a review of the published literature, we present the effect of R-NIR photons on nanoscopic interfacial water layers in mitochondria and cells as a novel understanding of the biomedical effects R-NIR light. The novel paradigm is in radical contrast to the theory that COX is the main absorber for R-NIR photons and responsible for the increase in ATP synthesis, a dogma propagated for more than 20 years.

Revisiting the Photon/Cell Interaction Mechanism in Low-Level Light Therapy.

Objective: Several reports claim that the enzyme cytochrome c oxidase (CCO) is the primary absorber for red-to-near-infrared (R-NIR) light in cells and causal for mitochondrial adenosine triphosphate (ATP) upregulation, and that pulsed R-NIR light has frequent therapeutic effects, which are superior to those of the continuous wave (CW) mode used in low-level light therapy (LLLT). Background data: Convincing evidence that the absorption of R-NIR photons by CCO is involved in mitochondrial ATP upregulations as well as a coherent explanation for the superiority of the pulsed irradiation mode is presently lacking in the literature. Methods: A comprehensive literature search and rigorous analysis of the data published on the idea that CCO is the primary absorber for R-NIR light, and of the claim that the effectivity of the pulsed irradiation mode can be derived from the absorption of R-NIR photons by CCO, reveal a number of severe inconsistencies. Results: A systematical analysis covering both the theory that CCO is the primary acceptor for R-NIR light and of its use to interpret differences between the biological effect of pulsed light and CW casts doubt on the general validity of the CCO-based hypothesis. Instead, we are offered a simple and conflict-free model accounting for both ATP upregulation and superiority of the pulsed mode in LLLT, which is in agreement with the results of recent laboratory experiments. Conclusions: CCO is not the primary acceptor for R-NIR light.

Aging Is a Sticky Business.

OBJECTIVE: The objective of this work is to put forward a mechanism by which low-level light [red-to near infrared (NIR) laser or light emitting diodes (LED)] is instrumental in the process of accelerating the healing of wounds. BACKGROUND DATA: Interaction modalities of low-level light with oxidatively stressed cells and tissues are the focus of intense research efforts. Several models of the light/cell-interaction mechanism have been proposed. In the most popular model, cytochrome c oxidase is believed to play the role of the principal acceptor for red-to NIR photons. METHODS: Using as an illustrative example the successful LED treatment of an edematous limb ulcer, the results of recent in vitro tests and complementary laboratory experiments are presented and discussed. RESULTS: The most plausible mechanism of biostimulatory effect of red-to NIR light consists of its impact on the nanoscopic interfacial water layers in mitochondria and the extracellular matrix (ECM) where mitochondrial reactive oxygen species (ROS) induce an increase in the viscosity of the water layers bound to the predominantly hydrophilic surfaces in the intramitochondrial space as well as the ECM, where the process progressively propagates with age. The biostimulatory effect of red-to NIR light consists of counteracting the ROS-induced elevation of interfacial water viscosities, thereby instantly restoring the normal mitochondrial function, including the synthesis of adenosine triphosphate (ATP) by the rotary motor (ATP synthase). CONCLUSIONS: An understanding of the mechanism of interaction of red-to NIR light with mitochondria, cells, and tissues safeguards progress in the field of low-level light therapy (LLLT) and puts us in the position to design better therapies.

Light Effect on Water Viscosity: Implication for ATP Biosynthesis.

Previous work assumed that ATP synthase, the smallest known rotary motor in nature, operates at 100% efficiency. Calculations which arrive to this result assume that the water viscosity inside mitochondria is constant and corresponds to that of bulk water. In our opinion this assumption is not satisfactory for two reasons: (1) There is evidence that the water in mitochondria prevails to 100% as interfacial water. (2) Laboratory experiments which explore the properties of interfacial water suggest viscosities which exceed those of bulk water, specifically at hydrophilic interfaces. Here, we wish to suggest a physicochemical mechanism which assumes intramitochondrial water viscosity gradients and consistently explains two cellular responses: The decrease and increase in ATP synthesis in response to reactive oxygen species and non-destructive levels of near-infrared (NIR) laser light, respectively. The mechanism is derived from the results of a new experimental method, which combines the technique of nanoindentation with the modulation of interfacial water layers by laser irradiation. Results, including the elucidation of the principle of light-induced ATP production, are expected to have broad implications in all fields of medicine.

Tuning the mitochondrial rotary motor with light.

Skin surface temperature has been proposed as an in vivo clinical biomarker for monitoring the detrimental effect of biostimulatory laser applications. In some cases, such as wound healing and cosmetic applications, the target of the irradiation is the skin surface. In other cases, the light has to reach deeper tissues, for instance, during the irradiation of internal body organs. Prerequisite for reproducible biostimulatory effects is that the light intensity surpasses a minimum threshold. Because of the loss of light intensity caused by absorption and scattering, targeting deeper tissues always implies that the intensity at the skin surface will be much higher than that at the target site. Derived from laboratory experiments which showed that virtually the same light which produces biostimulatory effects in cells in vitro and tissues in vivo is instrumental in reducing the viscous friction in nanoconfined systems, we arrive to a new understanding of the effect of biostimulatory levels of light on mitochondria. One immediate result is insight into strategies which promise to maximize the biostimulatory effect and minimize potential phototoxic effects during treatment of deeper tissues. Such optimization strategies are also promising for experimental and therapeutic in vitro applications, in particular in combination with cell-friendly microenvironments.

670 nm laser light and EGCG complementarily reduce amyloid-ß aggregates in human neuroblastoma cells: basis for treatment of Alzheimer's disease?

OBJECTIVE: The aim of the present study is to present the results of in vitro experiments with possible relevance in the treatment of Alzheimer's disease (AD). BACKGROUND DATA: Despite intensive research efforts, there is no treatment for AD. One root cause of AD is the extra- and intracellular deposition of amyloid-beta (Aß) fibrils in the brain. Recently, it was shown that extracellular Aß can enter brain cells, resulting in neurotoxicity. METHODS: After internalization of Aß(42) into human neuroblastoma (SH-EP) cells, they were irradiated with moderately intense 670-nm laser light (1000 Wm(-2)) and/or treated with epigallocatechin gallate (EGCG). RESULTS: In irradiated cells, Aß(42) aggregate amounts were significantly lower than in nonirradiated cells. Likewise, in EGCG-treated cells, Aß(42) aggregate amounts were significantly lower than in non-EGCG-treated cells. Except for the cells simultaneously laden with Aß(42) and EGCG, there was a significant increase in cell numbers in response to laser irradiation. EGCG alone had no effect on cell proliferation. Laser irradiation significantly increased ATP levels in Aß(42)-free cells, when compared to nonirradiated cells. Laser-induced clearance of Aß(42) aggregates occurred at the expense of cellular ATP. CONCLUSIONS: Irradiation with moderate levels of 670-nm light and EGCG supplementation complementarily reduces Aß aggregates in SH-EP cells. Transcranial penetration of moderate levels of red to near-infrared (NIR) light has already been amply exploited in the treatment of patients with acute stroke; the blood-brain barrier (BBB) penetration of EGCG has been demonstrated in animals. We hope that our approach will inspire a practical therapy for AD.

Pulsed laser light forces cancer cells to absorb anticancer drugs--the role of water in nanomedicine.

Anticancer drugs executing their function intracellularly enter cancer cells via diffusive processes. Complementary to these slow processes, cells can be forced to incorporate drugs by convection - a more efficient transport process. Transmembrane convection is induced by moderately intense pulsed laser light (or light emitting diodes) changing the structure of nanoscopic water layers in cells. This is a fundamental difference with the method of photodynamic therapy. In a model system we demonstrate that a total irradiation time of one minute is sufficient to completely inhibit proliferation of cancer cells. Transmembrane convection protects healthy cells from extended chemotherapy exposure, could be exploited to overcome multidrug resistance, and is a promising new tool in a variety of therapies as well as in skin rejuvenation.

Laser modulated transmembrane convection: Implementation in cancer chemotherapy.

Transmembrane diffusion imposes fundamental limits to the uptake of cytostatic drugs executing their function intracellularly. Here, we report that transmembrane convection-a mechanism exploiting the effect of moderately intense 670nm laser light on the density and viscosity of nanoscopic interfacial water layers (IWL) in the cell-forces cancer cells to uptake high doses of cytostatic drugs in a short time. Transmembrane convection is a viable alternative to established uptake forms (i.e., it works complementary to diffusive processes) and breaks the limits imposed by diffusion. We demonstrate the potency of the method in human cervical cancer cells, HeLa, using the anticancer compounds doxorubicin (DOX), methotrexate (MTX) and epigallocatechin gallate (EGCG). The method is applicable to virtually the entire chemotherapeutic arsenal and is expected to help overcome multidrug resistance in cancer cells.

Extraordinary anticancer effect of green tea and red light.

OBJECTIVE: Increasing observational evidence suggests that epigallocatechin gallate--the major polyphenolic component of green tea--is instrumental in suppressing the growth of cancer cells. Therefore, methods that promise to enhance the suppressive potential of green tea have the highest clinical relevance. BACKGROUND DATA: Human cervical cancer cells, HeLa, the first continuous cancer cell line, represent a mainstay model in cancer research. Green tea inhibited their growth, whereas their exposure to moderate levels of laser light resulted in an opposite effect. Both effects are individually documented in the literature. METHODS: HeLa cells were supplemented with green tea, irradiated with moderately intense laser light (670 nm) for 1 min, and incubated for 52 h. RESULTS: We found an extraordinary inhibition of HeLa cells by a combination of green tea and red light. We achieved an inhibition of 1,460%, compared with non-irradiated samples. CONCLUSION: Our result receives clinical relevance from a recent study in which epigallocatechin gallate suppressed the growth of melanoma in vivo.