The Reassessed Potential of SARS-CoV-2 Attenuation for COVID-19 Vaccine Development—A Systematic Review

Live-attenuated SARS-CoV-2 vaccines received relatively little attention during the COVID-19 pandemic. Despite this, several methods of obtaining attenuated coronaviruses are known. In this systematic review, the strategies of coronavirus attenuation, which may potentially be applied to SARS-CoV-2, were identified. PubMed, Scopus, Web of Science and Embase databases were searched to identify relevant articles describing attenuating mutations tested in vivo. In case of coronaviruses other than SARS-CoV-2, sequence alignment was used to exclude attenuating mutations that cannot be applied to SARS-CoV-2. Potential immunogenicity, safety and efficacy of the attenuated SARS-CoV-2 vaccine were discussed based on animal studies data. A total of 27 attenuation strategies, used to create 101 different coronaviruses, have been described in 56 eligible articles. The disruption of the furin cleavage site in the SARS-CoV-2 spike protein was identified as the most promising strategy. The replacement of core sequences of transcriptional regulatory signals, which prevents recombination with wild-type viruses, also appears particularly advantageous. Other important attenuating mutations encompassed mostly the prevention of evasion of innate immunity. Sufficiently attenuated coronaviruses typically caused no meaningful disease in susceptible animals and protected them from challenges with virulent virus. This indicates that attenuated COVID-19 vaccines may be considered as a potential strategy to fight the threat posed by SARS-CoV-2

Nicotine–melanin interaction

BACKGROUND The available literature suggests that nicotine may accumulate in human tissues containing melanin, which increases the biosynthesis of this pigment. Studies conducted on the interaction between nicotine and melanin do not explain the impact of this binding on the metabolism and distribution of nicotine, level of dependence, effectiveness of smoking cessation therapies and potential adverse effects of nicotine. The role of these interactions may be important for people with a high degree of skin pigmentation. It is necessary to answer questions concerning the nature of nicotine–melanin interaction as well as the effect of nicotine on human cells, tissues and organs containing melanin pigment. The aim of this study was to examine the ability of nicotine to bind to synthetic melanin and to evaluate the kinetics and the nature of these interactions. MATERIAL AND METHODS Nicotine–melanin complexes were analyzed by use of the Scatchard method. The amounts of nicotine bound to melanin were determined spectrophotometrically. RESULTS It has been demonstrated that nicotine forms complexes with melanin. The amounts of nicotine bound to melanin increase with rising initial concentrations and prolongation of incubation time. For the studied complexes, two classes of independent binding sites with association constants K1 = 2.44 × 104 M-1 and K2 = 7.72 × 102 M-1 have been found. CONCLUSIONS The obtained results indicate the possible role of melanin in side effects of nicotine and in smoking cessation therapies effectiveness among people with high levels of pigmentation.WSTĘP Dostępna literatura sugeruje, że nikotyna może kumulować się w ludzkich tkankach zawierających melaninę, co powoduje zwiększenie biosyntezy tego barwnika. Dotychczasowe badania nad oddziaływaniem nikotyny z melaniną nie wyjaśniają wpływu wiązania na metabolizm i dystrybucję nikotyny, poziom uzależnienia, zdolność do zaprzestania palenia czy zwiększenie ewentualnych działań niepożądanych nikotyny. Rola tych oddziaływań może mieć duże znaczenie w przypadku osób o wysokim stopniu pigmentacji skóry. Odpowiedzi wymagają pytania dotyczące charakteru wiązań między nikotyną a melaniną oraz zmian, jakie nikotyna może wywierać w komórkach, tkankach i narządach ludzkiego ciała, w których występuje melanina. Celem badań była ocena zdolności nikotyny do wiązania się z melaniną syntetyczną, a także ocena kinetyki wiązania i trwałości powstałych kompleksów. MATERIAŁ I METODY Kompleksy nikotyna–melanina oceniano metodą Scatcharda. Ilość nikotyny związanej z melaniną wyznaczono techniką spektrofotometrii UV-VIS. WYNIKI Wykazano, że nikotyna tworzy kompleksy z melaniną. Ilość nikotyny związanej z melaniną wzrasta wraz ze wzrostem stężenia początkowego oraz z wydłużaniem czasu inkubacji. Dla badanych kompleksów stwierdzono występowanie dwóch klas niezależnych miejsc wiążących o wartościach stałych trwałości K1 = 2,44 × 104 M-1 oraz K2 = 7,72 × 102 M-1. WNIOSKI Uzyskane wyniki wskazują na możliwą rolę melaniny w działaniach niepożądanych nikotyny oraz w problematyce zaprzestania palenia u osób o wysokim stopniu pigmentacji

A therapeutic potential of nicotine: reassessing the current paradigm of nicotine pharmacotherapy, literature review.

Introduction: Nicotine is a widely known alkaloid synthesized from tobacco plants, being a main constituent of tobacco smoke and cigarettes. Nicotine has also gained eminence as the therapeutic option in managing smoking cessation and even other health conditions. However, the therapeutic potential of nicotine in other diseases has yet to be completely assessed. This information void stems from an inherent aversion from researchers in assessing nicotine’s risk-benefit, due to its toxicities. We present information on the current body of evidence relating to non-traditional therapeutic applications of nicotine to fill this literature void. The purpose of this work is to present current literature on the therapeutic uses of nicotine in treating various diseases. Methods: Electronic search in PubMed for relevant research relating to the therapeutic potential of nicotine in various diseases. Results/conclusions: Nicotine has gained therapeutic significance as an active compound of the nicotine replacement therapy. Research show nicotine may have other therapeutic applications in some diseases. We discussed application of nicotine in diminished prevalence of Parkinson’s disease, decreasing symptoms of the Tourette’s syndrome, psychiatric diseases like chizophrenia, depression and management of pain. We also reviewed nicotine dosing, type of formulations, and compliance which are crucial factors in the therapeutic applications of nicotine

Radical Scavenging Is Not Involved in Thymoquinone-Induced Cell Protection in Neural Oxidative Stress Models

Thymoquinone (TQ), an active compound from Nigella sativa seeds, is often described as a pharmacologically relevant compound with antioxidative properties, while the synthesis of TQ in the plant via oxidations makes it inapplicable for scavenging radicals. Therefore, the present study was designed to reassess the radical scavenging properties of TQ and explore a potential mode of action. The effects of TQ were studied in models with mitochondrial impairment and oxidative stress induced by rotenone in N18TG2 neuroblastoma cells and rotenone/MPP+ in primary mesencephalic cells. Tyrosine hydroxylase staining revealed that TQ significantly protected dopaminergic neurons and preserved their morphology under oxidative stress conditions. Quantification of the formation of superoxide radicals via electron paramagnetic resonance showed an initial increase in the level of superoxide radicals in the cell by TQ. Measurements in both cell culture systems revealed that the mitochondrial membrane potential was tendentially lowered, while ATP production was mostly unaffected. Additionally, the total ROS levels were unaltered. In mesencephalic cell culture under oxidative stress conditions, caspase-3 activity was decreased when TQ was administered. On the contrary, TQ itself tremendously increased the caspase-3 activity in the neuroblastoma cell line. Evaluation of the glutathione level revealed an increased level of total glutathione in both cell culture systems. Therefore, the enhanced resistance against oxidative stress in primary cell culture might be a consequence of a lowered caspase-3 activity combined with an increased pool of reduced glutathione. The described anti-cancer ability of TQ might be a result of the pro-apoptotic condition in neuroblastoma cells. Our study provides evidence that TQ has no direct scavenging effect on superoxide radicals