Carnosic acid as potential anti-SARS-CoV-2 therapeutics: a mechanistic insight

Background/Objectives: Rosmarinus Officinalis L.(Rosemary) extract Carnosic acid(CA) has been investigated for its antimicrobial and antioxidative properties(1). Only limited number of publications reported the utilization of this extract in SARSCoV-2 infection. Also, the mechanistic understanding of CA remains to be determined. Our goal was to elucidate the potential role of CA in COVID19. To obtain mechanistic insight of pharmacogenomic action of CA, comprehensive in silico analyses were performed. Further in vitro experiments were done to illustrate the cytotoxicity of CA and confirm in silico findings. Method(s): CA was extracted from Rosmarinus Officinalis L. by HPLC. Stimulation assays were performed using the COVID19 samples. In silico pharmacogenomic properties of CA were performed by using SwissADME. SwissTargetPrediction tool was utilized to define the possible targets. SARS-CoV-2-interacting proteins were evaluated using STRING(2). To verify in silico findings, gene expression levels were analyzed using qPCR. Result(s): Among the top 15 SwissTargetPrediction target molecules(out of 100), Prostaglandin E synthase(PTGES) had the highest probability for CA. Among 332 proteins identified using the STRING, PGES2 was found to be interacting with the nsp7, important molecule for viral replication. The stimulation assays and gene expression analyses confirmed the viral inhibitory role of CA through PTGES pathway. Conclusion(s): To our knowledge, our work is the first to reveal the inhibitory role of CA in COVID19 through PTGES pathway. Given the crucial role of PTGES in inflammation, it is noteworthy to examine CA as potential anti-SARS-CoV2 therapeutics.

Identification of Potential Inhibitors for Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2) Angiotensin-converting Enzyme 2 and the Main Protease from Anatolian Traditional Plants

Background: The 2019 novel coronavirus disease (COVID-19) has caused a global health catastrophe by affecting the human population around the globe. Unfortunately, there is no specific medi-cation or treatment currently available for COVID-19. Objective: It is extremely important to find effective drug treatment in order to put an end to this pandemic period and return to normal daily life. In this context and considering the urgency, rather than focusing on the discovery of novel compounds, it is critical to explore the effects of existing herbal agents with proven antiviral properties on the virus. Methods: Molecular docking studies were carried out employing three different methods, Glide extra precision (XP) docking, induced fit docking (IFD), and molecular mechanics/generalized born surface area (MM/GBSA), to determine the potential antiviral and antibacterial effects of 58 phytochemicals present in Rosmarinus officinalis, Thymbra spicata, Satureja thymbra, and Stachys lavandulifolia plants against the main protease (Mpro) and angiotensin-converting enzyme 2 (ACE2) enzymes. Results: 7 compounds stood out among all the molecules, showing very high binding affinities. Accord-ing to our findings, the substances chlorogenic acid, rosmarinic acid, and rosmanol exhibited extremely significant binding affinities for both Mpro and ACE2 enzymes. Furthermore, carnosic acid and alpha-cadinol showed potent anti-Mpro activity, whereas caffeic acid and carvacrol exhibited promising anti-ACE2 activity. Conclusion: Chlorogenic acid, rosmarinic acid, rosmanol, carnosic acid, alpha-cadinol, caffeic acid, and carvacrol compounds have been shown to be powerful anti-SARS-CoV-2 agents in docking simulations against Mpro and ACE2 enzymes, as well as ADME investigations.

Potential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer's Disease, Parkinson's Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome.

Rosemary (Rosmarinus officinalis [family Lamiaceae]), an herb of economic and gustatory repute, is employed in traditional medicines in many countries. Rosemary contains carnosic acid (CA) and carnosol (CS), abietane-type phenolic diterpenes, which account for most of its biological and pharmacological actions, although claims have also been made for contributions of another constituent, rosmarinic acid. This review focuses on the potential applications of CA and CS for Alzheimer's disease (AD), Parkinson's disease (PD), and coronavirus disease 2019 (COVID-19), in part via inhibition of the NLRP3 inflammasome. CA exerts antioxidant, anti-inflammatory, and neuroprotective effects via phase 2 enzyme induction initiated by activation of the KEAP1/NRF2 transcriptional pathway, which in turn attenuates NLRP3 activation. In addition, we propose that CA-related compounds may serve as therapeutics against the brain-related after-effects of SARS-CoV-2 infection, termed "long-COVID." One factor that contributes to COVID-19 is cytokine storm emanating from macrophages as a result of unregulated inflammation in and around lung epithelial and endovascular cells. Additionally, neurological aftereffects such as anxiety and "brain fog" are becoming a major issue for both the pandemic and post-pandemic period. Many reports hold that unregulated NLRP3 inflammasome activation may potentially contribute to the severity of COVID-19 and its aftermath. It is therefore possible that suppression of NLRP3 inflammasome activity may prove efficacious against both acute lung disease and chronic neurological after-effects. Because CA has been shown to not only act systemically but also to penetrate the blood-brain barrier and reach the brain parenchyma to exert neuroprotective effects, we discuss the evidence that CA or rosemary extracts containing CA may represent an effective countermeasure against both acute and chronic pathological events initiated by SARS-CoV-2 infection as well as other chronic neurodegenerative diseases including AD and PD.

Rosemary and its protective potencies against COVID-19 and other cytokine storm associated infections: A molecular review

BACKGROUND: Nowadays, medicinal plants have attracted great interest in treatment of human diseases. Rosemary is a well-known medicinal plant which has been widely used for different therapeutic purposes. METHODS: This is a narrative reviewusing databases including PubMed, ISI, Scopus, ScienceDirect, Cochrane, and google scholar, the most authoritative articles were searched, screened, and analyzed. RESULTS: Rosemary is a natural antioxidant which removes reactive oxygen species from tissues and increases expression on Nrf2 gene. Rosemary and its metabolites reduce inflammation by inhibiting production of pro-inflammatory cytokines, decreasing expression of NF-kappa B, inhibiting infiltration of immune cells to inflamed sites, and affecting gut microbiome. Besides, rosmarinic acid in rosemary extract has positive effects on renin-angiotensin-system. Rosemary affects respiratory system by reducing oxidative stress, inflammation, muscle spasm, and also through anti-fibrotic properties. Carnosic acid is able to penetrate blood-brain-barrier and act against free radicals, ischemia and neurodegeneration in brain. Cardioprotective effects include correcting lipid profile, controlling blood pressure by inhibition of ACE, prevention of atherosclerosis, and reduction of cardiac muscle hypertrophy. CONCLUSIONS: Accordingly, rosemary supplementation has potential protective effects against COVID-19 and other cytokine storm associated infections, a conclusion that needs more evaluations in the next clinical trials.

Cancer chemopreventive role of fisetin: Regulation of cell signaling pathways in different cancers.

It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive compounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/ß-catenin, NF-κB and TRAIL/TRAIL-R by fisetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fisetin regulated autophagy in different cancers. In addition, this review also covers fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated inflammations. Furthermore, fisetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fledge and well-designed clinical trials of fisetin in different cancers. However, we still have to comprehensively analyze and fully unlock pharmacological potential of fisetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.

Nrf2 activator PB125® as a carnosic acid-based therapeutic agent against respiratory viral diseases, including COVID-19.

PB125® is a phytochemical composition providing potent Nrf2 activation as well as a number of direct actions that do not involve Nrf2. Nrf2 is a transcription actor that helps maintain metabolic balance by providing redox-sensitive expression of numerous genes controlling normal day-to-day metabolic pathways. When ordinary metabolism is upset by extraordinary events such as injury, pathogenic infection, air or water pollution, ingestion of toxins, or simply by the slow but incessant changes brought about by aging and genetic variations, Nrf2 may also be called into action by the redox changes resulting from these events, whether acute or chronic. A complicating factor in all of this is that Nrf2 levels decline with aging, leaving the elderly less able to maintain proper redox balance. The dysregulated gene expression that results can cause or exacerbate a wide variety of pathological conditions, including susceptibility to viral infections. This review examines the characteristics desirable in Nrf2 activators that have therapeutic potential, as well as some of the patterns of dysregulated gene expression commonly observed during pulmonary infections and the normalizing effects possible by judicious use of phytochemicals to increase the activation level of available Nrf2.