Long COVID, Music, Blood-Brain Barrier, and Nanomedicines

At the beginning of the first COVID-19 wave, it was believed that the life of the patients who had safely survived pulmonary complications caused by SARS-CoV-2 would soon return to normal. Today, we know that this is not for all patients the case. Unfortunately, for many patients, COVID-19 changed into Long COVID – not a life-threatening condition such as the short period of the infection with the coronavirus but with the potential to considerably reduce the quality of life. Notably, Long COVID manifests itself in major pathological alteration in the brain, besides other organs. It is unclear whether the alterations in the brain are reversible. Alterations include but are not limited to cognitive impairment and substantial reduction of grey matter. These clinical findings represent an urgent challenge for the design of nanomedicines targeting the brain and the mode of their application. The challenge comprises a third aspect, which is of physical nature and is the key to a revolution in nanomedicine: the blood-brain barrier (BBB). Even if a nanomedicine is effective in vitro, it remains therapeutically useless if it cannot cross the BBB, which safeguards that neither pathogens nor nanoparticles enter the best-protected organ in our body. Here, we present a theoretical model and discuss experimental results, which coherently indicate that it is possible to transiently open the BBB by its mechanical excitation and/or via chemical modification induced by music. © 2022, Andover House, Inc.. All rights reserved.

Supplement Gone Wrong: Drug-Induced Liver Injury Caused by Artemisinin

Introduction: Drug-induced liver injury (DILI) is defined as hepatic dysfunction caused by prescription medications, supplements, or xenobiotics after alternative causes have been excluded. As one of the leading causes of acute liver failure, DILI should be considered when patients present with hepatic dysfunction. We present a case of symptomatic DILI secondary to artemisinin use. Case Description/Methods: A 78-year-old Chinese man with no medical history presented to the hepatology clinic with 10 weeks of jaundice, weakness, and pruritis. He started taking Artemisinin/ Bioperine 12 weeks ago to prevent COVID-19 but stopped 3 weeks ago. He denied abdominal pain, a family history of liver disease, substance/alcohol use, and taking other concomitant drugs. Physical examination revealed scleral icterus and no other signs of chronic liver disease. Laboratory studies showed total bilirubin 11 mg/dL, alkaline phosphatase 293 U/L, aspartate transaminase 170 U/L, and alanine transaminase 196 U/L with negative workup for hepatitis A, B, and C. CT abdomen and MRCP were unremarkable for liver or biliary pathology. Further serological workup was negative and follow-up labs revealed normalization of liver enzymes and bilirubin. Given the patient's improvement, liver biopsy was not pursued. The patient was instructed to avoid supplements unless prescribed by a physician. Discussion(s): DILI is a global issue with an estimated annual incidence rate of 13.9 to 24.0 per 100,000 persons. Diagnosing DILI is important as it can cause acute liver injury and liver failure in certain cases. Since COVID-19 emerged, supplement use has increased given claims of boosting the immune system. Artemisinin is an herb used in traditional Chinese medicine with antimalarial activity investigated to be a possible COVID-19 treatment, but no current evidence exists to support it being effective against COVID-193. Our patient's supplement also contained Bioperine, a black pepper extract, which is likely benign. Contrarily, artemisinin is a well-described cause of idiosyncratic acute liver injury and hepatotoxicity, causing self-limited mild to moderate transaminitis but also severe cases requiring emergent livertransplantation. Our patient's unrevealing workup, his spontaneous improvement correlating with supplement discontinuation, and RUCAM score of 7 led to high suspicion of DILI secondary to artemisinin. Providers should always ask patients about supplement use and consider DILI when patients present with liver injury. (Table Presented).

Recent Advances in Imported Malaria Pathogenesis, Diagnosis, and Management.

Purpose of Review: Malaria is an important human parasitic disease affecting the population of tropical, subtropical regions as well as travelers to these areas.The purpose of this article is to provide clinicians practicing in non-endemic areas with a comprehensive overview of the recent data on microbiologic and pathophysiologic features of five Plasmodium parasites, clinical presentation of uncomplicated and severe cases, modern diagnostic methods, and treatment of malaria. Recent Findings: Employment of robust surveillance programs, rapid diagnostic tests, highly active artemisinin-based therapy, and the first malaria vaccine have led to decline in malaria incidence; however, emerging drug resistance, disruptions due to the COVID-19 pandemic, and other socio-economic factors have stalled the progress. Summary: Clinicians practicing in non-endemic areas such as the United States should consider a diagnosis of malaria in returning travelers presenting with fever, utilize rapid diagnostic tests if available at their practice locations in addition to microscopy, and timely initiate guideline-directed management as delays in treatment can lead to poor clinical outcomes.

Blackwater Fever Treated with Steroids in Nonimmune Patient, Italy.

Causes of blackwater fever, a complication of malaria treatment, are not completely clear, and immune mechanisms might be involved. Clinical management is not standardized. We describe an episode of blackwater fever in a nonimmune 12-year-old girl in Italy who was treated with steroids, resulting in a rapid clinical resolution.

Phytomedicines for Covid-19: Opportunities and Obstacles

COVID-19 is a disease caused by SARS-CoV-2 that can trigger respiratory tract infection. Due to its tendency to affect the upper respiratory tract (sinuses, nose and throat) or lower respiratory tract (windpipe and lungs), this disease is life-threatening and affects a large number of populations. This virus's unique and complex nature enhances the scope to look into the direction of herbal plants and their constituents for its prevention and treatment. The herbal remedies can have preventive as well as therapeutic actions. This review focuses on various aspects of using herbal medicines for COVID-19, as herbal constituents may also have adverse effects. Various studies revealed that some medicinal plants show life-threatening adverse effects, so selecting plants, and their related studies should be appropriate and strategic. This article includes various factors that should be considered before herbal drug use in COVID-19 patients. These are clinical trials, safety, molecular mechanism, and self-medication, which have been elaborated. This article also discusses the targets of covid-19 and different coronavirus strains. As before, treatment diagnosis of the disease is very important. Various patents have been filed and granted for its proper diagnosis so that its treatment can be easy.Copyright © 2022 Society of Pharmaceutical Sciences and Research. All rights reserved.

Terpenes, meroterpenoids, and artemisinin and SARS-CoV-2

The coronavirus disease-2019 (COVID-19) pandemic is caused by a novel coronavirus;the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Millions of cases and deaths to date have resulted in a global challenge for healthcare systems. There are currently no effective therapeutic approaches for the prevention and treatment of COVID-19. Therefore, the identification of effective therapeutics is a necessity. Terpenes, meroterpenoids, and artemisinin are natural products that could serve as a source of new drugs or as prototypes to develop effective pharmacotherapeutic agents. This chapter deals with the biological properties and nutraceutical application of terpenes, meroterpenoids, and artemisinin and also finds out the possible interaction and discusses the mechanism of action of these natural products against SARs-CoV-2. The information reviewed here might provide useful clues and lay the foundation for developing new terpenes, meroterpenoid, and artemisinin-derived drugs. © 2023 Elsevier Inc. All rights reserved.

ASSESSMENT OF CYTOTOXICITY AND ANTIVIRAL ACTIVITY AGAINST SARS-COV-2 OF THE MIXTURE OF LACTOFERRIN, ARTEMISININ, AND AZITHROMYCIN IN VITRO

Lactoferrin, artemisinin, and azithromycin exhibit a broad spectrum of antiviral, immunomodulatory, and anti-inflammatory effects. The experiments show that these drugs partially inhibit the infection caused by SARS-CoV-2 in vitro. This allows us to conclude that the effects on the entry of virions into cells mediated by each of these substances taken separately are insufficient for complete inhibition of the SARS-CoV-2 infection. The study was aimed to perform in vitro assessment of cytotoxicity and antiviral activity against the laboratory SARS-CoV-2 strain of the mixture of active ingredients: lactoferrin, artemisinin, and azithromycin. We used the Vero CCL81 (ATСС) cell line and the Dubrovka laboratory strain of SARS-CoV-2 (GenBank ID: MW161041.1), isolated in the Vero CCL81 cell culture from the nasopharyngeal swab of patient with СOVID-19. Cytotoxic effects and antiviral activity against SARS-CoV-2 of the drug mixture were assessed based on the cytopathic effects using the MTT (methylthiazolyldiphenyl-tetrazolium bromide) assay. Hydroxychloroquine was used as a reference drug. It has been shown that at high (MOI 100) and low (MOI 20) multiplicity of infection used in the Vero CCL 81 cell culture, the mixture of artemisinin, lactoferrin and azithromycin has a significant effect on the SARS-CoV-2 reproduction, and IC50 (half maximal inhibitory concentration) is estimated as the 1: 2 dilution in both cases. The findings make it possible to conclude that the studied mixture is low toxic and shows significant antiviral effects in vitro. © 2022 Group of Companies Med Expert, LLC. All rights reserved.

Recent Trends on Production Sources, Biosynthesis Pathways and Antiviral Efficacies of Artemisinin: A Candidate Phytomedicine against SARS-CoV-2.

BACKGROUND: Artemisinin is a lactone sesquiterpenoid with an endo-peroxide bridge in the 1, 2, 3-trioxane structure employed for the treatment and management of lethal viral diseases. In the current review, emphasis has been given on the production of artemisinin from natural sources with biosynthesis pathways and potential antiviral activity. METHODS: A wide-ranging inquiry on artemisinin was made electronically on the basis of articles published in peer-reviewed journals, abstracts, published in conference proceedings, government reports, preprints, books, Master's and Ph.D. theses, etc. The research was carried out in different International scientific databases like Academic Search, Biological Abstracts, BIOSIS, BioOne Previews, CabDirect, Cochrane Library, Pubmed/Medline, GeoRef, Google Scholar, JSTOR, Journal Citation Reports, Mendeley, Publons, Researchgate, Scopus, SciELO, Springer Link, Science Direct, Web of Science, Taylor and Francis with particular keywords. RESULTS: The evidence reviewed here indicates that out of the hundreds of species of the genus Artemisia mentioned in the literature, only 37 Artemisia species are reported to possess artemisinin naturally in their extracts with variable concentrations. This review further discusses the biosynthesis pathways and antiviral activities of artemisinin and its derivatives which have been used against more than 12 viral disease categories. CONCLUSION: On the whole, it is concluded that the primary natural sources of artemisinin and its derivatives are the Artemisia plants with antiviral activity, which are essential candidates for drug development against SARS-CoV-2 mainly from those Artemisia species screened for SARS-CoV- 2 infection.

AabHLH113 integrates jasmonic acid and abscisic acid signaling to positively regulate artemisinin biosynthesis in Artemisia annua.

Artemisinin, a sesquiterpene lactone isolated from Artemisia annua, is in huge market demand due to its efficient antimalarial action, especially after the COVID-19 pandemic. Many researchers have elucidated that phytohormones jasmonic acid (JA) and abscisic acid (ABA) positively regulate artemisinin biosynthesis via types of transcription factors (TFs). However, the crosstalk between JA and ABA in regulating artemisinin biosynthesis remains unclear. Here, we identified a novel ABA- and JA-induced bHLH TF, AabHLH113, which positively regulated artemisinin biosynthesis by directly binding to the promoters of artemisinin biosynthetic genes, DBR2 and ALDH1. The contents of artemisinin and dihydroartemisinic acid increased by 1.71- to 2.06-fold and 1.47- to 2.23-fold, respectively, in AabHLH1113 overexpressed A. annua, whereas they decreased by 14-36% and 26-53%, respectively, in RNAi-AabHLH113 plants. Furthermore, we demonstrated that AabZIP1 and AabHLH112, which, respectively, participate in ABA and JA signaling pathway to regulate artemisinin biosynthesis, directly bind to and activate the promoter of AabHLH113. Collectively, we revealed a complex network in which AabHLH113 plays a key interrelational role to integrate ABA- and JA-mediated regulation of artemisinin biosynthesis.

Artemisinins in Combating Viral Infections Like SARS-CoV-2, Inflammation and Cancers and Options to Meet Increased Global Demand.

Artemisinin is a natural bioactive sesquiterpene lactone containing an unusual endoperoxide 1, 2, 4-trioxane ring. It is derived from the herbal medicinal plant Artemisia annua and is best known for its use in treatment of malaria. However, recent studies also indicate the potential for artemisinin and related compounds, commonly referred to as artemisinins, in combating viral infections, inflammation and certain cancers. Moreover, the different potential modes of action of artemisinins make these compounds also potentially relevant to the challenges the world faces in the COVID-19 pandemic. Initial studies indicate positive effects of artemisinin or Artemisia spp. extracts to combat SARS-CoV-2 infection or COVID-19 related symptoms and WHO-supervised clinical studies on the potential of artemisinins to combat COVID-19 are now in progress. However, implementing multiple potential new uses of artemisinins will require effective solutions to boost production, either by enhancing synthesis in A. annua itself or through biotechnological engineering in alternative biosynthesis platforms. Because of this renewed interest in artemisinin and its derivatives, here we review its modes of action, its potential application in different diseases including COVID-19, its biosynthesis and future options to boost production.

Artificial Intelligence Derived Artemisinin Drug Compound Acts as an Effective Candidate against SARS-CoV-2 Receptors: An In-Silico Study to Combat COVID-19

Background: Global outburst of coronavirus has challenged the whole world to discover drugs to combat the current pandemic. Repurposing drugs is a promising approach as it provides new openings to challenge the emerging COVID-19. However, in the epoch of big data, artificial intelligence (AI) technology offers to leverage computational methods for finding new candidate drugs through an In-silico approach. Aim and Objectives: The aim and objectives of our present work basically are the designing of a plant-derived compound against the COVID-19 receptors which might act as effective therapy along with predicting the outcome of the disease with a deep learning program language that is python (anaconda) 2.7 version. Methodology: Artificial Intelligence technology helps in understanding the interactions of coronavirus with receptors through the computer-aided drug designing process (CADD). The ligand-protein interactions were prepared with the Maestro (Schrödinger) program which aids to study the docking pose of artemisinin compound with SARS-CoV-2 receptors like 7CTT, a nonstructural protein (NSP) and 7MY3 Spike glycoprotein. Thus, Artificial Intelligence technology examines the drug-target interaction with Neural Networking built with a deep learning machine algorithm and predicts the outcome of the disease with python program language. Results: Artemisinin exhibited the highest antiviral activity against the SARS-CoV-2 receptors like 7CTT and 7MY3. The three-dimensional structures of the ligands and SARS-CoV-2 receptors were retrieved from the PubChem Open Chemistry Database. The ligand-protein interactions were performed with the help of the Maestro (Schrödinger) program, which revealed MM/GBSA values of 7CTT interaction with derivative ligands of antimalarial compounds such as D95 (-45.424), artemisinin (-35.222), MPD (-31,021), MRD (-21.952) and 6FGC (-34.089), whereas with 7MY3 spike glycoprotein interactions MMGBSA values for D95 (-26.304), MPD(-18.658), MRD(-28.03) and 6FGC (-13.47) binding affinities have followed Lipinski rule of 5 and further predicted the outcome with random forest decision tree with an accuracy of about 75% with python program. Conclusion: Repurposing of the drug through an In-silico approach against the SARS-CoV-2 virus revealed its antiviral actions. The docking studies approach has shown the XP score, gliding energy, and MMGBSA values which were predicted with a deep learning program built with Artificial Intelligence technology. © 2022,Jordan Journal of Biological Sciences. All Rights Reserved.

An Overview of Biotechnological Applications in Ayurveda: Amalgamation of Modern Techniques and Science

Health systems and their trends are continually evolving with advanced research on new tools and techniques. Since every health system has its limitations, there is a requirement for the integration of different medical systems to better serve mankind. In this direction, a practitioner of modern medicine should take into consideration traditional medicine practices, while the traditional medicine practitioner should also integrate the beneficial strategies of modern medicine. In spite of different approaches, the aim of all these medical systems is the same, which is to serve mankind by treating various health problems. Although traditional medicine has the potential to treat a variety of diseases, its acceptance by the global community is less than that of modern medicine due to inadequate scientific validation of its therapeutic benefits. In recent years, many new diseases have emerged, perhaps due to changes in geography, environment, weather conditions, and soil composition. A complete treatment of such diseases is a challenge for all medical practitioners, whether belonging to modern or traditional medicine. Therefore, an in-depth multidisciplinary research is needed to find an effective therapeutic strategy by connecting modern and traditional medical systems with biomedical sciences. In this direction, biotechnology can play an important role in developing a diagnostic method and treatment protocol. The present review provides an overview of the available Ayurvedic treatment options and future possibilities in which biotechnology may assist as a service provider. Copyright © 2023 Bentham Science Publishers.

In Vivo, in Vitro Evaluation of the Effect of Mixed Plant Extract Used in the Prevention of the Reproduction & Transmission of Corona Virus inside Cells

It has become vital to look for innovative antiviral medications from plants and other natural sources as alternatives for prophylaxis during the novel coronavirus disease 2019 (COVID-19) pandemic. The antiviral potential of mixed extract (artemisinin and linen seed) is reviewed in this study for the treatment and prophylaxis of coronavirus disease. Based on their origin, native area, utilized plant parts, and antiviral potentials, therapeutic herbs and crops have been described in detail. It has been detailed how plant-derived natural antiviral chemicals may play a part in the development of plant-based coronavirus medications. Objective: This study highlights the effect of the mixed extract (artemisinin and linen seed) as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection. Material & Methods: 18 mice was selected in this study & divided into 3 group: Group A: Containing 6 mice were only fed without any medication or virus administrated to be a control group. Group B: Containing 6 mice injected by COVID-19 without the administration of the treatment. Group C: Containing 6 mice injected by COVID-19 and after 5 days of injection, the extract was administrated. Result: we can concluded that the mixture prevent the virus to inter the cell without any effect on the human cell especially if we know the human body can remove all the part of mixture within one to two days. Conclusion: The active ingredient(s) in the extracts from A. annua are probably other than artemisinin or a mixture of ingredients that impede viral infection at a stage downstream of viral entry. Additional research will look at in vivo activity to see if A. annua can cure SARS-CoV-2 infections at a reasonable price.

Molecular docking studies on the phytoconstituents as therapeutic leads against SARS-CoV-2

Because of the present pandemic researchers are seeking for phytocandidates that can inhibit or stop SARS-CoV-2. The main protease (Mpro) of SARS-CoV-2 and spike glycoprotein (S) are both suppressed by bioactive compounds found in plants that work by docking them together. The Mpro proteins 6LU7 (complex with an inhibitor N3) and 5C3N (space group C2221) were employed in docking research. PyRx and AutoDock Vina software were used as docking engine. 22 identified phytoconstituents were selected from IMPPAT, a manually curated database, on the basis of their antiviral effects. Docking studies showed that phytoconstituents β-amyrin (-8.4 kcal/mol), withaferin A (-8.3 kcal/mol), oleanolic acid (-7.8 kcal/mol), and patentiflorin A (-8.1 kcal/mol) had the best results against 5C3N Mpro protein whereas kuwanon L (-7.1 kcal/mol), β-amyrin (-6.9 kcal/mol), oleanolic acid (-6.8 kcal/mol), cucurbitacin D (-6.5 kcal/mol), and quercetin (-6.5 kcal/mol) against 6LU7 Mpro protein. All the compounds were examined for their ADMET characteristics using SwissDock. Present research reports that the phytoconstituents along with docking score will be helpful for future drug development against Covid-19. © 2022 Industrial Chemistry Research Institute. All rights reserved.

Let's Not Miss the Treatable Ones: Two Cases of Neonatal Sepsis Due to Malaria.

Congenital malaria is the direct infection of an infant with a malarial parasite from the mother either during pregnancy or at birth. Neonatal malaria occurs due to an infective mosquito bite after birth. Neonatal and congenital malaria (NCM) can occasionally present with life-threatening neonatal sepsis and rarely with neonatal jaundice. These conditions are typically managed by general pediatricians, especially in remote areas without access to specialized care. A high clinical index of suspicion is required to diagnose neonatal and congenital malaria, given that their presentation can mimic other more common neonatal conditions. We present two neonates with malaria, highlighting the importance of considering this treatable entity in the differential.

New insights on malaria

Malaria is long known as a deadly vector borne infection, caused by five parasite species of the coccidian genus Plasmodia that are present in as many as 85 countries. Despite significant progresses have been achieved to control the infection by early diagnosis and artemisinin combination treatment, insecticide-treated nets and indoor residual spraying, malaria still represents a major public health issue in many endemic low-income countries. New diagnostic tools of higher sensitivity and specificity are now available for use in endemic countries to better guide diagnosis and treatment. In particular, highly sensitive rapid antigenic tests are now available and the loop-mediated isothermal amplification is a very promising and highly sensitive diagnostic tool. After 2015, decreasing morbidity and mortality trends have been stagnating because of limited funding, emergence of parasite and vector resistance to drugs and insecticides respectively and, recently, by the disrupting effect of COVID-19 pandemic. The incomplete knowledge of the complex immunity of malaria infection has slowed the development of an effective vaccine. However, in 2021, the RTS-S vaccine, however of suboptimal protective efficacy, has been made available for routine use in children above 5 months of age. Population movements has increased the chance of observing imported malaria in non-endemic areas, where malaria competent vectors may still exist.

Impact of antimalarial resistance and COVID-19 pandemic on malaria care among pregnant women in Northern Uganda (ERASE): protocol of a prospective observational study.

BACKGROUND: Uganda accounts for 5% of all malaria cases and deaths reported globally and, in endemic countries, pregnancy is a risk factor for both acquisition of P. falciparum infection and development of severe malaria. In recent years, malaria control has been threatened by COVID-19 pandemic and by the emergence, in Northern Uganda, of both resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine. METHODS: In this facility-based, prospective, observational study, pregnant women will be recruited at antenatal-care visits and followed-up until delivery. Collected data will explore the incidence of asymptomatic parasitemia and malaria-related outcomes, as well as the attitudes towards malaria prevention, administration of intermittent preventive treatment, healthcare seeking behavior and use of insecticide-treated nets. A subpopulation of women diagnosed with malaria will be recruited and their blood samples will be analyzed for detection of genetic markers of resistance to artemisinin derivatives and sulfadoxine-pyrimethamine. Also, to investigate the impact of COVID-19 on malaria care among pregnant women, a retrospective, interrupted-time series will be conducted on at the study sites for the period January 2018 to December 2021. DISCUSSION: The present study will explore the impact of COVID-19 pandemic on incidence of malaria and malaria-related adverse outcomes, along with the prevalence of resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine. To our knowledge, this is the first study aiming to explore the combined effect of these factors on a cohort of pregnant women. TRIAL REGISTRATION: This study has been registered on the ClinicalTrials.gov public website on 26th April, 2022. CLINICALTRIALS: gov Identifier: NCT05348746.

ARTEMISIA SPECIES AND ARTEMISININ DERIVATIVES AS ANTIVIRAL AGENTS AGAINST COVID-19. CURRENT KNOWLEDGE: CHEMISTRY, PHARMACOLOGY AND CLINICAL EVIDENCE

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the reason behind the third zoonotic outbreak from the Coronaviridae family during the 21st century. COVID-19 was declared a pandemic by the WHO on 11 March 2020, and it has been posing a challenge for the health care system all around the world. Research groups worldwide are trying to find potential leads for drugs against SARS-CoV-2. Investigating natural products and extracts from known medicinal plants has been one area of focus in searching for potential inhibitors of SARS-CoV-2. This review aims to highlight the importance of including natural plants and plants derived compounds in this investigation. We particularly focused on compounds from Artemisia species (artemisinin and its derivatives), as this plant is highly valuable and has various pharmacological profiles.

Chemical characterization of Artemisia annua L. subcritical extract

The aerial parts of Artemisia annua L. from Bulgaria were extracted with 1,1,1,2-tetrafluoroethane. Static two-stage extraction at a pressure of 8 and 12 bar was used at a relatively low temperature. The yield was 2%. The chemical profile of the product was reported for the first time. GC-MS analysis showed that the extract contained the essential oil constituents, but in lower concentrations. In total, 28 components were identified, the main ones being artemisia ketone (26.2%), camphor (10.7%), and eucalyptol (9.1%). Artheanin B (3.7%) and arteannuic acid (3.7%) were found to be cometabolites and precursors of artemisinin. The content of the sesquiterpene lactone artemisinin, determined spectrophotometrically, was found to be 1.28 ± 0.10 %. The results revealed that the extract is of interest with the presence of biologically active substances used as a modern anti-malaria and potential anti-coronavirus agent. © 2022 Bulgarian Academy of Sciences, Union of Chemists in Bulgaria.