Encefalitis autoinmune tras vacunación e infección por el SARS-CoV-2 en un paciente con narcolepsia de tipo 1 / Autoimmune encephalitis mediated by postvaccination and infection of SARS-CoV-2 in a patient with a narcolepsy type 1

Introducción Presentamos un paciente diagnosticado de narcolepsia de tipo 1 que desarrolló una encefalitis autoinmune posvacunal y/o tras una infección por el SARS-CoV-2. Caso clínico Paciente de 23 años que es remitido a urgencias por trastorno del lenguaje y temblor, acompañados de cefalea, trastorno del comportamiento, disfunción autonómica, crisis focal motora derecha y letargo. El paciente había sido vacunado siete semanas antes con la primera dosis de la vacuna Moderna (ARN mensajero) y, cuatro semanas después de la vacunación, presentó una infección por el SARS-CoV-2 con test de antígenos positivo. Resultados La exploración neurológica mostró un nivel de conciencia normal y una afasia mixta de predominio motor (campimetría, pares craneales, reflejos y sensibilidad normales). El test de reacción en cadena de la polimerasa para la COVID-19 fue negativo. En el líquido cefalorraquídeo se apreció una linfocitosis y proteínas elevadas. Los cultivos para hongos y bacterias fueron negativos. Los anticuerpos onconeuronales fueron normales. La resonancia magnética cerebral mostró en la secuencia de difusión una restricción con afectación cortical y morfología giral en el hemisferio cerebral izquierdo, y distribución parcheada con afectación de lóbulo frontal y temporal izquierdos. Una tomografía axial computarizada de tórax-abdomen-pelvis fue normal, al igual que las ecografías pélvica y escrotal. Al paciente se le trató con plasmaféresis y corticoides, con buena evolución clínica y resolución casi completa de las anomalías en la neuroimagen. Conclusión Se trata de un paciente con narcolepsia de tipo 1 con criterios de encefalitis autoinmune de comienzo subagudo. La infección por el SARS-CoV-2 o la vacunación, o ambas, constituyen un riesgo para desarrollar una o más enfermedades autoinmunes con la edad –como sucede en este caso–, lo que permite comprender la implicación de procesos inmunomediados en la fisiopatología de estas enfermedades. (AU)

INTRODUCTION We present a narcolepsy type 1 patient that develop an autoimmune encephalitis post vaccine and/or a SARS-CoV-2 infection.CASE REPORTAt 23 years old, the patient was referred to the emergency room with difficult speaking, headache and tremor followed by changes in behavior, autonomic dysfunction, right focal motor seizure and lethargy. He has received seven weeks before mRNA-1273 (Moderna) vaccine followed by a SARS-CoV-2 infection four weeks after vaccination (positive antigen test).RESULTSThe neurological examination was normal (visual fields, cranial nerves, motor, sensory and reflexes). Nasopharyngeal swab polymerase chain reaction (PCR) testing for COVID-19 was negative. Cerebrospinalfluid (CSF) had highly elevated protein and lymphocytic pleocytosis. CSF bacterial and fungal cultures for viral infections were negative. Brain magnetic resonance imaging (MRI) showed no abnormality on the non-enhanced sequences but the diffusion weighted imaging showed restricted diffusion with high signal on the left hemisphere mainly in the cerebral cortex with a gyro morphology, patched distribution with involvement of the temporal and frontal lobes. Chest, abdomen and pelvis computed tomography; pelvic and scrotum ultrasound, showed no malignancy. Onconeural antibodies were negative. The patient was treated with plasmapheresis and corticosteroids with a good clinical outcome and near complete resolution of the MRI abnormalities. CONCLUSION. The patient fulfilled the diagnostic criteria for autoimmune encephalitis with subacute onset. COVID-19 infection and vaccination could constitute a risk in a patient with narcolepsy as in this case and, could help to provide better understanding of the implication of immune-mediated processes in the pathophysiology of the diseases. (AU)

Moringa oleifera and Its Biochemical Compounds: Potential Multi-targeted Therapeutic Agents Against COVID-19 and Associated Cancer Progression.

The Coronavirus disease-2019 (COVID-19) pandemic is a global concern, with updated pharmacological therapeutic strategies needed. Cancer patients have been found to be more susceptible to severe COVID-19 and death, and COVID-19 can also lead to cancer progression. Traditional medicinal plants have long been used as anti-infection and anti-inflammatory agents, and Moringa oleifera (M. oleifera) is one such plant containing natural products such as kaempferol, quercetin, and hesperetin, which can reduce inflammatory responses and complications associated with viral infections and multiple cancers. This review article explores the cellular and molecular mechanisms of action of M. oleifera as an anti-COVID-19 and anti-inflammatory agent, and its potential role in reducing the risk of cancer progression in cancer patients with COVID-19. The article discusses the ability of M. oleifera to modulate NF-κB, MAPK, mTOR, NLRP3 inflammasome, and other inflammatory pathways, as well as the polyphenols and flavonoids like quercetin and kaempferol, that contribute to its anti-inflammatory properties. Overall, this review highlights the potential therapeutic benefits of M. oleifera in addressing COVID-19 and associated cancer progression. However, further investigations are necessary to fully understand the cellular and molecular mechanisms of action of M. oleifera and its natural products as anti-inflammatory, anti-COVID-19, and anti-cancer strategies.

Magnesium and vitamin D in long COVID syndrome; do they help?

Since the start of the COVID-19 pandemic, it has become increasingly clear that the disease can have relevant multisystemic and long-term effects, and several studies have attempted to identify key determinants of the disease course. Here we discuss recent evidence suggesting that, in long COVID patients, combined magnesium and vitamin D deficiencies associate with a higher number of clinical manifestations, as compared to patients with normal levels of both nutrients. We highlight the potential synergistic effects of these deficiencies and propose that future studies should explore a causal link with the risk of developing long COVID. Most importantly, randomized clinical trials are needed to determine if magnesium and vitamin D supplementation can improve long COVID symptoms, providing a safe and affordable support therapy to the benefit of patients and society.

Self-Assembling Sulfated Lactobacillus Exopolysaccharide Nanoparticles as Adjuvants for SARS-CoV-2 Subunit Vaccine Elicit Potent Humoral and Cellular Immune Responses.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic since its onset in 2019, and the development of effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to induce potent and long-lasting immunity remains a priority. Herein, we prepared two Lactobacillus exopolysaccharide (EPS) nanoparticle adjuvants (NPs 7-4 and NPs 8-2) that were constructed by using sulfation-modified EPS and quaternization-modified chitosan. These two NPs displayed a spherical morphology with sizes of 39 and 47 nm. Furthermore, the zeta potentials of NPs 7-4 and NPs 8-2 were 50.40 and 44.40 mV, respectively. In vitro assays demonstrated that NPs could effectively adsorb antigenic proteins and exhibited a sustained release effect. Mouse immunization tests showed that the NPs induced the expression of cytokines and chemokines at the injection site and promoted the uptake of antigenic proteins by macrophages. Mechanically, the NPs upregulated the expression of pattern recognition receptors (toll-like receptors and nod-like receptors) and activated the immune response of T cells and the production of neutralizing antibodies. In addition, the NP adjuvants had favorable immune-enhancing effects in cats, which are of great significance for controlling the trans-host transmission and re-endemicity of SARS-CoV-2. Overall, we demonstrated that NP-adjuvanted SARS-CoV-2 receptor binding domain proteins could induce robust specific humoral and cellular immunity.

COVID-19-induced acute loss of consciousness in Marchiafava-Bignami disease: a case report.

Among the various manifestations of COVID-19, the neurological implications of SARS-CoV-2 infection are of significant concern. Marchiafava-Bignami disease (MBD), a neurodegenerative disorder, exhibits a clinical spectrum ranging from mild progressive dementia in its chronic form to states of acute coma and varied mortality rates. Acute MBD primarily occurs in chronic alcoholics and malnourished individuals and is characterized by sudden loss of consciousness, seizures, confusion, and psychosis. We herein report a case of MBD presenting as acute loss of consciousness after the development of COVID-19. The patient presented with a history of fever and upper respiratory infection and was diagnosed with SARS-CoV-2 infection. He developed a neurological syndrome characterized by altered consciousness and convulsions, and brain magnetic resonance imaging revealed abnormal signals in the corpus callosum and frontoparietal lobes. Considering his alcohol intake history and the absence of other differential diagnoses, we diagnosed him with acute MBD triggered by COVID-19. After high-dose vitamin B1 and corticosteroid therapy, his clinical symptoms improved. In this case, we observed a temporal sequence between the development of COVID-19 and acute exacerbation of MBD. This case adds to the mounting evidence suggesting the potential effect of SARS-CoV-2 on the neurological system.

Impact of Lianhua Qingwen on viral shedding in omicron mild/asymtomatic patients: a real-world study.

Background: Lianhuaqingwen (LHQW), a traditional Chinese medicine comprised of 13 herbal extracts renowned for their robust heat-clearing and detoxifying properties, has gained widespread utilization in China but has yet to garner similar recognition abroad. It is believed to exhibit efficacy in ameliorating symptoms in individuals afflicted with coronavirus disease 2019 (COVID-19). However, the precise impact of LHQW on viral shedding (VS), particularly in the context of mild or asymptomatic infections caused by the Omicron BF.4/5 or BF.7 variants of COVID-19, remained inadequately elucidated. Consequently, a real-world study was conducted, involving patients diagnosed with COVID-19, with the primary objective of ascertaining the effectiveness of LHQW in this specific clinical context. Methods: We conducted an investigation on Omicron-infected patients through a single-center, propensity score-matched real-world study conducted at Xiaotangshan Fangcang Hospital from May to November 2022. A total of 3,368 COVID-19 patients were enrolled in the study, all of whom presented mild or asymptomatic infections caused by either BF.4/5 or BF.7 strains of the virus. Demographic and clinical data were systematically collected from medical records. Patients were allocated to receive treatment with LHQW (designated as the treatment group) or received no LHQW treatment (designated as the not-treated/no-treatment group). Viral load was quantified utilizing quantitative real-time PCR (qPCR), and the duration of VS was defined as the time interval between the initial negative test result and the date of COVID-19 diagnosis or symptom onset. Results: The study encompassed a cohort of 3,368 patients, and following propensity score matching, a subset of 296 patients was meticulously chosen for subsequent analysis. Notably, baseline characteristics exhibited disparities between the treatment and not-treated/no-treatment groups. However, post-matching, these characteristics achieved a commendable level of comparability. Our findings unequivocally demonstrated that there existed no statistically significant disparity in VS. This holds true when comparing patients subjected to LHQW treatment against those not administered LHQW, as well as when contrasting individuals presenting asymptomatic and mild COVID-19 manifestations. Conclusion: No statistically significant difference in VS was observed between patients who underwent LHQW treatment and those who did not. Additional investigations are imperative to provide a comprehensive assessment of LHQW's efficacy, particularly in patients afflicted with severe COVID-19 or those infected with viral strains distinct from BF.4/5 or BF.7.

Clinical and immunologic features of co-infection in COVID-19 patients, along with potential traditional Chinese medicine treatments.

Objectives: With the increasing number of people worldwide infected with SARS-CoV-2, the likelihood of co-infection and/or comorbidities is rising. The impact of these co-infections on the patient's immune system remains unclear. This study aims to investigate the immunological characteristics of secondary infections in hospitalized COVID-19 patients, and preliminarily predict potential therapeutic effects of traditional Chinese medicine and their derivatives for the treatment of co-infections. Methods: In this retrospective cohort study, we included 131 hospitalized patients with laboratory-confirmed COVID-19, of whom there were 64 mild and 67 severe cases. We analyzed clinical characteristics and immunologic data, including circulating immune cell numbers, levels of inflammatory factors and viral load, comparing COVID-19 patients with and without co-infection. Results: Among 131 hospitalized COVID-19 patients, 41 (31.3%) were co-infection positive, with 33 (80.5%) having severe disease and 14 (34.1%) of them resulting in fatalities. Co-infected patients exhibited significantly higher severity and mortality rates compared to non-co-infected counterparts. Co-infected patients had significantly lower absolute counts of lymphocytes, total T lymphocytes, CD4+ T cells, CD8+ T cells and B lymphocytes, while levels of hs-CRP, PCT and IL-6 were significantly elevated compared to non-co-infected patients. Additionally, the viral load of co-infected patients was significantly higher than non-co-infected patients. Conclusion: Co-infection emerges as a dangerous factor for COVID-19 patients, elevating the risk of severe pneumonia and mortality. Co-infection suppresses the host's immune response by reducing the number of lymphocytes and increasing inflammation, thereby diminishing the antiviral and anti-infective effects of the immune system, which promotes the severity of the disease. Therefore, it is crucial to implement infection prevention measures to minimize the spread of co-infections among COVID-19 hospitalized patients. Additionally, changes in these biomarkers provide a theoretical basis for the effective treatment of co-infections with traditional Chinese medicine.

Inhibitory effect of food-functioned phytochemicals on dysregulated inflammatory pathways triggered by SARS-CoV-2: a mechanistic review.

Inflammatory cascades of the dysregulated inflammatory pathways in COVID-19 can cause excessive production of pro-inflammatory cytokines and chemokines leading to cytokine storm syndrome (CSS). The molecular cascades involved in the pathways may be targeted for discovery of new anti-inflammatory agents. Many plant extracts have been used clinically in the management of COVID-19, however, their immunosuppressive activities were mainly investigated based on in silico activity. Dietary flavonoids of the extracts such as quercetin, luteolin, kaempferol, naringenin, isorhamnetin, baicalein, wogonin, and rutin were commonly identified as responsible for their inhibitory effects. The present review critically analyzes the anti-inflammatory effects and mechanisms of phytochemicals, including dietary compounds against cytokine storm (CS) and hyperinflammation via inhibition of the altered inflammatory pathways triggered by SARS-CoV-2, published since the emergence of COVID-19 in December 2019. Only a few phytochemicals, mainly dietary compounds such as nanocurcumin, melatonin, quercetin, 6-shagoal, kaempferol, resveratrol, andrographolide, and colchicine have been investigated either in in silico or preliminary clinical studies to evaluate their anti-inflammatory effects against COVID-19. Sufficient pre-clinical studies on safety and efficacy of anti-inflammatory effects of the phytochemicals must be performed prior to proper clinical studies to develop them into therapeutic adjuvants in the prevention and treatmemt of COVID-19 symptoms.

Vitamin D Supplementation in Neonatal and Infant MIS-C Following COVID-19 Infection.

To date, the SARS-CoV-2 pandemic still represents a great clinical challenge worldwide, and effective anti-COVID-19 drugs are limited. For this reason, nutritional supplements have been investigated as adjuvant therapeutic approaches in disease management. Among such supplements, vitamin D has gained great interest, due to its immunomodulatory and anti-inflammatory actions both in adult and pediatric populations. Even if there is conflicting evidence about its prevention and/or mitigation effectiveness in SARS-CoV-2 infection, several studies demonstrated a strict correlation between hypovitaminosis D and disease severity in acute COVID-19 and MIS-C (multisystem inflammatory syndrome in children). This narrative review offers a resume of the state of the art about vitamin D's role in immunity and its clinical use in the context of the current pandemic, specially focusing on pediatric manifestations and MIS-C. It seems biologically reasonable that interventions aimed at normalizing circulating vitamin D levels could be beneficial. To help clinicians in establishing the correct prophylaxis and/or supportive therapy with vitamin D, well-designed and adequately statistically powered clinical trials involving both adult and pediatric populations are needed. Moreover, this review will also discuss the few other nutraceuticals evaluated in this context.

Boosting the immunogenicity of the CoronaVac SARS-CoV-2 inactivated vaccine with Huoxiang Suling Shuanghua Decoction: a randomized, double-blind, placebo-controlled study.

Introduction: In light of the public health burden of the COVID-19 pandemic, boosting the safety and immunogenicity of COVID-19 vaccines is of great concern. Numerous Traditional Chinese medicine (TCM) preparations have shown to beneficially modulate immunity. Based on pilot experiments in mice that showed that supplementation with Huoxiang Suling Shuanghua Decoction (HSSD) significantly enhances serum anti-RBD IgG titers after inoculation with recombinant SARS-CoV-2 S-RBD protein, we conducted this randomized, double-blind, placebo-controlled clinical trial aimed to evaluate the potential immunogenicity boosting effect of oral HSSD after a third homologous immunization with Sinovac's CoronaVac SARS-CoV-2 (CVS) inactivated vaccine. Methods: A total of 70 participants were randomly assigned (1:1 ratio) to receive a third dose of CVS vaccination and either oral placebo or oral HSSD for 7 days. Safety aspects were assessed by recording local and systemic adverse events, and by blood and urine biochemistry and liver and kidney function tests. Main outcomes evaluated included serum anti-RBD IgG titer, T lymphocyte subsets, serum IgG and IgM levels, complement components (C3 and C4), and serum cytokines (IL-6 and IFN-γ). In addition, metabolomics technology was used to analyze differential metabolite expression after supplementation with HSSD. Results: Following a third CVS vaccination, significantly increased serum anti-RBD IgG titer, reduced serum IL-6 levels, increased serum IgG, IgM, and C3 and C4 levels, and improved cellular immunity, evidenced by reduce balance deviations in the distribution of lymphocyte subsets, was observed in the HSSD group compared with the placebo group. No serious adverse events were recorded in either group. Serum metabolomics results suggested that the mechanisms by which HSSD boosted the immunogenicity of the CVS vaccine are related to differential regulation of purine metabolism, vitamin B6 metabolism, folate biosynthesis, arginine and proline metabolism, and steroid hormone biosynthesis. Conclusion: Oral HSSD boosts the immunogenicity of the CVS vaccine in young and adult individuals. This trial provides clinical reference for evaluation of TCM immunomodulators to improve the immune response to COVID-19 vaccines.

Potential therapeutic effects and nano-based delivery systems of mesenchymal stem cells and their isolated exosomes to alleviate acute respiratory distress syndrome caused by COVID-19.

The severe respiratory effects of the coronavirus disease 2019 (COVID-19) pandemic have necessitated the immediate development of novel treatments. The majority of COVID-19-related fatalities are due to acute respiratory distress syndrome (ARDS). Consequently, this virus causes massive and aberrant inflammatory conditions, which must be promptly managed. Severe respiratory disorders, notably ARDS and acute lung injury (ALI), may be treated safely and effectively using cell-based treatments, mostly employing mesenchymal stem cells (MSCs). Since the high potential of these cells was identified, a great deal of research has been conducted on their use in regenerative medicine and complementary medicine. Multiple investigations have demonstrated that MSCs and their products, especially exosomes, inhibit inflammation. Exosomes serve a critical function in intercellular communication by transporting molecular cargo from donor cells to receiver cells. MSCs and their derived exosomes (MSCs/MSC-exosomes) may improve lung permeability, microbial and alveolar fluid clearance, and epithelial and endothelial repair, according to recent studies. This review focuses on COVID-19-related ARDS clinical studies involving MSCs/MSC-exosomes. We also investigated the utilization of Nano-delivery strategies for MSCs/MSC-exosomes and anti-inflammatory agents to enhance COVID-19 treatment.

Does Western or Chinese Zodiac Sign Predict COVID Infections and Death?

INTRODUCTION: Humans have been fascinated by and studying the sky since the beginning of time. Beliefs in Chinese and Western astrology persist in modern society and have gained increasing interest in light of the COVID-19 pandemic. Zodiac signs are typified by certain qualities, for example, obsessive-compulsive traits in Libras and Virgos or the highly social traits in Leos and Geminis. We investigate whether the various characteristics or personalities purported of assigned birth signs may alter the predisposition to COVID-19 infections or mortality. METHODS: This is a retrospective, single-center cohort study of 2545 adult patients with confirmed COVID-19 infection presenting to the emergency room over a 14-month period (September 2020 to November 2021). COVID-19 infectivity was determined based on polymerase chain reaction (PCR) testing. Western and Chinese Zodiac signs were designated using date of birth. Both Zodiac signs were evaluated for risk of infection and death. RESULTS: Mortality rates across the zodiac and astrology signs showed no statistical difference using the 12-sample test for equality of proportions. Coincidentally, the mean age for the deceased was 74.5 years, and it was 53.9 years for those alive, resulting in a difference of 20.6 years. A two-sample t-test confirms that the observed difference of 20.6 years of age between the two groups is statistically significant with a p-value <0.05. The coefficient of the predictor age is statistically significant. The odds ratio estimate of age is 1.06, with the corresponding 95% confidence interval (CI) being (1.048, 1.073). This means that the odds of dying increase by 6% for every additional year. DISCUSSION: Astrology once held a significant impact on beliefs in medicine and continues in Chinese and Ayurvedic medicine. Our study utilized local data to determine if COVID-19 infection rates and mortality might have a relationship to astrological designations of Chinese and Western zodiac signs. Data analysis demonstrated that there was no statistical significance found between Western and Chinese Zodiac signs and mortality or infections. Similar to many previous studies, age can be a risk factor for mortality.

A dual-target SPR screening system for simultaneous ligand discovery of SARS-CoV-2 spike protein and its receptor ACE2 from Chinese herbs.

Traditional Chinese Medicine (TCM) is a supremely valuable resource for the development of drug discovery. Few methods are capable of hunting for potential molecule ligands from TCM towards more than one single protein target. In this study, a novel dual-target surface plasmon resonance (SPR) biosensor was developed to perform targeted compound screening of two key proteins involved in the cellular invasion process of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): the spike (S) protein receptor binding domain (RBD) and the angiotensin-converting enzyme 2 (ACE2). The screening and identification of active compounds from six Chinese herbs were conducted taking into consideration the multi-component and multi-target nature of Traditional Chinese Medicine (TCM). Puerarin from Radix Puerariae Lobatae was discovered to exhibit specific binding affinity to both S protein RBD and ACE2. The results highlight the efficiency of the dual-target SPR system in drug screening and provide a novel approach for exploring the targeted mechanisms of active components from Chinese herbs for disease treatment.

A mini-review of the anti-SARS-CoV-2 potency of Amaryllidaceae alkaloids.

BACKGROUND: Nature has perennially served as an infinite reservoir of diverse chemicals with numerous applications benefiting humankind. In recent years, due to the emerging COVID-19 pandemic, there has been a surge in studies on repurposing natural products as anti-SARS-CoV-2 agents, including plant-derived substances. Among all types of natural products, alkaloids remain one of the most important groups with various known medicinal values. The current investigation focuses on Amaryllidaceae alkaloids (AAs) since AAs have drawn significant scientific attention as anti-SARS-CoV-2 agents over the past few years. PURPOSE AND STUDY DESIGN: This study serves as a mini-review, summarizing recent advances in studying the anti-SARS-CoV-2 potency of AAs, covering two aspects: structure-activity relationship and mechanism of action (MOA). METHODS: The study covers the period from 2019 to 2023. The information in this review were retrieved from common databases including Web of Science, ScienceDirect, PubMed and Google scholar. Reported anti-SARS-CoV-2 potency, cytotoxicity and possible biological targets of AAs were summarized and classified into different skeletal subclasses. Then, the structure-activity relationship (SAR) was explored, pinpointing the key pharmacophore-related structural moieties. To study the mechanism of action of anti-SARS-CoV-2 AAs, possible biological targets were discussed. RESULTS: In total, fourteen research articles about anti-SARS-CoV-2 was selected. From the SAR point of view, four skeletal subclasses of AAs (lycorine-, galanthamine-, crinine- and homolycorine-types) appear to be promising for further investigation as anti-SARS-CoV-2 agents despite experimental inconsistencies in determining in vitro half maximal inhibitory effective concentration (EC50). Narciclasine, haemanthamine- and montanine-type skeletons were cytotoxic and devoid of anti-SARS-CoV-2 activity. The lycorine-type scaffold was the most structurally diverse in this study and preliminary structure-activity relationships revealed the crucial role of ring C and substituents on rings A, C and D in its anti-SARS-CoV-2 activity. It also appears that two enantiomeric skeletons (haemanthamine- and crinine-types) displayed opposite activity/toxicity profiles regarding anti-SARS-CoV-2 activity. Pharmacophore-related moieties of the haemanthamine/crinine-type skeletons were the substituents on rings B, C and the dioxymethylene moiety. All galanthamine-type alkaloids in this study were devoid of cytotoxicity and it appears that varying substituents on rings C and D could enhance the anti-SARS-CoV-2 potency. Regarding MOAs, initial experimental results suggested Mpro and RdRp as possible viral targets. Dual functionality between anti-inflammatory activity on host cells and anti-SARS-CoV-2 activity on the SARS-CoV-2 virus of isoquinoline alkaloids, including AAs, were suggested as the possible MOAs to alleviate severe complications in COVID-19 patients. This dual functionality was proposed to be related to the p38 MAPK signaling pathway. CONCLUSION: Overall, Amaryllidaceae alkaloids appear to be promising for further investigation as anti-SARS-CoV-2 agents. The skeletal subclasses holding the premise for further investigation are lycorine-, crinine-, galanthamine- and homolycorine-types.

In vitro pharmacokinetic behavior in lung of harringtonine, an antagonist of SARS-CoV-2 associated proteins: New insights of inhalation therapy for COVID-19.

BACKGROUND: Recent studies have shown that harringtonine (HT) could specifically bind with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and host cell transmembrane serine protease 2 (TMPRSS2) to block membrane fusion, which is an effective antagonist for SARS-CoV-2. PURPOSE: Our study focused on in-depth exploration of in vitro pharmacokinetic characteristics of HT in lung. METHODS: HPLC-fluorescence detection method was used to detect changes of HT content. Incubation systems of lung microsomes for phase I metabolism and UGT incubation systems for phase II metabolism were performed to elucidate metabolites and metabolic mechanisms of HT, and then the metabolic enzyme phenotypes for HT were clarified by chemical inhibition method and recombinant enzyme method. Through metabolomics, we comprehensively evaluated the physiological dynamic changes in SD rat and human lung microsomes, and revealed the relationship between metabolomics and pharmacological activity of HT. RESULTS: HPLC-fluorescence detection method showed strong specificity, high accuracy, and good stability for rapid quantification of HT. We confirmed that HT mainly underwent phase I metabolism, and the metabolites of HT in different species were all identified as 4'-demethyl HT, with metabolic pathway being hydrolysis reaction. CYP1A2 and CYP2E1 participated in HT metabolism, but as HT metabolism was not NADPH dependent, the esterase HCES1 in lung also played a role. The main KEGG pathways in SD rat and human lung microsomes were cortisol synthesis and secretion, steroid hormone biosynthesis and linoleic acid metabolism, respectively. The downregulated key biomarkers of 11-deoxycortisol, 21-deoxycortisol and 9(10)-EpOME suggested that HT could prevent immunosuppression and interfere with infection and replication of SARS-CoV-2. CONCLUSION: HT was mainly metabolized into 4'-demethyl HT through phase I reactions, which was mediated by CYP1A2, CYP2E1, and HCES1. The downregulation of 11-deoxycortisol, 21-deoxycortisol and 9(10)-EpOME were key ways of HT against SARS-CoV-2. Our study was of great significance for development and clinical application of HT in the treatment of COVID-19.

An open trial of biofeedback for long COVID.

OBJECTIVE: Biofeedback is a therapeutic treatment model that teaches self-regulation of autonomic functions to alleviate stress-related symptoms. "Long COVID" refers to chronic physical and cognitive sequelae post-SARS-CoV-2 infection. This study examined the efficacy of a six-week intervention, consisting of weekly one-hour sessions combining heart rate variability and temperature biofeedback, for alleviating mood symptoms, somatic symptoms and sleep disturbance of patients diagnosed with long COVID. METHODS: Data were collected from 20 adult participants aged 22-63 (Mage = 44.1, SDage = 12.2) with varying long COVID symptoms. Within this single arm design, 16 of the 20 participants completed all six sessions of biofeedback; 14 completed an assessment at the three-month post-treatment time point. RESULTS: Participants self-reported significant improvements in somatic, anxiety, and depressive symptoms, sleep quality, quality of life, and number of "bad days" immediately after the intervention and three months later (Cohen's d effect size (ES) = 1.09-0.46). Reduced number of medical doctor visits (ES = 0.85) and prescription drug use over the last month (odds ratio = 0.33), as well as improved emotional wellbeing (ES = 0.97) were observed at the three-month time point only. CONCLUSION: Results suggest that this short, readily scalable intervention can be potentially efficacious in alleviating symptoms of long COVID. Despite notable improvements, the major limitation of this study is its lack of control group. While a randomized trial merits study, biofeedback appears to be a brief, effective, non-invasive, and low-cost treatment option for patients with chronic somatic symptoms secondary to SARS-CoV-2 infection. CLINICALTRIALS: govID: NCT05120648.

Nigella sativa for the treatment of COVID-19 patients: A rapid systematic review and meta-analysis of randomized controlled trials.

Nigella sativa is an herbal therapy for various afflictions. It has some potential to be a promising option as an efficacious treatment for COVID-19 patients that can contribute to global healthcare as a relatively cheap therapy but evidence of its use from randomized controlled trials (RCTs) is limited. Therefore, to explore the effect of N. sativa in combating COVID-19, we undertook this meta-analysis. We searched several databases to retrieve all RCTs investigating N. sativa for the treatment of COVID-19 as compared to placebo or standard care. We used RevMan 5.4 for all analyses with risk ratio (RR) or odds ratio (OR) as the effect measures. We included a total of seven RCTs in this review. N. sativa significantly reduced the risk of all-cause mortality in patients with COVID-19 compared to the control group (RR 0.27, 95% CI: 0.10 to 0.72; I 2 = 0%). N. sativa significantly reduced the rate of viral PCR positivity (RR 0.62, 95% CI: 0.39 to 0.97; I 2 = 0%). We did not find any significant difference in the risk of hospitalization (RR 0.26, 95% CI: 0.04 to 1.54; I 2 = 0%) and the rate of no recovery (OR 0.48, 95% CI: 0.20 to 1.15; I 2 = 84%) between the two groups. N. sativa is an easily available herbal medicine that may decrease the risk of mortality and improve virological clearance in COVID-19 patients. However, our results are limited by the small number of RCTs available. Further large-scale RCTs are needed to better understand the anti-inflammatory and antiviral effects of N. sativa in COVID-19 patients.

Inhibitory Efficacy of Main Components of Scutellaria baicalensis on the Interaction between Spike Protein of SARS-CoV-2 and Human Angiotensin-Converting Enzyme II.

Blocking the interaction between the SARS-CoV-2 spike protein and the human angiotensin-converting enzyme II (hACE2) protein serves as a therapeutic strategy for treating COVID-19. Traditional Chinese medicine (TCM) treatments containing bioactive products could alleviate the symptoms of severe COVID-19. However, the emergence of SARS-CoV-2 variants has complicated the process of developing broad-spectrum drugs. As such, the aim of this study was to explore the efficacy of TCM treatments against SARS-CoV-2 variants through targeting the interaction of the viral spike protein with the hACE2 receptor. Antiviral activity was systematically evaluated using a pseudovirus system. Scutellaria baicalensis (S. baicalensis) was found to be effective against SARS-CoV-2 infection, as it mediated the interaction between the viral spike protein and the hACE2 protein. Moreover, the active molecules of S. baicalensis were identified and analyzed. Baicalein and baicalin, a flavone and a flavone glycoside found in S. baicalensis, respectively, exhibited strong inhibitory activities targeting the viral spike protein and the hACE2 protein, respectively. Under optimized conditions, virus infection was inhibited by 98% via baicalein-treated pseudovirus and baicalin-treated hACE2. In summary, we identified the potential SARS-CoV-2 inhibitors from S. baicalensis that mediate the interaction between the Omicron spike protein and the hACE2 receptor. Future studies on the therapeutic application of baicalein and baicalin against SARS-CoV-2 variants are needed.

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies.

We provide promising computational (in silico) data on phytochemicals (compounds 1-10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1-10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1-10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.