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1.
J Pharmacol Exp Ther ; 381(2): 129-136, 2022 05.
Статья в английский | MEDLINE | ID: covidwho-2152871

Реферат

The incidence of fatal drug overdoses in the United States is an alarming public health threat that has been exacerbated by the COVID-19 pandemic, resulting in over 100,000 deaths between April 2020 and April 2021. A significant portion of this is attributable to widespread access to fentanyl and other synthetic opioids, alone or in combination with heroin or psychostimulants, such as cocaine or methamphetamine. Monoclonal antibodies (mAb) offer prophylactic and therapeutic interventions against opioid overdose by binding opioids in serum, reducing distribution of drug to the brain and other organs. Here, we investigated the efficacy of a leading antifentanyl mAb, clone HY6-F9, in reversal and prevention of fentanyl-induced toxicity compared with the opioid receptor antagonist naloxone (NLX) in rats. In postexposure models, rats were challenged with fentanyl, followed by HY6-F9, NLX, or both. HY6-F9 reversed fentanyl-induced antinociception, respiratory depression, and bradycardia, and rats retained protection against additional challenges for at least 1 week. Although intravenous NLX reversed fentanyl-induced respiratory depression more rapidly than mAb alone, kinetics of reversal by intravenous mAb were similar to subcutaneous NLX. Coadministration of mAb and NLX provided greater protection than individual treatments against high doses of fentanyl. Prophylactic administration of mAb reduced the ED50 of NLX approximately twofold against 2.25 mg/kg of fentanyl. Finally, mAb sequestered fentanyl and its metabolite norfentanyl in serum and reduced brain concentrations of fentanyl. These results support the translation of mAb as medical interventions alone or in combination with NLX to prevent and reverse fentanyl-related overdose. SIGNIFICANCE STATEMENT: Fentanyl-related overdoses have increased dramatically in the US and worldwide. Currently, approved pharmacotherapies for treatment of opioid use disorder and reversal of overdose are not sufficient to curb the incidence of opioid-related deaths. Additionally, fentanyl and its potent analogs present a potential risk from use in deliberate poisoning or chemical attacks. This study demonstrates the use of monoclonal antibodies as a countermeasure to fentanyl-induced toxicity in pre- and postexposure scenarios, supporting their use in combination with the opioid antagonist naloxone.


Тема - темы
COVID-19 , Drug Overdose , Respiratory Insufficiency , Analgesics, Opioid/therapeutic use , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Drug Overdose/drug therapy , Fentanyl , Humans , Naloxone/pharmacology , Naloxone/therapeutic use , Narcotic Antagonists/pharmacology , Pandemics , Rats , Respiratory Insufficiency/drug therapy
2.
Int J Mol Sci ; 23(22)2022 Nov 18.
Статья в английский | MEDLINE | ID: covidwho-2143226

Реферат

Although pulmonary fibrosis (PF) is considered a rare disease, the incidence thereof has increased steadily in recent years, while a safe and effective cure remains beyond reach. In this study, the potential of tocotrienol-rich fractions (TRF) and carotene to alleviate PF was explored. PF was induced in Sprague-Dawley rats via a single intratracheal bleomycin (BLM) (5 mg/kg) instillation. These rats were subsequently treated with TRF, carotene, pirfenidone (Pir) and nintedanib (Nin) for 28 days via gavage administration, whereafter histopathological performance, biochemical functions and molecular alterations were studied in the lung tissues. Our results showed that TRF, carotene, Nin and Pir all ameliorated PF by reducing inflammation and resisting oxidative stress to varying degrees. The related mechanisms involved the TGF-ß1/Smad, PI3K/Akt and NF-κB signaling pathways. Ultimately, our findings revealed that, when combined with TRF, the therapeutic effects of Nin and Pir on PF were enhanced, indicating that TRF may, indeed, provide promising potential for use in combination therapy in the treatment of PF.


Тема - темы
Pulmonary Fibrosis , Tocotrienols , Rats , Animals , Pulmonary Fibrosis/metabolism , Tocotrienols/pharmacology , Tocotrienols/therapeutic use , Phosphatidylinositol 3-Kinases/metabolism , Rats, Sprague-Dawley , Carotenoids/therapeutic use
3.
Int J Mol Sci ; 23(22)2022 Nov 10.
Статья в английский | MEDLINE | ID: covidwho-2110130

Реферат

Angiotensin-converting enzyme 2 (ACE2) is a target of interest for both COVID-19 and cardiovascular disease management. Even though lower ACE2 levels may be beneficial in SARS-CoV-2 infectivity, maintaining the ACE1/ACE2 balance is also crucial for cardiovascular health. So far, reports describing conditions capable of altering ACE2 protein levels, especially via dietary components, are limited. In this study, the effects of omega-3 polyunsaturated fatty acids (n3-PUFA) on the protein levels of ACE1 and ACE2 in rodent tissues, human endothelial and kidney cell lines, and human plasma were examined. The ability of n3-PUFA to affect the entry of the SARS-CoV-2 pseudovirus into cells was also tested. Docosahexaenoic acid (DHA), and in some cases eicosapentaenoic acid (EPA), but not α-linoleic acid (ALA), reduced both ACE1 and ACE2 (non-glycosylated p100 and glycosylated p130 forms) in the heart, aorta, and kidneys of obese rats, as well as in human EA.hy926 endothelial and HEK293 kidney cells. Dietary supplementation with either DHA or ALA had no effect on plasma soluble ACE2 levels in humans. However, treatment of HEK293 cells with 80 and 125 µM DHA for 16 h inhibited the entry of the SARS-CoV-2 pseudovirus. These results strongly suggest that DHA treatment may reduce the ability of SARS-CoV-2 to infect cells via a mechanism involving a decrease in the absolute level of ACE2 protein as well as its glycosylation. Our findings warrant further evaluation of long-chain n3-PUFA supplements as a novel option for restricting SARS-CoV-2 infectivity in the general population.


Тема - темы
COVID-19 , Fatty Acids, Omega-3 , Humans , Rats , Animals , Angiotensin-Converting Enzyme 2 , SARS-CoV-2 , HEK293 Cells , Fatty Acids, Omega-3/pharmacology , Virus Internalization , Docosahexaenoic Acids/pharmacology
4.
PLoS Negl Trop Dis ; 16(10): e0010898, 2022 Oct.
Статья в английский | MEDLINE | ID: covidwho-2098682

Реферат

Rift Valley fever (RVF) is a disease of animals and humans associated with abortions in ruminants and late-gestation miscarriages in women. Here, we use a rat model of congenital RVF to identify tropisms, pathologies, and immune responses in the placenta during vertical transmission. Infection of late-gestation pregnant rats resulted in vertical transmission to the placenta and widespread infection throughout the decidua, basal zone, and labyrinth zone. Some pups from infected dams appeared normal while others had gross signs of teratogenicity including death. Histopathological lesions were detected in placenta from pups regardless of teratogenicity, while teratogenic pups had widespread hemorrhage throughout multiple placenta layers. Teratogenic events were associated with significant increases in placental pro-inflammatory cytokines, type I interferons, and chemokines. RVFV displays a high degree of tropism for all placental tissue layers and the degree of hemorrhage and inflammatory mediator production is highest in placenta from pups with adverse outcomes. Given the potential for RVFV to emerge in new locations and the recent evidence of emerging viruses, like Zika and SARS-CoV-2, to undergo vertical transmission, this study provides essential understanding regarding the mechanisms by which RVFV crosses the placenta barrier.


Тема - темы
COVID-19 , Rift Valley Fever , Rift Valley fever virus , Zika Virus Infection , Zika Virus , Humans , Female , Pregnancy , Rats , Animals , Rats, Sprague-Dawley , Placenta/pathology , SARS-CoV-2 , Ruminants
5.
PLoS One ; 17(10): e0271850, 2022.
Статья в английский | MEDLINE | ID: covidwho-2089379

Реферат

Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir's effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.


Тема - темы
COVID-19 , DNA, Mitochondrial , Animals , Child, Preschool , Humans , Male , Rats , Adenosine Monophosphate/pharmacology , Alanine , DNA Copy Number Variations , DNA, Mitochondrial/genetics , DNA-Directed RNA Polymerases/genetics , Mammals/genetics , Mitochondria/genetics , Nucleosides , RNA, Viral , SARS-CoV-2 , Sequence Deletion
6.
Emerg Microbes Infect ; 11(1): 2724-2734, 2022 Dec.
Статья в английский | MEDLINE | ID: covidwho-2087655

Реферат

The development of safe and effective vaccines to respond to COVID-19 pandemic/endemic remains a priority. We developed a novel subunit protein-peptide COVID-19 vaccine candidate (UB-612) composed of: (i) receptor binding domain of SARS-CoV-2 spike protein fused to a modified single-chain human IgG1 Fc; (ii) five synthetic peptides incorporating conserved helper and cytotoxic T lymphocyte (Th/CTL) epitopes derived from SARS-CoV-2 structural proteins (three from S2 subunit, one from membrane and one from nucleocapsid), and one universal Th peptide; (iii) aluminum phosphate as adjuvant. The immunogenicity and protective immunity induced by UB-612 vaccine were evaluated in four animal models: Sprague-Dawley rats, AAV-hACE2 transduced BALB/c mice, rhesus and cynomolgus macaques. UB-612 vaccine induced high levels of neutralizing antibody and T-cell responses, in all animals. The immune sera from vaccinated animals neutralized the SARS-CoV-2 original wild-type strains and multiple variants of concern, including Delta and Omicron. The vaccination significantly reduced viral loads, lung pathology scores, and disease progression after intranasal and intratracheal challenge with SARS-CoV-2 in mice, rhesus and cynomolgus macaques. UB-612 has been tested in primary regimens in Phase 1 and Phase 2 clinical studies and is currently being evaluated in a global pivotal Phase 3 clinical study as a single dose heterologous booster.


Тема - темы
COVID-19 , Viral Vaccines , Rats , Mice , Humans , Animals , SARS-CoV-2 , COVID-19 Vaccines , Broadly Neutralizing Antibodies , Pandemics/prevention & control , COVID-19/prevention & control , Rats, Sprague-Dawley , Spike Glycoprotein, Coronavirus , Antibodies, Neutralizing , Vaccines, Subunit/genetics , Mice, Inbred BALB C , Macaca mulatta , Antibodies, Viral
7.
Molecules ; 27(20)2022 Oct 18.
Статья в английский | MEDLINE | ID: covidwho-2081847

Реферат

Griseofulvin is an antifungal polyketide metabolite produced mainly by ascomycetes. Since it was commercially introduced in 1959, griseofulvin has been used in treating dermatophyte infections. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its potential to disrupt mitosis and cell division in human cancer cells and arrest hepatitis C virus replication. In addition to these inhibitory effects, we and others found griseofulvin may enhance ACE2 function, contribute to vascular vasodilation, and improve capillary blood flow. Furthermore, molecular docking analysis revealed that griseofulvin and its derivatives have good binding potential with SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting its inhibitory effects on SARS-CoV-2 entry and viral replication. These findings imply the repurposing potentials of the FDA-approved drug griseofulvin in designing and developing novel therapeutic interventions. In this review, we have summarized the available information from its discovery to recent progress in this growing field. Additionally, explored is the possible mechanism leading to rare hepatitis induced by griseofulvin. We found that griseofulvin and its metabolites, including 6-desmethylgriseofulvin (6-DMG) and 4- desmethylgriseofulvin (4-DMG), have favorable interactions with cytokeratin intermediate filament proteins (K8 and K18), ranging from -3.34 to -5.61 kcal mol-1. Therefore, they could be responsible for liver injury and Mallory body (MB) formation in hepatocytes of human, mouse, and rat treated with griseofulvin. Moreover, the stronger binding of griseofulvin to K18 in rodents than in human may explain the observed difference in the severity of hepatitis between rodents and human.


Тема - темы
COVID-19 , Polyketides , Mice , Humans , Rats , Animals , Griseofulvin/pharmacology , Antifungal Agents/pharmacology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Molecular Docking Simulation , Spike Glycoprotein, Coronavirus , Keratins/metabolism , RNA-Dependent RNA Polymerase
8.
J Ethnopharmacol ; 299: 115674, 2022 Dec 05.
Статья в английский | MEDLINE | ID: covidwho-2069311

Реферат

ETHNOPHARMACOLOGICAL RELEVANCE: Zukamu granules (ZKMG), as the preferred drug for the treatment of colds in Uygur medical theory, has been used for 1500 years. It is also widely used in China and included in the National Essential Drugs List (2018 edition). It has unique anti-inflammatory, antitussive and analgesic effects. AIM OF THE STUDY: Aiming at the research of traditional Chinese medicine (TCM) with the characteristics of overall regulation of body diseases and the immune regulation mechanism with the concept of integrity, this paper put forward the integrated application of network composite module analysis and animal experiment verification to study the immune regulation mechanism of TCM. MATERIALS AND METHODS: The active components and targets of ZKMG were predicted, and network module analysis was performed to explore their potential immunomodulatory mechanisms. Then acute lung injury (ALI) mice and idiopathic pulmonary fibrosis (IPF) rats were used as pathological models to observe the effects of ZKMG on the pathological conditions of infected ALI and IPF rats, determine the contents of Th1, Th2 characteristic cytokines and immunoglobulins, and study the intervention of GATA3/STAT6 signal pathway. RESULTS: The results of network composite module analysis showed that ZKMG contained 173 pharmacodynamic components and 249 potential targets, and four key modules were obtained. The immunomodulatory effects of ZKMG were related to T cell receptor signaling pathway. The validation results of bioeffects that ZKMG could carry out bidirectional immune regulation on Th1/Th2 cytokines in the stage of ALI and IPF, so as to play the role of regulating immune homeostasis and organ protection. CONCLUSIONS: The network composite module analysis and verification method is an exploration to study the immune regulation mechanism of TCM by combining the network module prediction analysis with animal experiments, which provides a reference for subsequent research.


Тема - темы
Acute Lung Injury , Antitussive Agents , Drugs, Chinese Herbal , Immunomodulating Agents , Acute Lung Injury/drug therapy , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antitussive Agents/therapeutic use , Cytokines/metabolism , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Drugs, Essential/therapeutic use , Immunomodulating Agents/pharmacology , Immunomodulating Agents/therapeutic use , Mice , Network Pharmacology/methods , Rats , Receptors, Antigen, T-Cell/therapeutic use
10.
Kidney Blood Press Res ; 47(9): 565-575, 2022.
Статья в английский | MEDLINE | ID: covidwho-2064352

Реферат

INTRODUCTION: The angiotensin-converting enzyme 2 (ACE2) as well as the transmembrane protease serine type 2 (TMPRSS2) have been found to play roles in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). SARS-CoV-2 infection risk and severity of COVID-19 might be indicated by the expression of ACE2 and TMPRSS2 in the lung. METHODS: A high-salt diet rat model and renin-angiotensin-aldosterone system (RAAS) blockade were used to test whether these factors affect ACE2 and TMPRSS2 expression in the lung. A normal (0.3% NaCl), a medium (2% NaCl), or a high (8% NaCl) salt diet was fed to rats for 12 weeks, along with enalapril or telmisartan, before examining the lung for histopathological alteration. Using immunofluorescence and qRT-PCR, the localization as well as mRNA expression of ACE2 and TMPRSS2 were investigated. RESULTS: The findings provide evidence that both TMPRSS2 and ACE2 are highly expressed in bronchial epithelial cells as well as ACE2 was also expressed in alveolar type 2 cells. High-salt diet exposure in rats leads to elevated ACE2 expression on protein level. Treatment with RAAS blockers had no effect on lung tissue expression of ACE2 and TMPRSS2. CONCLUSIONS: These findings offer biological support regarding the safety of these drugs that are often prescribed to COVID-19 patients with cardiovascular comorbidity. High salt intake, on the other hand, might adversely affect COVID-19 outcome. Our preclinical data should stimulate clinical studies addressing this point of concern.


Тема - темы
COVID-19 , Renin-Angiotensin System , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Animals , Enalapril/pharmacology , Lung , RNA, Messenger/metabolism , Rats , Renin-Angiotensin System/drug effects , Serine Endopeptidases , Sodium Chloride, Dietary/adverse effects , Telmisartan/pharmacology
11.
Respir Res ; 23(1): 249, 2022 Sep 17.
Статья в английский | MEDLINE | ID: covidwho-2038754

Реферат

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening disease caused by the induction of inflammatory cytokines and chemokines in the lungs. There is a dearth of drug applications that can be used to prevent cytokine storms in ARDS treatment. This study was designed to investigate the effects of tocilizumab and dexamethasone on oxidative stress, antioxidant parameters, and cytokine storms in acute lung injury caused by oleic acid in rats. METHODS: Adult male rats were divided into five groups: the CN (healthy rats, n = 6), OA (oleic acid administration, n = 6), OA + TCZ-2 (oleic acid and tocilizumab at 2 mg/kg, n = 6), OA + TCZ-4 (oleic acid and tocilizumab at 4 mg/kg, n = 6), and OA + DEX-10 (oleic acid and dexamethasone at 10 mg/kg, n = 6) groups. All animals were euthanized after treatment for histopathological, immunohistochemical, biochemical, PCR, and SEM analyses. RESULTS: Expressions of TNF-α, IL-1ß, IL-6, and IL-8 cytokines in rats with acute lung injury induced by oleic acid were downregulated in the TCZ and DEX groups compared to the OA group (P < 0.05). The MDA level in lung tissues was statistically lower in the OA + TCZ-4 group compared to the OA group. It was further determined that SOD, GSH, and CAT levels were decreased in the OA group and increased in the TCZ and DEX groups (P < 0.05). Histopathological findings such as thickening of the alveoli, hyperemia, and peribronchial cell infiltration were found to be similar when lung tissues of the TCZ and DEX groups were compared to the control group. With SEM imaging of the lung tissues, it was found that the alveolar lining layer had become indistinct in the OA, OA + TCZ-2, and OA + TCZ-4 groups. CONCLUSIONS: In this model of acute lung injury caused by oleic acid, tocilizumab and dexamethasone were effective in preventing cytokine storms by downregulating the expression of proinflammatory cytokines including TNF-α, IL-1ß, IL-6, and IL-8. Against the downregulation of antioxidant parameters such as SOD and GSH in the lung tissues caused by oleic acid, tocilizumab and dexamethasone upregulated them and showed protective effects against cell damage.


Тема - темы
Acute Lung Injury , Respiratory Distress Syndrome , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/prevention & control , Animals , Antibodies, Monoclonal, Humanized , Antioxidants/adverse effects , Cytokine Release Syndrome , Cytokines/pharmacology , Dexamethasone/pharmacology , Down-Regulation , Interleukin-6 , Interleukin-8 , Lung , Male , Oleic Acid/toxicity , Rats , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/drug therapy , Superoxide Dismutase , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation
12.
Biomed Pharmacother ; 155: 113666, 2022 Nov.
Статья в английский | MEDLINE | ID: covidwho-2027928

Реферат

Acute lung injury (ALI) and its more serious form; acute respiratory distress syndrome are major causes of COVID-19 related mortality. Finding new therapeutic targets for ALI is thus of great interest. This work aimed to prepare a biocompatible nanoformulation for effective pulmonary delivery of the herbal drug; tanshinone-IIA (TSIIA) for ALI management. A nanoemulsion (NE) formulation based on bioactive natural ingredients; rhamnolipid biosurfactant and tea-tree oil, was developed using a simple ultrasonication technique, optimized by varying oil concentration and surfactant:oil ratio. The selected TSIIA-NE formulation showed 105.7 nm diameter and a PDI âˆ¼ 0.3. EE exceeded 98 % with biphasic sustained drug release and good stability over 3-months. In-vivo efficacy was evaluated in lipopolysaccharide (LPS)-induced ALI model. TSIIA-NE (30 µg/kg) was administered once intratracheally 2 h after LPS instillation. Evaluation was performed 7days post-treatment. Pulmonary function assessment, inflammatory, oxidative stress and glycocalyx shedding markers analysis in addition to histopathological examination of lung tissue were performed. When compared to untreated rats, in-vivo efficacy study demonstrated 1.4 and 1.9-fold increases in tidal volume and minute respiratory volume, respectively, with 32 % drop in wet/dry lung weight ratio and improved levels of arterial blood gases. Lung histopathology and biochemical analysis of different biomarkers in tissue homogenate and bronchoalveolar lavage fluid indicated that treatment may ameliorate LPS-induced ALI symptoms thorough anti-oxidative, anti-inflammatory effects and inhibition of glycocalyx degradation. TSIIA-NE efficacy was superior to free medication and blank-NE. The enhanced efficacy of TSIIA bioactive nanoemulsion significantly suggests the pharmacotherapeutic potential of bioactive TSIIA-NE as a promising nanoplatform for ALI.


Тема - темы
Acute Lung Injury , COVID-19 , Rats , Animals , Lipopolysaccharides/pharmacology , Glycocalyx/pathology , COVID-19/drug therapy , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Lung , Anti-Inflammatory Agents/pharmacology , Surface-Active Agents/pharmacology , Gases/adverse effects , Gases/metabolism , Tea/metabolism
13.
Elife ; 112022 08 25.
Статья в английский | MEDLINE | ID: covidwho-2025329

Реферат

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to pose a serious threat to public health and has so far resulted in over six million deaths worldwide. Mass vaccination programs have reduced the risk of serious illness and death in many people, but the virus continues to persist and circulate in communities across the globe. Furthermore, the current vaccines may be less effective against the new variants of the virus, such as Omicron and Delta, which are continually emerging and evolving. Therefore, it is urgent to develop effective vaccines that can provide broad protection against existing and future forms of SARS-CoV-2. There are several different types of SARS-CoV-2 vaccine, but they all work in a similar way. They contain molecules that induce immune responses in individuals to help the body recognize and more effectively fight SARS-CoV-2 if they happen to encounter it in the future. These immune responses may be so specific that new variants of a virus may not be recognized by them. Therefore, a commonly used strategy for producing vaccines with broad protection is to make multiple vaccines that each targets different variants and then mix them together before administering to patients. Here, Zhang et al. took a different approach by designing a new vaccine candidate against SARS-CoV2 that contained three different versions of part of a SARS-CoV2 protein ­ the so-called spike protein ­ all linked together as one molecule. The different versions of the spike protein fragment were designed to include key features of the fragments found in Omicron and several other SARS-CoV-2 variants. The experiments found that this candidate vaccine elicited a much higher immune response against Omicron and other SARS-CoV-2 variants in rats than an existing SARS-CoV-2 vaccine. It was also effective as a booster shot after a first vaccination with the existing SARS-CoV-2 vaccine. These findings demonstrate that the molecule developed by Zhang et al. induces potent and broad immune responses against different variants of SARS-CoV-2 including Omicron in rats. The next steps following on from this work are to evaluate the safety and immunogenicity of this vaccine candidate in clinical trials. In the future, it may be possible to use a similar approach to develop new broad-spectrum vaccines against other viruses.


Тема - темы
COVID-19 Vaccines , COVID-19 , Animals , Antibodies, Neutralizing , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19/prevention & control , Humans , Rats , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
14.
PLoS One ; 17(9): e0273715, 2022.
Статья в английский | MEDLINE | ID: covidwho-2021939

Реферат

Alcohol use disorder is a medical condition that impacts millions of individuals worldwide. Although there are a few pharmacotherapeutic options for alcohol-dependent individuals; there is a need for the development of novel and more effective therapeutic approaches. Alcohol and nicotine are commonly co-abused, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Desformylflustrabromine (dFBr), a positive allosteric modulator of the α4ß2 nAChRs has been shown to reduce nicotine intake, compulsive-like behavior and neuropathic pain in animal models. dFBr has also been previously shown to cross the blood-brain-barrier. We have recently shown that dFBr can attenuate the response to an acute, hypnotic dose of ethanol, via ß2 nAchR. Here, we have investigated the effect of dFBr in modulating ethanol consumption using the intermittent access two-bottle choice (IA2BC) model of voluntary ethanol consumption in male and female Sprague Dawley rats. We show that dFBr selectively reduced ethanol but not sucrose consumption in the IA2BC model. Furthermore, dFBr decreased preference for ethanol in both male and female rats. No rebound increase in ethanol intake was observed after the washout period after dFBr treatment. The ability of dFBr to decrease ethanol consumption, along with its previously demonstrated ability to decrease nicotine self-administration in rodents, suggest that dFBr is an attractive therapeutic candidate to target both nicotine and alcohol abuse.


Тема - темы
Nicotine , Receptors, Nicotinic , Animals , Ethanol , Female , Hydrocarbons, Brominated , Indole Alkaloids , Male , Nicotine/pharmacology , Rats , Rats, Sprague-Dawley
15.
Small ; 18(40): e2203746, 2022 10.
Статья в английский | MEDLINE | ID: covidwho-2013794

Реферат

Bloodstream infection caused by antimicrobial resistance pathogens is a global concern because it is difficult to treat with conventional therapy. Here, scavenger magnetic nanoparticles enveloped by nanovesicles derived from blood cells (MNVs) are reported, which magnetically eradicate an extreme range of pathogens in an extracorporeal circuit. It is quantitatively revealed that glycophorin A and complement receptor (CR) 1 on red blood cell (RBC)-MNVs predominantly capture human fecal bacteria, carbapenem-resistant (CR) Escherichia  coli, and extended-spectrum beta-lactamases-positive (ESBL-positive) E. coli, vancomycin-intermediate Staphylococcus aureus (VISA), endotoxins, and proinflammatory cytokines in human blood. Additionally, CR3 and CR1 on white blood cell-MNVs mainly contribute to depleting the virus envelope proteins of Zika, SARS-CoV-2, and their variants in human blood. Supplementing opsonins into the blood significantly augments the pathogen removal efficiency due to its combinatorial interactions between pathogens and CR1 and CR3 on MNVs. The extracorporeal blood cleansing enables full recovery of lethally infected rodent animals within 7 days by treating them twice in series. It is also validated that parameters reflecting immune homeostasis, such as blood cell counts, cytokine levels, and transcriptomics changes, are restored in blood of the fatally infected rats after treatment.


Тема - темы
Bacteremia , COVID-19 , Escherichia coli Infections , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Bacteremia/microbiology , COVID-19/drug therapy , Carbapenems/metabolism , Cytokines/metabolism , Endotoxins/metabolism , Escherichia coli/metabolism , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Glycophorins/metabolism , Homeostasis , Humans , Microbial Sensitivity Tests , Opsonin Proteins/metabolism , Rats , Receptors, Complement/metabolism , Rodentia/metabolism , SARS-CoV-2 , Viral Envelope Proteins/metabolism , beta-Lactamases/metabolism
16.
Dokl Biol Sci ; 505(1): 95-99, 2022 Aug.
Статья в английский | MEDLINE | ID: covidwho-2008770

Реферат

The article focuses on the pathogenetic mechanisms of posttraumatic stress disorder (PTSD), which is associated with psychological stress because of the coronavirus pandemic. The molecular mechanisms responsible for disease susceptibility in some individuals and stress resistance in others are amongst crucial research interests of experimental and clinical medicine. Priority data were obtained to indicate that distortions of synthesis and metabolism and, most significantly, a switch between two energy transport forms, glucose and lipids, underlie myocardial dysfunction in young and old stress-sensitive Wistar rats in a PTSD model. Histochemistry and polarization microscopy showed energy deficit in cardiomyocytes and signs of ischemic and hypoxic areas emerging in the myocardium as a result of an accumulation of NADH and NADPH, which initiate excessive production of reactive oxygen species.


Тема - темы
Cardiovascular Diseases , Stress Disorders, Post-Traumatic , Animals , Cardiovascular Diseases/complications , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Myocardium/pathology , Rats , Rats, Wistar , Risk Factors
17.
Biomacromolecules ; 23(9): 3960-3967, 2022 09 12.
Статья в английский | MEDLINE | ID: covidwho-2000842

Реферат

Continued SARS-CoV-2 transmission among the human population has meant the evolution of the virus to produce variants of increased infectiousness and virulence, coined variants of concern (VOCs). The last wave of pandemic infections was driven predominantly by the delta VOC, but because of continued transmission and adaptive mutations, the more highly transmissible omicron variant emerged and is now dominant. However, due to waning immunity and emergence of new variants, vaccines alone cannot control the pandemic. The application of an antiviral coating to high-touch surfaces and physical barriers such as masks are an effective means to inactivate the virus and their spread. Here, we demonstrate an environmentally friendly water-borne polymer coating that can completely inactivate SARS-CoV-2 independent of the infectious variant. The polymer was designed to target the highly glycosylated spike protein on the virion surface and inactivate the virion by disruption of the viral membrane through a nano-mechanical process. Our findings show that, even with low amounts of coating on the surface (1 g/m2), inactivation of alpha, delta, and omicron VOCs and degradation of their viral genome were complete. Furthermore, our data shows that the polymer induces little to no skin sensitization in mice and is non-toxic upon oral ingestion in rats. We anticipate that our transparent polymer coating can be applied to face masks and many other surfaces to capture and inactivate the virus, aiding in the reduction of SARS-CoV-2 transmission and evolution of new variants of concern.


Тема - темы
COVID-19 , SARS-CoV-2 , Animals , COVID-19/prevention & control , Humans , Mice , Polymers , Rats , SARS-CoV-2/genetics , Virion
18.
Nutrients ; 14(17)2022 Aug 25.
Статья в английский | MEDLINE | ID: covidwho-1997735

Реферат

The consumption of processed foods has increased compared to that of fresh foods in recent years, especially due to the coronavirus disease 2019 pandemic. Here, we evaluated the health effects of clarified apple juices (CAJs, devoid of pectin and additives) processed to different degrees, including not-from-concentrate (NFC) and from-concentrate (FC) CAJs. A 56-day experiment including a juice-switch after 28 days was designed. An integrated analysis of 16S rRNA sequencing and untargeted metabolomics of cecal content were performed. In addition, differences in the CAJs tested with respect to nutritional indices and composition of small-molecule compounds were analyzed. The NFC CAJ, which showed a higher phenolic content resulting from the lower processing degree, could improve microbiota diversity and influence its structure. It also reduced bile acid and bilirubin contents, as well as inhibited the microbial metabolism of tryptophan in the gut. However, we found that these effects diminished with time by performing experiment extension and undertaking juice-switching. Our study provides evidence regarding the health effects of processed foods that can potentially be applied to public health policy decision making. We believe that NFC juices with a lower processing degree could potentially be healthier than FC juice.


Тема - темы
COVID-19 , Gastrointestinal Microbiome , Malus , Animals , Fruit and Vegetable Juices , Malus/chemistry , Metabolomics/methods , RNA, Ribosomal, 16S/genetics , Rats
19.
Int J Mol Sci ; 23(16)2022 Aug 18.
Статья в английский | MEDLINE | ID: covidwho-1997643

Реферат

Acute lung injury (ALI) as a model of acute respiratory distress syndrome is characterized by inflammation, complex coagulation, and hematologic abnormalities which result in the formation of fibrin-platelet microthrombi in the pulmonary vessels with the rapid development of progressive respiratory dysfunction. We hypothesize that a nebulized fibrinolytic agent, non-immunogenic staphylokinase (nSta), may be useful for ALI therapy. First, the effect of the nebulized nSta (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg) on the coagulogram parameters was studied in healthy rats. ALI was induced in mice by nebulized administration of lipopolysaccharide (LPS) at a dose of 10 mg/kg. nSta (0.2 mg/kg, 0.4 mg/kg or 0.6 mg/kg) was nebulized 30 min, 24 h, and 48 h after LPS administration. The level of pro-inflammatory cytokines was determined in the blood on the 8th day after LPS and nSta administration. The assessment of lung damage was based on their weighing and microscopic analysis. Fibrin/fibrinogen deposition in the lungs was determined by immunohistochemistry. After nSta nebulization in healthy rats, the fibrinogen blood level as well as activated partial thromboplastin time and prothrombin time did not change. In the nebulized ALI model, the mice showed an increase in lung weight due to their edema and rising fibrin deposition. An imbalance of proinflammatory cytokines was also found. Forty percent of mice with ALI without nSta nebulization had died. Nebulized nSta at a dose of 0.2 mg/kg reduced the severity of ALI: a decrease in interstitial edema and inflammatory infiltration was noted. At a dose of 0.4 mg/kg of nebulized nSta, the animals showed no peribronchial edema and the bronchi had an open clear lumen. At a dose of 0.6 mg/kg of nebulized nSta, the manifestations of ALI were completely eliminated. A significant dose-dependent reduction of the fibrin-positive areas in the lungs of mice with ALI was established. Nebulized nSta had a normalizing effect on the proinflammatory cytokines in blood- interleukin (IL)-1α, IL-17A, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These data showed the effectiveness of nebulized nSta and the perspectives of its clinical usage in COVID-19 patients with acute respiratory distress syndrome (ARDS).


Тема - темы
Acute Lung Injury , COVID-19 , Respiratory Distress Syndrome , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Animals , Disease Models, Animal , Fibrin/pharmacology , Fibrinogen/therapeutic use , Lipopolysaccharides/toxicity , Lung , Metalloendopeptidases , Mice , Rats , Respiratory Distress Syndrome/drug therapy
20.
FASEB J ; 36(9): e22494, 2022 09.
Статья в английский | MEDLINE | ID: covidwho-1997082

Реферат

In a rat middle cerebral artery occlusion (MACo) model of ischemic stroke, intracerebroventricular administration of human recombinant hepatocyte growth factor (HGF) mitigated motor impairment and cortical infarction. Recombinant HGF reduced MCAo-induced TNFα and IL1ß expression, and alleviated perilesional reactivation of microglia and astrocyte. All of the aforementioned beneficial effects of HGF were antagonized by an inhibitor to the type II transmembrane serine protease matriptase (MTP). MCAo upregulated MTP mRNA and protein in the lesioned cortex. MTP protein, not the mRNA, was increased further by recombinant HGF but reduced when MTP inhibitor (MTPi) was added to the treatment. Changes of the endogenous active HGF by MCAo, HGF or MTPi paralleled with the changes of MTP protein under the same conditions whilst neither HGF mRNA nor the total endogenous HGF protein were altered. These data showed that the therapeutic effects of HGF in stroke brain is attributed to its proteolytic activation and that MTP is a main protease of the event. MCAo enhanced MTP mRNA and thus protein expression; the initial use of the recombinant active HGF stabilized MCAo-induced MTP protein and subsequent activation of endogenous latent HGF which in turn stabilized further MTP protein. A reciprocal regulation between MTP and HGF appears to be present where MTP promotes HGF activation and the active HGF prevents MTP protein turnover. This study, for the first time, shows that MTP can participate in neural protection in stroke brain through activation of HGF. The cycles of HGF-MTP regulation achieved preservation of the neurological activity.


Тема - темы
Hepatocyte Growth Factor , Stroke , Animals , Brain/metabolism , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/metabolism , Humans , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Neuroprotection , RNA, Messenger/metabolism , Rats , Serine Endopeptidases , Serine Proteases/metabolism , Stroke/metabolism
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