77 research outputs found

    Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

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    <p>Abstract</p> <p>Background</p> <p>Alpha-1 antitrypsin (AAT) is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT) gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD) mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA).</p> <p>Methods</p> <p>DBA/1 mice were immunized with bovine type II collagen (bCII) to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT). Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF), antibodies against both bovine (bCII) and mouse collagen II (mCII) were tested by ELISA.</p> <p>Results</p> <p>Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8)-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially.</p> <p>Conclusion</p> <p>These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.</p

    The protective effects of plasma gelsolin on stroke outcome in rats

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    <p>Abstract</p> <p>Background</p> <p>To date, recombinant tissue plasminogen activator (rtPA) is the only approved drug for ischemic stroke. It is intravenously administered functioning as a thrombolytic agent and is used to obtain reperfusion of the affected area of the brain. Excitotoxicity, inflammation and apoptosis are all involved in delayed neuronal death following stroke and offer multiple opportunities to intervene with neuroprotective agents. Gelsolin (GSN) is an actin- and calcium-binding protein mediating the disassembly of actin filaments and activity of calcium channels. It also functions as a regulator of apoptosis and inflammatory responses. This study tests the hypothesis that increasing the concentration of the form of GSN known as plasma GSN (pGSN) near an infarct will provide neuroprotection following ischemic stroke.</p> <p>Methods</p> <p>We induced middle cerebral artery occlusion (MCAO) in male rats via intracranial injection of endothelin-1 (ET-1), a potent vasoconstrictor, and then treated with local delivery of pGSN. Whole brain laser Doppler perfusion imaging was performed through the skull to assess MCAO effectiveness. Cylinder and vibrissae tests evaluated sensorimotor function before and 72 h after MCAO. Infarct volumes were examined 72 h after MCAO via 2, 3, 5-triphenyltetrazolium chloride (TTC) assay.</p> <p>Results</p> <p>Estimates of relative cerebral perfusion were significantly decreased in all groups receiving MCAO with no differences detected between treatments. Despite equivalent initial strokes, the infarct volume of the pGSN treatment group was significantly reduced compared with the untreated MCAO rats at 72 h. ET-1 induced significant deficits in both cylinder and vibrissae tests while pGSN significantly limited these deficits.</p> <p>Conclusion</p> <p>Gelsolin could be a promising drug for protection against neurodegeneration following ischemic stroke.</p

    The under-appreciated world of the serpin family of serine proteinase inhibitors

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    In the practice of medicine, many fundamental biological pathways that require tight on/off control, such as inflammation and circulatory homeostasis, are regulated by serine proteinases, but we rarely consider the unique protease inhibitors that, in turn, regulate these proteases. The serpins are a family of proteins with a shared tertiary structure, whose members largely act as serine protease inhibitors, found in all forms of life, ranging from viruses, bacteria, and archaea to plants and animals. These proteins represent up to 2-10% of proteins in the human blood and are the third most common protein family

    The Effect of DNA-Dependent Protein Kinase on Adeno-Associated Virus Replication

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    BACKGROUND: DNA-dependent protein kinase (DNA-PK) is a DNA repair enzyme and plays an important role in determining the molecular fate of the rAAV genome. However, the effect this cellular enzyme on rAAV DNA replication remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we characterized the roles of DNA-PK on recombinant adeno-associated virus DNA replication. Inhibition of DNA-PK by a DNA-PK inhibitor or siRNA targeting DNA-PKcs significantly decreased replication of AAV in MO59K and 293 cells. Southern blot analysis showed that replicated rAAV DNA formed head-to-head or tail-to-tail junctions. The head-to-tail junction was low or undetectable suggesting AAV-ITR self-priming is the major mechanism for rAAV DNA replication. In an in vitro replication assay, anti-Ku80 antibody strongly inhibited rAAV replication, while anti-Ku70 antibody moderately decreased rAAV replication. Similarly, when Ku heterodimer (Ku70/80) was depleted, less replicated rAAV DNA were detected. Finally, we showed that AAV-ITRs directly interacted with Ku proteins. CONCLUSION/SIGNIFICANCE: Collectively, our results showed that that DNA-PK enhances rAAV replication through the interaction of Ku proteins and AAV-ITRs

    Boosting Oxygen Electrocatalysis by Combining Iron Nanoparticles with Single Atoms

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    The development of high-performance non-noble metal-based oxygen electrocatalysts is crucial for the practical application of zinc–air batteries. Most of them suffer from low intrinsic activity and poor stability, failing to meet the needs of practical applications. Here, we report an efficient and durable bifunctional oxygen electrocatalyst of Fe@Fe-SAC composite (SAC stands for single atoms on carbon). A facile and ease-to-scale-up process synthesizes it. Fe single-atom and Fe nanoparticles are anchored on nitrogen-doped porous carbon, with the latter encapsulated by the graphitic shell. It exhibits appealing activity and durability in a basic electrolyte, requiring a half-wave potential of 0.805 V for oxygen reduction reaction (ORR) and an overpotential of only 348 mV to deliver a current density of 10 mA cm−2 for oxygen evolution reaction (OER). Both activities are comparable to the corresponding benchmarking electrocatalyst of Pt/C for ORR and IrO2 for OER. The superior activities are attributed to the strong electronic interaction between metal single-atom and nanoparticles. The favorable stability is ascribed to the physical encapsulation of carbon coatings on nanoparticles. This work presents a feasible scheme for designing and large-scale preparation of high-performance non-noble metal-based bifunctional oxygen electrocatalysts

    Boosting Oxygen Electrocatalysis by Combining Iron Nanoparticles with Single Atoms

    No full text
    The development of high-performance non-noble metal-based oxygen electrocatalysts is crucial for the practical application of zinc–air batteries. Most of them suffer from low intrinsic activity and poor stability, failing to meet the needs of practical applications. Here, we report an efficient and durable bifunctional oxygen electrocatalyst of Fe@Fe-SAC composite (SAC stands for single atoms on carbon). A facile and ease-to-scale-up process synthesizes it. Fe single-atom and Fe nanoparticles are anchored on nitrogen-doped porous carbon, with the latter encapsulated by the graphitic shell. It exhibits appealing activity and durability in a basic electrolyte, requiring a half-wave potential of 0.805 V for oxygen reduction reaction (ORR) and an overpotential of only 348 mV to deliver a current density of 10 mA cm−2 for oxygen evolution reaction (OER). Both activities are comparable to the corresponding benchmarking electrocatalyst of Pt/C for ORR and IrO2 for OER. The superior activities are attributed to the strong electronic interaction between metal single-atom and nanoparticles. The favorable stability is ascribed to the physical encapsulation of carbon coatings on nanoparticles. This work presents a feasible scheme for designing and large-scale preparation of high-performance non-noble metal-based bifunctional oxygen electrocatalysts

    The Prevalence, Features, Influencing Factors, and Solutions for COVID-19 Vaccine Misinformation: Systematic Review

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    BackgroundDuring the COVID-19 pandemic, infodemic spread even more rapidly than the pandemic itself. The COVID-19 vaccine hesitancy has been prevalent worldwide and hindered pandemic exiting strategies. Misinformation around COVID-19 vaccines is a vital contributor to vaccine hesitancy. However, no evidence systematically summarized COVID-19 vaccine misinformation. ObjectiveThis review aims to synthesize the global evidence on misinformation related to COVID-19 vaccines, including its prevalence, features, influencing factors, impacts, and solutions for combating misinformation. MethodsWe performed a systematic review by searching 5 peer-reviewed databases (PubMed, Embase, Web of Science, Scopus, and EBSCO). We included original articles that investigated misinformation related to COVID-19 vaccines and were published in English from January 1, 2020, to August 18, 2022. We excluded publications that did not cover or focus on COVID-19 vaccine misinformation. The Appraisal tool for Cross-Sectional Studies, version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2), and Critical Appraisal Skills Programme Checklist were used to assess the study quality. The review was guided by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and registered with PROSPERO (CRD42021288929). ResultsOf the 8864 studies identified, 91 observational studies and 11 interventional studies met the inclusion criteria. Misinformation around COVID-19 vaccines covered conspiracy, concerns on vaccine safety and efficacy, no need for vaccines, morality, liberty, and humor. Conspiracy and safety concerns were the most prevalent misinformation. There was a great variation in misinformation prevalence, noted among 2.5%-55.4% in the general population and 6.0%-96.7% in the antivaccine/vaccine hesitant groups from survey-based studies, and in 0.1%-41.3% on general online data and 0.5%-56% on antivaccine/vaccine hesitant data from internet-based studies. Younger age, lower education and economic status, right-wing and conservative ideology, and having psychological problems enhanced beliefs in misinformation. The content, format, and source of misinformation influenced its spread. A 5-step framework was proposed to address vaccine-related misinformation, including identifying misinformation, regulating producers and distributors, cutting production and distribution, supporting target audiences, and disseminating trustworthy information. The debunking messages/videos were found to be effective in several experimental studies. ConclusionsOur review provides comprehensive and up-to-date evidence on COVID-19 vaccine misinformation and helps responses to vaccine infodemic in future pandemics. Trial RegistrationPROSPERO CRD42021288929; https://tinyurl.com/2prejtf
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