ABSTRACT
Neste artigo de opinião, apresento uma breve história do desenvolvimento de vacinas, comentando sobre as formas clássicas de produção de vacinas utilizando o próprio agente infeccioso. Em seguida, abordo as vacinas virais, discutindo seus benefícios e dificuldades e a questão dos sorotipos virais, bem como as vacinas bacterianas e seu relativo sucesso. Apresento nossos estudos sobre doença cardíaca reumática e o desenvolvimento de uma vacina contra infecções estreptocócicas. Também discuto plataformas vacinais, especialmente os sucessos alcançados com vacinas de vetores virais não replicantes e, acima de tudo, o grande êxito das vacinas de RNA mensageiro (mRNA). As vacinas de mRNA tornaram-se possíveis somente após os avanços obtidos com a substituição de nucleotídeos que reduziam a ação da imunidade inata. Serão todas as vacinas desenvolvidas a partir de mRNA no futuro? Em seguida, abordo a questão das vias de administração de vacinas, seja por via subcutânea, intradérmica, intramuscular ou nasal. Exponho dados do meu laboratório sobre o desenvolvimento de uma vacina de instilação nasal que induziu uma resposta de proteção da mucosa, prevenindo a infecção e, consequentemente, a transmissão do SARS-CoV-2. Posteriormente, discuto quais vacinas futuras poderiam ser desenvolvidas para além das doenças infecciosas agudas. Por fim, discuto as vantagens do desenvolvimento de vacinas seguras, eficazes e de uso múltiplo, bem como a forma de torná-las acessíveis à população mundial, promovendo a equidade em saúde.
In this opinion article, I provide a brief history of vaccine development, commenting on the classic ways of producing vaccines using the infectious agent itself. I address viral vaccines, discussing their benefits and challenges and the issue of viral serotypes, as well as bacterial vaccines and their relative success. I present our studies on rheumatic heart disease and the development of a vaccine against streptococcal infection. I also discuss vaccine platforms, highlighting the success achieved with non-replicating viral vector-based vaccines and, especially, with messenger RNA (mRNA) vaccines. mRNA vaccines only became possible after the advances provided by the replacement of nucleotides that reduced the action of the innate immune system. Will all vaccines be made from mRNA in the future? Then, I address the issue of vaccine administration routes, whether subcutaneously, intradermally, intramuscularly, or intranasal. I present data from my laboratory on the development of an intranasal vaccine that induced a protective mucosal response, preventing infection and, consequently, the transmission of SARSCoV- 2. I discuss which future vaccines could be developed beyond acute infectious diseases. Finally, I discuss the advantages of developing safe, effective, multiple-use vaccines and how to make them accessible worldwide by promoting health equity.
Subject(s)
Humans , History, 21st CenturyABSTRACT
Abstract MCH1 is a synthetic macamide that has shown in vitro inhibitory activity on fatty acid amide hydrolase (FAAH), an enzyme responsible for endocannabinoid metabolism. This inhibition can modulate endocannabinoid and dopamine signaling in the nucleus accumbens (NAc), potentially having an antidepressant-like effect. The present study aimed to evaluate the effect of the in vivo administration of MCH1 (3, 10, and 30 mg/kg, ip) in 2-month-old BALB/c male mice (n=97) on forced swimming test (FST), light-dark box (LDB), and open field test (OFT) and on early gene expression changes 2 h after drug injection related to the endocannabinoid system (Cnr1 and Faah) and dopaminergic signaling (Drd1 and Drd2) in the NAc core. We found that the 10 mg/kg MCH1 dose reduced the immobility time compared to the vehicle group in the FST with no effect on anxiety-like behaviors measured in the LDB or OFT. However, a 10 mg/kg MCH1 dose increased locomotor activity in the OFT compared to the vehicle. Moreover, RT-qPCR results showed that the 30 mg/kg MCH1 dose increased Faah gene expression by 2.8-fold, and 10 mg/kg MCH1 increased the Cnr1 gene expression by 4.3-fold compared to the vehicle. No changes were observed in the expression of the Drd1 and Drd2 genes in the NAc at either MCH1 dose. These results indicated that MCH1 might have an antidepressant-like effect without an anxiogenic effect and induces significant changes in endocannabinoid-related genes but not in genes of the dopaminergic signaling system in the NAc of mice.
ABSTRACT
La infección por el virus SARS-CoV-2, conocida como COVID-19, ha causado alta morbilidad y mortalidad en el mundo. Después de haber descifrado el código genético del virus y haber desarrollado un gran trabajo investigativo en la creación de vacunas, con diversas estrategias de acción, se ha logrado disminuir la morbi mortalidad. Fue necesario acelerar el proceso de producción de vacunas, lo cual estuvo facilitado por el avanzado conocimiento científico en el campo de la genética y la virología, para brindar a la especie humana una protección eficaz y segura contra la agresiva y progresiva infección. Las vacunas se clasifican de acuerdo con su mecanismo de acción, existen vacunas basadas en vectores virales que no se replican, vacunas recombinantes, otras basadas en virus atenuados y virus inactivos, y (la gran novedad de la ciencia actual) las vacunas basadas en ARN mensajero y ADN. Estas últimas han demostrado una gran eficacia y seguridad en la prevención de la infección por el SARS-CoV-2, también han impactado de manera fuerte, por lo que han reducido la infección y la mortalidad en la población. En consecuencia, cada día que pasa desde que se inició el periodo de vacunación mundial, se evidencia una reducción en la curva de contagio y mortalidad por COVID-19.
The infection produced by the SARS-CoV-2 virus, known as COVID-19, has caused high morbidity and mortality across the world. After having deciphered the virus's genoma and carried out investigative endeavors that led to the creation of a variety of vaccines with different mechanisms of action, it has been possible to decrease the morbidity and mortality associated with the virus. It was necessary to accelerate the vaccine production process, which was facilitated by advanced scientific knowledge within the disciplines of genetics and virology, in order to provide the human species with a safe and effective form of protection against the aggressive and progressive infection. Vaccines are classified differently depending on their action mechanisms: there are some based on non-replicating viral vectors, recombinant vaccines, ones that are based on attenuated or inactivated viruses, and (the greatest novelty of current scientific developments) vaccines based on DNA and messenger RNA. The latter has demonstrated significant efficacy and safety in the prevention of the SARS-CoV-2 infection as observed in preliminary studies, and they have meaningfully impacted the population by reducing the rates of infection and mortality. As a result, decreased levels of spread of and mortality from COVID-19 have been evidenced across the globe following the beginning of the vaccine distribution period.
A infecção pelo vírus SARS-CoV-2, conhecido como COVID-19, tem causado elevada morbidade e mortalidade no mundo. Depois de ter decifrado o código genético do virus e de ter realizado um grande trabalho de investigação na criação de vacinas, com diversas estratégias de ação, a morbilidade e a mortalidade foram reduzidas. Foi necessário acelerar o processo de produção de vacinas, facilitado por conhecimentos científicos avançados no domínio da genética e da virologia, para proporcionar à espécie humana uma proteção eficaz e segura contra a infecção agressiva e progressiva. As vacinas são classificadas de acordo com seu mecanismo de ação, existem vacinas baseadas em vetores virais que não se replicam, vacinas recombinantes, outras baseadas em virus atenuados e vírus inativos, e (a grande novidade da ciência atual) vacinas baseadas em RNA mensageiro e ADN. Estas últimas demonstraram grande eficácia e segurança na prevenção da infecção por SARS-CoV-2, mas também tiveram um forte impacto, razão pela qual reduziram a infecção e a mortalidade na população. Consequentemente, a cada dia que passa desde o início do período global de vacinação, fica evidente uma redução na curva de contágio e mortalidade por COVID-19.
Subject(s)
HumansABSTRACT
@#Objective To establish and verify a universal and stable potency test method in vitro for SARS-CoV-2 mRNA vaccine,so as to use it for the quality control of SARS-CoV-2 mRNA vaccine.Methods ELISA kits that could bind well to S protein of SARS-CoV-2 variants,as well as transfected cells,cell plating concentrations and doses for transfection were screened,and then a potency test method for SARS-CoV-2 mRNA vaccine in vitro was established and verified.Results An ELISA kit was found with good binding ability to S protein of each variant,and HEK293T cells were determined as the transfection cells,with the plating concentration of 2.5 × 10~5 cells/mL and the transfection dose of 4 μg/well in the 6-well plate.An universal and stable potency test method for SARS-CoV-2 mRNA vaccine in vitro was established.The verification results showed that the method met the quality control needs.Conclusion The established potency test method in vitro for SARS-CoV-2 mRNA vaccine has good relative accuracy,linearity,intermediate precision and range,and can be applied to the quality control of SARS-CoV-2 mRNA vaccines
ABSTRACT
@#mRNA vaccine delivers antigen-encoding mRNA into human cells, which translates into corresponding antigen proteins in cells, and induce effective immune responses. Compared with traditional vaccines, mRNA vaccines have good safety profile, short development cycle, and high immune efficacy, and can stimulate both cellular immune response and humoral immune response. With the development of nucleotide modification technology and delivery technology, mRNA vaccines also have broad application prospects. This paper reviews mRNA technology and its application in vaccines, in the hope of offering theoretical and practical insights to researchers engaged or to be engaged in the development of mRNA vaccines.
ABSTRACT
Objective To construct a universal influenza mRNA vaccine and evaluate its immunogenicity.Methods The antigen sequence of hemagglutinin(HA),nucleoprotein(NP)and matrix protein 2 ectodomain(M2e)in influenza A/California/04/2009 was optimized.HA,NP and 3 tandem M2e(3M2e)were cloned into pcDNA3.1 vector,respectively.Then the mRNAs were synthesized by linearization,in vitro transcription,enzymatic capping and enzymatic tailing,and named as mRNA-HA,mRNA-NP and mRNA-3M2e,respectively.The protein expression of the 3 kinds of mRNAs in 293T cells was detected by immunofluorescence assay.Comb-mRNA vaccine was prepared by enveloped mRNA-HA,mRNA-NP and mRNA-3M2e with lipid nanoparticles,respectively,and the particle size and potential were identified.Twenty-eight 6-week-old female BALB/c mice(18～22 g)were randomly divided into LNP group(n=14)and Comb-mRNA group(n=14).Hemagglutination inhibition(HI)method and microneutralization(MN)test were used to evaluate the serum antibody titer induced by Comb-mRNA vaccines.The mice were infected by 5LD50 wild-type H1 N1 influenza virus to evaluate the protective efficacy.Results The mRNA-HA,mRNA-NP and mRNA-3M2e were successfully constructed,and the 3 mRNAs could be expressed in 293T cells.The average size of mRNA encapsulated by lipid nanoparticles was 119.53±6.5 nm,and the average potential was-8.23±1.3 mV.The geometric mean titer(GMT)of HI and MN in the Comb-mRNA group were 179.6 and 201.6,compared with the LNP group.The ratio of IFN-γ+CD4+/CD8+Tcells was increased.The Comb-mRNA group could provide protection against 5LD50 wild type influenza H1 N1 virus after 2 weeks of booster immunization.Conclusion Comb-mRNA,an influenza vaccine candidate,can induce immune responses and protect mice from influenza virus challenge.
ABSTRACT
ObjectiveTo illustrate the mechanism of COVID-19 vaccine in the T cell immune response. MethodsBased on the characteristics of T cell and B cell immune response， we matched the data of incubation periods across the SARS-CoV-2 prototype strain， Delta variants， and Omicron variants and effectiveness of mRNA and inactivated COVID-19 vaccines for analysis. ResultsThe effectiveness of mRNA COVID-19 vaccine against infection and onset was consistent with incubation period principally being ≥5 days. In contrast， the effectiveness of inactivated COVID-19 vaccine was consistent with incubation period principally being ≥8 days. ConclusionIt may be interpreted by faster T cell immune response stimulated by mRNA vaccine， compared to B cell immune response byinactivated vaccine.
ABSTRACT
Objective@#To analyse the expression of differential mRNA in the plasma exosomes in patients with latent tuberculosis infection (LTBI) and active tuberculosis (ATB) using high-throughput sequencing, so as to provide insights into differential diagnosis of LTBI and ATB.@*Methods@#The plasma samples were collected from the patients treated at The Affiliated Hospital of Hangzhou Normal University, including 16 cases of LTBI and 21 cases of ATB. The exosomes were extracted by Invitrogen extracellular extracts purification kit, and the size and morphology of exosomes were observed by transmission electron microscope (TEM). The exosomes were identified by Western blotting. Total RNA was extracted from plasma exosomes using high-throughput sequencing, differential expression mRNA was identified, and gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Two differential mRNAs with the highest differential expression fold were selected, and five patients with ATB and three patients with LTBI were recruited for verification using real-time quantitative PCR.@*Results@#The sequencing results of plasma exosomes showed that compared with ATB patients, 2 875 differentially expressed mRNAs were detected in exosomes of LTBI patients, of which 1 002 mRNAs were up-regulated and 1 873 mRNAs were down-regulated. The most significant differentially expressed downregulated and upregulated mRNA were M6PR and RGPD5, respectively. GO analysis and KEGG pathway analysis showed that differential mRNAs were enriched in protein serine kinase activity, rRNA binding molecular function, human cytomegalovirus infection, pancreatic cancer, endometrial cancer, insulin signaling pathway and FoxO signaling pathway. The real-time quantitative PCR showed that the expression of differential mRNA was consistent with sequencing. Compared with ATB patients, the relative expression level of M6PR in plasma exosomes in LTBI patients (0.954±0.212) was downregulated compared with that of ATB patients (2.168±0.226), while the relative expression level of RGPD5 (2.126±0.200) was upregulated compared with that of ATB patients (0.588±0.129) (both P<0.05).@*Conclusions@#There is a difference in mRNA expression of plasma exosomes between patients with LTBI and ATB. M6PR and RGPD5 may become markers for distinguishing plasma exosomes between LTBI and ATB.
ABSTRACT
@#Objective To establish and verify a universal and stable potency test method in vitro for SARS-CoV-2 mRNA vaccine,so as to use it for the quality control of SARS-CoV-2 mRNA vaccine.Methods ELISA kits that could bind well to S protein of SARS-CoV-2 variants,as well as transfected cells,cell plating concentrations and doses for transfection were screened,and then a potency test method for SARS-CoV-2 mRNA vaccine in vitro was established and verified.Results An ELISA kit was found with good binding ability to S protein of each variant,and HEK293T cells were determined as the transfection cells,with the plating concentration of 2.5 × 10~5 cells/mL and the transfection dose of 4 μg/well in the 6-well plate.An universal and stable potency test method for SARS-CoV-2 mRNA vaccine in vitro was established.The verification results showed that the method met the quality control needs.Conclusion The established potency test method in vitro for SARS-CoV-2 mRNA vaccine has good relative accuracy,linearity,intermediate precision and range,and can be applied to the quality control of SARS-CoV-2 mRNA vaccines.
ABSTRACT
Aim To screen and study the expression of long non-coding RNA (IncRNA) in rats with middle cerebral artery occlusion (MCAO) with MCAO treated with Tao Hong Si Wu decoction (THSWD) and determine the possible molecular mechanism of THSWD in treating MCAO rats. Methods Three cerebral hemisphere tissue were obtained from the control group, MCAO group and MCAO + THSWD group. RNA sequencing technology was used to identify IncRNA gene expression in the three groups. THSWD-regulated IncRNA genes were identified, and then a THSWD-regu-lated IncRNA-mRNA network was constructed. MCODE plug-in units were used to identify the modules of IncRNA-mRNA networks. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) were used to analyze the enriched biological functions and signaling pathways. Cis- and trans-regulatory genes for THSWD-regulated IncRNAs were identified. Reverse transcription real-time quantitative pol-ymerase chain reaction (RT-qPCR) was used to verify IncRNAs. Molecular docking was used to identify IncRNA-mRNA network targets and pathway-associated proteins. Results In MCAO rats, THSWD regulated a total of 302 IncRNAs. Bioinformatics analysis suggested that some core IncRNAs might play an important role in the treatment of MCAO rats with THSWD, and we further found that THSWD might also treat MCAO rats through multiple pathways such as IncRNA-mRNA network and network-enriched complement and coagulation cascades. The results of molecular docking showed that the active compounds gallic acid and a-mygdalin of THSWD had a certain binding ability to protein targets. Conclusions THSWD can protect the brain injury of MCAO rats through IncRNA, which may provide new insights for the treatment of ischemic stroke with THSWD.
ABSTRACT
ABSTRACT Objective: Recent studies have shown a relationship between adipose tissue and coronary artery disease (CAD). The ABCA1 transporter regulates cellular cholesterol content and reverses cholesterol transport. The aim of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) R230C, C-17G, and C-69T and their expression in epicardial and mediastinal adipose tissue in Mexican patients with CAD. Subjects and methods: The study included 71 patients with CAD and a control group consisting of 64 patients who underwent heart valve replacement. SNPs were determined using TaqMan probes. mRNA was extracted using TriPure Isolation from epicardial and mediastinal adipose tissue. Quantification and expression analyses were done using RT-qPCR. Results: R230C showed a higher frequency of the GG genotype in the CAD group (70.4%) than the control group (57.8%) [OR 0.34, 95% CI (0.14-0.82) p = 0.014]. Similarly, C-17G (rs2740483) showed a statistically significant difference in the CC genotype in the CAD group (63.3%) in comparison to the controls (28.1%) [OR 4.42, 95% CI (2.13-9.16), p = 0.001]. mRNA expression in SNP R230C showed statistically significant overexpression in the AA genotype compared to the GG genotype in CAD patients [11.01 (4.31-15.24) vs. 3.86 (2.47-12.50), p = 0.015]. Conclusion: The results suggest that the GG genotype of R230C and CC genotype of C-17G are strongly associated with the development of CAD in Mexican patients. In addition, under-expression of mRNA in the GG genotype in R230C is associated with patients undergoing revascularization.
ABSTRACT
ABSTRACT Purpose: To evaluate macular chorioretinal flow changes on optical coherence tomography angiography, in participants who received inactivated and messenger RNA (mRNA) vaccines to prevent coronavirus disease 2019 (COVID-19). Methods: In this prospective cohort study, healthy participants who received two doses of an inactivated COVID-19 vaccine (CoronaVac) and then one dose of an mRNA vaccine (BNT162b2) were examined before and after each vaccination. Ophthalmologic examination and imaging with optical coherence tomography angiography were performed during each visit. We evaluated vascular densities in the superficial and deep capillary plexuses in foveal, parafoveal, and perifoveal areas; the foveal avascular zone; and choriocapillaris flows (in 1- and 6-mm-diameter areas). Results: One eye in each of the 24 participants was assessed. Superficial capillary plexus vascular densities in the parafoveal area were significantly lower after the second dose of the CoronaVac vaccine than after the first dose. In the deep capillary plexus, vascular attenuation was observed only in the parafoveal region after the first CoronaVac dose. However, in all regions, the deep capillary plexus vascular densities and subfoveal choriocapillaris flow were significantly decreased after the second CoronaVac dose. After the BNT162b2 dose, the superficial capillary plexus vascular densities, the deep capillary plexus vascular densities, and subfoveal choriocapillaris flow of most regions were significantly lower than those before vaccinations. Conclusion: Vascular attenuation, observed particularly after the second dose of the CoronaVac vaccine, may explain the pathogenesis of postvaccine ocular ischemic disorders reported in the literature. However, these disorders are extremely rare, and the incidence of thrombotic events caused by COVID-19 itself is higher.
ABSTRACT
Abstract Objective To compare the effectiveness and safety of non-mRNA versus mRNA COVID-19 vaccines on pregnant women and their newborns in a systematic review with meta-analysis. Data sources We searched PubMed, Embase, and Cochrane Central in May 2023. Study selection The search strategy yielded 4451 results, 16 studies were fully reviewed. We selected case-control studies analysing non-mRNA versus mRNA vaccines. Data collection and analysis: we assessed the risk of bias using the Cochrane Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. Standardised mean differences were pooled using random-effect models. Data synthesis We identified 8 prospective and retrospective studies with a total of 32,153 patients. Non-mRNA vaccines were associated with a higher incidence of fever (OR 2.67; 95% CI 2.08-3.43; p<0.001), and a lower incidence of fetal or neonatal death (OR 0.16; 95% CI 0.08-0.33; p<0.001). In subgroup analyses, the Jansen vaccine (Ad26.COV2.S) was found to have a higher rate of premature labor/delivery (OR 4.48; 95% CI 1.45-13.83; p=0.009) and missed/spontaneous abortion (OR 1.90; 95% CI 1.09-3.30; p=0.02), as compared with the Pfizer (BNT162b2) vaccine. Conclusion non-mRNA vaccines are associated with a lower incidence of fetal or neonatal death among pregnant women who receive a Covid19 vaccine, although at an increased rate of pyrexia compared with mRNA vaccines. Other studies are required for better assessment. PROSPERO CRD42023421814
ABSTRACT
Los niños cursan mayormente la infección por el virus SARS-CoV-2 en forma leve. Sin embargo, de forma muy infrecuente algunos pueden desarrollar una patología con marcada gravedad denominada síndrome inflamatorio multisistémico en niños relacionado temporalmente con COVID-19 (SIM-C). Dado su reciente surgimiento, aún hay aspectos de su fisiopatología que se desconocen. La posibilidad de recidiva en caso de reinfección o ante la vacunación contra SARS-CoV-2 son nuevos interrogantes a los que nos enfrentamos. Reportamos una serie de casos de 4 pacientes adolescentes que cursaron SIM-C y meses después han sido vacunados contra SARS-CoV-2 con plataformas ARN mensajero (ARNm) sin presentar recurrencia de la enfermedad ni efectos adversos cardiológicos
In most cases, children with SARS-CoV-2 have a mild infection. However, very rarely, some children may develop a severe disease called multisystem inflammatory syndrome in children temporally associated with COVID-19 (MIS-C). Given its recent emergence, some aspects of its pathophysiology are still unknown. The possibility of recurrence in case of reinfection or SARS-CoV-2 vaccination are new questions we are facing. Here we report a case series of 4 adolescent patients who developed MIS-C and, months later, received the SARS-CoV-2 vaccine with messenger RNA (mRNA) platforms without disease recurrence or cardiac adverse events.
Subject(s)
Humans , Male , Female , Adolescent , COVID-19 Vaccines/administration & dosage , COVID-19/complications , COVID-19/prevention & control , Vaccination , SARS-CoV-2 , mRNA Vaccines/administration & dosageABSTRACT
Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy. The first monoclonal antibody authorized for treating human epidermal growth receptor 2 (HER2)-positive breast cancer is trastuzumab. However, resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes. To address this issue, tumor microenvironment (TME) pH-responsive nanoparticles (NPs) were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer (BCa). This nanoplatform is comprised of a methoxyl-poly (ethylene glycol)-b-poly (lactic-co-glycolic acid) copolymer with a TME pH-liable linker (Meo-PEG-Dlink m -PLGA) and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction. When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously, they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface. With the intracellular mRNA release to up-regulate PTEN expression, the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells, thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.
ABSTRACT
Lipid-formulated RNA vaccines have been widely used for disease prevention and treatment, yet their mechanism of action and individual components contributing to such actions remain to be delineated. Here, we show that a therapeutic cancer vaccine composed of a protamine/mRNA core and a lipid shell is highly potent in promoting cytotoxic CD8+ T cell responses and mediating anti-tumor immunity. Mechanistically, both the mRNA core and lipid shell are needed to fully stimulate the expression of type I interferons and inflammatory cytokines in dendritic cells. Stimulation of interferon-β expression is exclusively dependent on STING, and antitumor activity from the mRNA vaccine is significantly compromised in mice with a defective Sting gene. Thus, the mRNA vaccine elicits STING-dependent antitumor immunity.
ABSTRACT
The extraordinary advantages associated with mRNA vaccines, including their high efficiency, relatively low severity of side effects, and ease of manufacture, have enabled them to be a promising immunotherapy approach against various infectious diseases and cancers. Nevertheless, most mRNA delivery carriers have many disadvantages, such as high toxicity, poor biocompatibility, and low efficiency in vivo, which have hindered the widespread use of mRNA vaccines. To further characterize and solve these problems and develop a new type of safe and efficient mRNA delivery carrier, a negatively charged SA@DOTAP-mRNA nanovaccine was prepared in this study by coating DOTAP-mRNA with the natural anionic polymer sodium alginate (SA). Intriguingly, the transfection efficiency of SA@DOTAP-mRNA was significantly higher than that of DOTAP-mRNA, which was not due to the increase in cellular uptake but was associated with changes in the endocytosis pathway and the strong lysosome escape ability of SA@DOTAP-mRNA. In addition, we found that SA significantly increased the expression of LUC-mRNA in mice and achieved certain spleen targeting. Finally, we confirmed that SA@DOTAP-mRNA had a stronger antigen-presenting ability in E. G7-OVA tumor-bearing mice, dramatically inducing the proliferation of OVA-specific CLTs and ameliorating the antitumor effect. Therefore, we firmly believe that the coating strategy applied to cationic liposome/mRNA complexes is of potential research value in the field of mRNA delivery and has promising clinical application prospects.
ABSTRACT
We summarize the most important advances in RNA delivery and nanomedicine. We describe lipid nanoparticle-based RNA therapeutics and the impacts on the development of novel drugs. The fundamental properties of the key RNA members are described. We introduced recent advances in the nanoparticles to deliver RNA to defined targets, with a focus on lipid nanoparticles (LNPs). We review recent advances in biomedical therapy based on RNA drug delivery and state-of-the-art RNA application platforms, including the treatment of different types of cancer. This review presents an overview of current LNPs based RNA therapies in cancer treatment and provides deep insight into the development of future nanomedicines sophisticatedly combining the unparalleled functions of RNA therapeutics and nanotechnology.
ABSTRACT
@#Type 2 diabetes mellitus(T2DM)was a chronic,non-communicable disease with a combination of multiple genetic and environmental factors,of which the main characteristics included insufficient insulin secretion and insulin resistance.Insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2/IMP2),an important insulin secretion-related protein in human body,is mainly expressed in tissues and cells such as pancreas,fat and intestine.It has been confirmed that IGF2BP2 can down-regulate the expression of IGF2 and the function damage of the related islet β cell is an important cause of T2DM and vascular complications.Therefore,IGF2BP2 gene can be used as an important predictor for diabetes mellitus risk.This paper reviews the correlation between IGF2BP2 gene and T2DM.
ABSTRACT
OBJECTIVE To study the mechanism of interfering with long non-coding RNA nicotinamide nucleotide transhydrogenase-antisense RNA1 （LncRNA NNT-AS1） expressing to reduce paclitaxel （TAX） resistance in non-small cell lung cancer （NSCLC） cells. METHODS NSCLC TAX-resistant cell line （A549/TAX） was constructed， and the expressions of LncRNA NNT-AS1 in normal， parental， and drug-resistant cells were observed. The targeting relationship of microRNA-582-5p （miR-582- 5p） with LncRNA NNT-AS1 and high mobility group box2 （HMGB2） was verified. A549/TAX cells were cultured in vitro to observe the effects of interfering with LncRNA NNT-AS1 alone or interfering with LncRNA NNT-AS1 and miR-582-5p on the expressions of LncRNA NNT-AS1 and miR-582-5p， the mRNA and protein expressions of HMGB2， cell viability， clone formation and apoptosis. The effects of interfering with LncRNA NNT-AS1 on tumor growth and the expression of miR-582-5p and the mRNA and protein expressions of HMGB2 in tumor tissue were observed in nude mice. RESULTS Compared with normal cells， LncRNA NNT-AS1 was highly expressed in parental and drug-resistant cells （P＜0.05）， showing an increasing trend. It was validated that miR-582-5p had a targeting relationship with LncRNA NNT-AS1 and HMGB2. After interfering with the expression of LncRNA NNT-AS1， the expression of LncRNA NNT-AS1 and the mRNA and protein expressions of HMGB2， cell viability and the number of cloned cells in A549/TAX cell， decreased significantly， while the expression of miR-582-5p and the apoptotic rate increased significantly （P＜0.05）； simultaneously interfering with the expression of miR-582-5p could reverse above changes （P＜ 0.05）. Interfering with the expression of LncRNA NNT-AS1 in tumor cell could significantly reduce tumor volume and tumor weight of nude mice bearing tumors； at the same time， the expression of miR-582-5p was up-regulated significantly and the mRNA and protein expressions of HMGB2 were down-regulated significantly （P＜0.05）. CONCLUSIONS Interfering with the expression of LncRNA NNT-AS1 may alleviate TAX chemotherapy resistance in NSCLC through targeted up-regulation of miR-582-5p and down-regulation of HMGB2.