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1.
Viruses ; 16(10)2024 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-39459934

RESUMO

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus, the cause of genital herpes, and its infection can increase the risk of HIV-1 infection. After initial infection, HSV-2 can establish lifelong latency within the nervous system, which is likely associated with the virus-mediated immune evasion. In this study, we found that HSV-2 UL24 significantly inhibited the activation of the IFN-ß promoter and the production of IFN-ß at both mRNA and protein levels. Of importance, the inhibitory effect of HSV-2 on IFN-ß production was significantly impaired in the context of HSV-2 infection when UL24 was knocked down. Additional studies revealed that, although the full-length HSV-2 UL24 affected cell cycle and viability to some extent, its N-terminal 1-202AA domain showed no obvious cytotoxicity while its C-terminal 201-281 AA domain had a minimal impact on cell viability. Further studies showed that the N-terminal 1-202 AA domain of HSV-2 UL24 (HSV-2 UL24-N) was the main functional region responsible for the inhibition of IFN-ß production mediated by HSV-2 UL24. This domain significantly suppressed the activity of RIG-IN, MAVS, TBK-1, IKK-ε, or the IRF-3/5D-activated IFN-ß promoter. Mechanistically, HSV-2 UL24-N suppressed IRF-3 phosphorylation, resulting in the inhibition of IFN-ß production. The findings of this study highlight the significance of HSV-2 UL24 in inhibiting IFN-ß production, revealing two potential roles of UL24 during HSV-2 infection: facilitating immune evasion and inducing cell cycle arrest.


Assuntos
Herpesvirus Humano 2 , Fator Regulador 3 de Interferon , Interferon beta , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 2/fisiologia , Interferon beta/metabolismo , Interferon beta/genética , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 3 de Interferon/genética , Humanos , Fosforilação , Proteínas Virais/metabolismo , Proteínas Virais/genética , Regiões Promotoras Genéticas , Evasão da Resposta Imune , Animais , Transdução de Sinais , Células HEK293 , Chlorocebus aethiops , Linhagem Celular , Interações Hospedeiro-Patógeno , Células Vero
2.
BMC Emerg Med ; 24(1): 174, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39333918

RESUMO

BACKGROUND: Rapid sequence intubation (RSI) is a crucial step in the resuscitation process for critically ill patients, and the judicious use of sedative drugs during RSI significantly influences the clinical outcomes of patients. Ketamine is a commonly used anesthetic sedative; however, its impact on the mortality of patients undergoing RSI has yielded inconsistent findings. Therefore, we conducted a systematic review and meta-analysis investigating ketamine's role in RSI to provide insights into selecting appropriate sedatives for critically ill patients. METHODS: In this systematic review and meta-analysis, we conducted a systematic search on MEDLINE (PubMed), Embase, and Cochrane Central Register of Controlled Trials, without restricting to randomized controlled trials (RCTs) or cohort studies. The search was performed from inception until Dec 12, 2023, with no language restrictions. All studies comparing the use of sedatives, including ketamine, and documenting in-hospital mortality were included in this study. RESULTS: A total of 991 studies were identified, out of which 15 studies (5 RCTs and 10 cohort studies) involving 16,807 participants fulfilled the inclusion criteria. No significant impact on in-hospital mortality was observed with the use of ketamine compared to other drugs during RSI (OR 0.90, 95%CI 0.72 to 1.12). Low-quality evidence suggested that ketamine might reduce mortality within the first seven days of hospitalization (OR 0.42, 95%CI 0.19 to 0.93), but it may also have a potential effect on prolonging ICU-free days at day 28 (MD -0.71, 95%CI -1.38 to -0.05). There were no significant differences in the results of the other RSI-related outcomes, such as physiological function and adverse events. CONCLUSIONS: Based on existing studies, ketamine showed no significant difference compared to other sedatives in terms of in-hospital mortality, physiological impact, and side effects following RSI. However, it may reduce mortality within 7 days while probably prolong the length of stay in the ICU. TRIAL REGISTRATION: CRD42023478020.


Assuntos
Ketamina , Indução e Intubação de Sequência Rápida , Humanos , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/efeitos adversos , Estado Terminal , Mortalidade Hospitalar , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Indução e Intubação de Sequência Rápida/efeitos adversos , Indução e Intubação de Sequência Rápida/métodos
3.
Nat Commun ; 15(1): 6961, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138183

RESUMO

Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.


Assuntos
Antígenos CD4 , Camelídeos Americanos , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Anticorpos de Domínio Único , HIV-1/imunologia , HIV-1/efeitos dos fármacos , Anticorpos de Domínio Único/farmacologia , Anticorpos de Domínio Único/imunologia , Animais , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Humanos , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Camelídeos Americanos/imunologia , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/farmacologia , Camundongos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Conformação Proteica , Feminino , Internalização do Vírus/efeitos dos fármacos , Células HEK293 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Monoclonais
4.
Basic Clin Pharmacol Toxicol ; 135(2): 180-194, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39004790

RESUMO

BACKGROUND: Various postoperative sedation protocols with different anaesthetics lead to profound effects on the outcomes for post-cardiac surgery patients. However, a comprehensive analysis of optimal postoperative sedation strategies for patients in the intensive care unit (ICU) after cardiac surgery is lacking. METHODS: We systematically searched for randomized controlled trials (RCTs) in databases including PubMed and Embase. The primary outcome measured the duration of mechanical ventilation (MV) in the ICU, and the secondary outcome encompassed the length of stay (LOS) in the ICU and hospital and the monitoring adverse events. RESULTS: The literature included 18 RCTs (1652 patients) with 13 sedation regimens. Dexmedetomidine plus ketamine and sevoflurane were associated with a significantly reduced duration of MV when compared with propofol. Our results also suggested that dexmedetomidine plus ketamine may associated with a shorter LOS in ICU, and sevoflurane associated with a shorter LOS in the hospital, respectively. CONCLUSIONS: The combination of dexmedetomidine and ketamine seems to be a better option for adult patients needing sedation after cardiac surgery, and the incidence of side effects is lower with dexmedetomidine. These findings have potential implications for medication management in the perioperative pharmacotherapy of cardiac surgery patients.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Dexmedetomidina , Hipnóticos e Sedativos , Ketamina , Tempo de Internação , Respiração Artificial , Sevoflurano , Humanos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Unidades de Terapia Intensiva , Ketamina/administração & dosagem , Metanálise em Rede , Cuidados Pós-Operatórios/métodos , Propofol/administração & dosagem , Propofol/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sevoflurano/administração & dosagem
5.
Small ; 20(42): e2402482, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38855997

RESUMO

Hydrogel as a solar evaporator shows great potential in freshwater production. However, hydrogels often lead to an imbalance between solar energy input and water supply management due to their excessively high saturated water content. Thus, achieving a stable water-energy-balance in hydrogel evaporators remains challenging. Here, by tortuosity engineering designed water transport channels, a seamless high-tortuosity/low-tortuosity/high-tortuosity structured hydrogel (SHLH structure hydrogel) evaporator is developed, which enables the hydrogel with customized water transport rate, leading to the controlled water supply at the evaporator interface. An excellent equilibrium between the photothermal conversion and water supply is established, and the maximum utilization of solar energy is realized, thereby achieving an excellent evaporation rate of 3.64 kg m-2 h-1 under one solar illumination. This tortuosity engineering controlled SHLH structured evaporator provides a novel strategy to attain water-energy-balance and expands new approaches for constructing hydrogel-based evaporators with tailored water transportation capacity.

6.
ACS Nano ; 18(27): 17749-17763, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38935412

RESUMO

The rapid development of the SARS-CoV-2 vaccine has been used to prevent the spread of coronavirus 2019 (COVID-19). However, the ongoing and future pandemics caused by SARS-CoV-2 variants and mutations underscore the need for effective vaccines that provide broad-spectrum protection. Here, we developed a nanoparticle vaccine with broad protection against divergent SARS-CoV-2 variants. The corresponding conserved epitopes of the preexisting neutralizing (CePn) antibody were presented on a self-assembling Helicobacter pylori ferritin to generate the CePnF nanoparticle. Intranasal immunization of mice with CePnF nanoparticles induced robust humoral, cellular, and mucosal immune responses and a long-lasting immunity. The CePnF-induced antibodies exhibited cross-reactivity and neutralizing activity against different coronaviruses (CoVs). CePnF vaccination significantly inhibited the replication and pathology of SARS-CoV-2 Delta, WIV04, and Omicron strains in hACE2 transgenic mice and, thus, conferred broad protection against these SARS-CoV-2 variants. Our constructed nanovaccine targeting the conserved epitopes of the preexisting neutralizing antibodies can serve as a promising candidate for a universal SARS-CoV-2 vaccine.


Assuntos
Anticorpos Neutralizantes , Vacinas contra COVID-19 , COVID-19 , Epitopos , Nanopartículas , SARS-CoV-2 , Animais , Anticorpos Neutralizantes/imunologia , SARS-CoV-2/imunologia , Camundongos , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/virologia , Nanopartículas/química , Vacinas contra COVID-19/imunologia , Epitopos/imunologia , Epitopos/química , Humanos , Anticorpos Antivirais/imunologia , Camundongos Transgênicos , Feminino , Camundongos Endogâmicos BALB C , Nanovacinas
7.
PLoS One ; 19(5): e0303469, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38768153

RESUMO

Sepsis-Associated Liver Injury (SALI) is an independent risk factor for death from sepsis. The aim of this study was to develop an interpretable machine learning model for early prediction of 28-day mortality in patients with SALI. Data from the Medical Information Mart for Intensive Care (MIMIC-IV, v2.2, MIMIC-III, v1.4) were used in this study. The study cohort from MIMIC-IV was randomized to the training set (0.7) and the internal validation set (0.3), with MIMIC-III (2001 to 2008) as external validation. The features with more than 20% missing values were deleted and the remaining features were multiple interpolated. Lasso-CV that lasso linear model with iterative fitting along a regularization path in which the best model is selected by cross-validation was used to select important features for model development. Eight machine learning models including Random Forest (RF), Logistic Regression, Decision Tree, Extreme Gradient Boost (XGBoost), K Nearest Neighbor, Support Vector Machine, Generalized Linear Models in which the best model is selected by cross-validation (CV_glmnet), and Linear Discriminant Analysis (LDA) were developed. Shapley additive interpretation (SHAP) was used to improve the interpretability of the optimal model. At last, a total of 1043 patients were included, of whom 710 were from MIMIC-IV and 333 from MIMIC-III. Twenty-four clinically relevant parameters were selected for model construction. For the prediction of 28-day mortality of SALI in the internal validation set, the area under the curve (AUC (95% CI)) of RF was 0.79 (95% CI: 0.73-0.86), and which performed the best. Compared with the traditional disease severity scores including Oxford Acute Severity of Illness Score (OASIS), Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction Score (LODS), Systemic Inflammatory Response Syndrome (SIRS), and Acute Physiology Score III (APS III), RF also had the best performance. SHAP analysis found that Urine output, Charlson Comorbidity Index (CCI), minimal Glasgow Coma Scale (GCS_min), blood urea nitrogen (BUN) and admission_age were the five most important features affecting RF model. Therefore, RF has good predictive ability for 28-day mortality prediction in SALI. Urine output, CCI, GCS_min, BUN and age at admission(admission_age) within 24 h after intensive care unit(ICU) admission contribute significantly to model prediction.


Assuntos
Aprendizado de Máquina , Sepse , Humanos , Sepse/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Hepatopatias/mortalidade , Fatores de Risco , Prognóstico
8.
Mol Ther ; 32(7): 2316-2327, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38734901

RESUMO

HIV-1 infection remains a public health problem with no cure. Although antiretroviral therapy (ART) is effective for suppressing HIV-1 replication, it requires lifelong drug administration due to a stable reservoir of latent proviruses and may cause serious side effects and drive the emergence of drug-resistant HIV-1 variants. Gene therapy represents an alternative approach to overcome the limitations of conventional treatments against HIV-1 infection. In this study, we constructed and investigated the antiviral effects of an HIV-1 Tat-dependent conditionally replicating adenovirus, which selectively replicates and expresses the diphtheria toxin A chain (Tat-CRAds-DTA) in HIV-1-infected cells both in vitro and in vivo. We found that Tat-CRAds-DTA could specifically induce cell death and inhibit virus replication in HIV-1-infected cells mediated by adenovirus proliferation and DTA expression. A low titer of progeny Tat-CRAds-DTA was also detected in HIV-1-infected cells. In addition, Tat-CRAds-DTA showed no apparent cytotoxicity to HIV-1-negative cells and demonstrated significant therapeutic efficacy against HIV-1 infection in a humanized mouse model. The findings in this study highlight the potential of Tat-CRAds-DTA as a new gene therapy for the treatment of HIV-1 infection.


Assuntos
Adenoviridae , Toxina Diftérica , Terapia Genética , Vetores Genéticos , Infecções por HIV , HIV-1 , Replicação Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Humanos , HIV-1/genética , Toxina Diftérica/genética , Animais , Adenoviridae/genética , Infecções por HIV/terapia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Camundongos , Terapia Genética/métodos , Vetores Genéticos/genética , Modelos Animais de Doenças , Linhagem Celular , Células HEK293 , Expressão Gênica , Fragmentos de Peptídeos
9.
Mol Ther ; 32(3): 689-703, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38268188

RESUMO

Passive delivery of antibodies to mucosal sites may be a valuable adjunct to COVID-19 vaccination to prevent infection, treat viral carriage, or block transmission. Neutralizing monoclonal IgG antibodies are already approved for systemic delivery, and several clinical trials have been reported for delivery to mucosal sites where SARS-CoV-2 resides and replicates in early infection. However, secretory IgA may be preferred because the polymeric complex is adapted for the harsh, unstable external mucosal environment. Here, we investigated the feasibility of producing neutralizing monoclonal IgA antibodies against SARS-CoV-2. We engineered two class-switched mAbs that express well as monomeric and secretory IgA (SIgA) variants with high antigen-binding affinities and increased stability in mucosal secretions compared to their IgG counterparts. SIgAs had stronger virus neutralization activities than IgG mAbs and were protective against SARS-CoV-2 infection in an in vivo murine model. Furthermore, SIgA1 can be aerosolized for topical delivery using a mesh nebulizer. Our findings provide a persuasive case for developing recombinant SIgAs for mucosal application as a new tool in the fight against COVID-19.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Animais , Camundongos , Humanos , Imunoglobulina A Secretora , SARS-CoV-2/genética , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Anticorpos Monoclonais , Imunoglobulina G , Anticorpos Antivirais
10.
Food Funct ; 15(2): 794-808, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38131276

RESUMO

Dietary administration is a promising strategy for intervention in non-alcoholic fatty liver disease (NAFLD). Our research team has identified a biologically active component, the panaxadiol saponin component (PDS-C) isolated from total saponins of panax ginseng, which has various pharmacological and therapeutic functions. However, the efficacy and mechanism of PDS-C in NAFLD were unclear. This study aimed to elucidate the hepatoprotective effects and underlying action mechanism of PDS-C in NAFLD. Mice were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD and treated with PDS-C and metformin as the positive control for 12 weeks. PDS-C significantly alleviated liver function, hepatic steatosis and blood lipid levels, reduced oxidative stress and inflammation in NAFLD mice. In vitro, PDS-C has been shown to reduce lipotoxicity and ROS levels while enhancing the antioxidant and anti-inflammatory capabilities in HepG2 cells induced by palmitic acid. PDS-C induced AMPK phosphorylation, leading to upregulation of the Nrf2/HO1 pathway expression and downregulation of the NFκB protein level. Furthermore, our observations indicate that PDS-C supplementation improves insulin resistance and glucose homeostasis in NAFLD mice, although its efficacy is not as pronounced as metformin. In conclusion, these results demonstrate the hepatoprotective efficacy of PDS-C in NAFLD and provide potential opportunities for developing functional products containing PDS-C.


Assuntos
Ginsenosídeos , Metformina , Hepatopatia Gordurosa não Alcoólica , Saponinas , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/metabolismo , Saponinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos
11.
Brain Res ; 1819: 148537, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37591459

RESUMO

BACKGROUND: Depression is one of the most common mental diseases and the leading cause of disability worldwide. A dysfunctional gut microbiota-brain axis is one of the main pathological bases of depression. Irisin, an exercise-related myokine, reduces depression-like behaviors and may guide the relief of depressive symptoms by exercise. However, its underlying mechanism remains unclear. METHODS: Fibronectin type III domain containing 5 (Fndc5)/Irisin was knocked out in male wide-type C57BL/6N mice using CRISPR-cas9. The depression and anxiety symptoms were examined in irisin knockout and control mice with or without chronic unpredictable mild stress by sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Fecal microbiota was assessed by 16S rRNA sequencing and microbiota-related metabolites using liquid chromatography with tandem mass spectrometry. Differential metabolites were analyzed with the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: The knockout mice showed anxiety- and depression-like behaviors and altered diversity and richness of gut microbiota. At the phylum level, these mice had decreased Firmicutes and increased Bacteroidota populations, while at the genus level, they exhibited a low relative abundance of Lactobacillus and Bifidobacterium. Moreover, knocking out of Irisin gene in these mice significantly reduced N-desmethyl-mifepristone (RU 42633) and elevated (-)-stercobilin levels. The KEGG results showed that the microbiota-related metabolites affected by irisin mainly clustered into arginine and proline metabolism and affected the mechanistic target of rapamycin kinase (mTOR) signaling pathway. CONCLUSION: Our findings show that Fndc5/irisin deficiency causes depression in mice by inducing dysbiosis of gut microbiota and changes in microbiota-related metabolites.


Assuntos
Microbioma Gastrointestinal , Animais , Masculino , Camundongos , Depressão/metabolismo , Disbiose , Fibronectinas , Microbioma Gastrointestinal/genética , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S
12.
Vaccines (Basel) ; 11(7)2023 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-37514957

RESUMO

Although conventional vaccine approaches have proven to be successful in preventing infectious diseases in past decades, for vaccine development against emerging/re-emerging viruses, one of the main challenges is rapid response in terms of design and manufacture. mRNA vaccines can be designed and produced within days, representing a powerful approach for developing vaccines. Furthermore, mRNA vaccines can be scaled up and may not have the risk of integration. mRNA vaccines are roughly divided into non-replicating mRNA vaccines and self-amplifying RNA (saRNA) vaccines. In this review, we provide an overview of saRNA vaccines, and discuss future directions and challenges in advancing this promising vaccine platform to combat emerging/re-emerging viruses.

13.
Molecules ; 28(12)2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37375411

RESUMO

Pentagalloyl glucose (PGG) is a natural hydrolyzable gallotannin abundant in various plants and herbs. It has a broad range of biological activities, specifically anticancer activities, and numerous molecular targets. Despite multiple studies available on the pharmacological action of PGG, the molecular mechanisms underlying the anticancer effects of PGG are unclear. Here, we have critically reviewed the natural sources of PGG, its anticancer properties, and underlying mechanisms of action. We found that multiple natural sources of PGG are available, and the existing production technology is sufficient to produce large quantities of the required product. Three plants (or their parts) with maximum PGG content were Rhus chinensis Mill, Bouea macrophylla seed, and Mangifera indica kernel. PGG acts on multiple molecular targets and signaling pathways associated with the hallmarks of cancer to inhibit growth, angiogenesis, and metastasis of several cancers. Moreover, PGG can enhance the efficacy of chemotherapy and radiotherapy by modulating various cancer-associated pathways. Therefore, PGG can be used for treating different human cancers; nevertheless, the data on the pharmacokinetics and safety profile of PGG are limited, and further studies are essential to define the clinical use of PGG in cancer therapies.


Assuntos
Glucose , Taninos Hidrolisáveis , Humanos , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/metabolismo
15.
Int J Clin Pract ; 2023: 6733465, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36743822

RESUMO

Sepsis is a high-incidence disease and demands intensive care. Finding effective treatment is the key to cure sepsis. Studies have shown a lower level of vitamin C in patients with sepsis. Therefore, vitamin C supplementation has become one of the measures to treat sepsis. However, the clinical studies of vitamin C in the treatment of sepsis have been controversial. We performed a meta-analysis to evaluate vitamin C's efficacy and safety in the treatment of sepsis. We searched four electronic databases: PubMed, Embase, Web of Science, and the Cochrane Library, and two researchers independently screened 24 eligible RCTs published in English. Our review demonstrates that intravenous (IV) vitamin C might improve short-term mortality (RR, 0.82; 95% CI, 0.65-1.02; P=0.07; and I 2 = 45%) and overall mortality (RR, 0.86; 95% CI, 0.74-1.01; P=0.06; and I 2 = 51%) of patients with sepsis. Moreover, the SOFA score of patients with sepsis improved significantly after treatment with vitamin C for over 72 hours (RR, 0.26; 95% CI, 0.09-0.42; P=0.002; and I 2 = 0%). The main results of our study were moderate-quality evidence. More high-quality, multicenter RCTs are needed to provide more substantial evidence on the efficacy and safety of IV vitamin C for sepsis.


Assuntos
Ácido Ascórbico , Sepse , Humanos , Ácido Ascórbico/uso terapêutico , Vitaminas/uso terapêutico , Sepse/tratamento farmacológico , Estudos Multicêntricos como Assunto
16.
Artigo em Inglês | MEDLINE | ID: mdl-36569343

RESUMO

Background: Acute monocytic leukemia belongs to type M5 of acute myeloid leukemia (AML) classified by FAB, which appears a high incidence of extramedullary infiltration (EMI) and poor prognosis. In this study, we observed the inhibitory effect of ginsenoside Rk3 on the EMI of monocytic leukemia cells and initially explored its related mechanism of targeting the miR-3677-5p/CXCL12 axis. Methods: The MTT assay and colony formation assay were used to detect the inhibitory effect of Rk3 on proliferation. Both cellular migration and invasion were observed by the Transwell assay. The expression levels of miR-3677-5p, CXCL12, and CXCR4 were detected by RT-qPCR and Western blot, as well as overexpression of miR-3677-5p by transfected with lentivirus and detection of a dual luciferase reporter gene. The expression of MMP2 and TIMP2 was detected by immunofluorescence. Results: Rk3 effectively inhibits the proliferation, migration, and invasion associated with EMI of leukemia. The leukemia cells of M5 patients with EMI showed low expression of miR-3677-5p but high expression of the mRNA of CXCL12 and CXCR4. Overexpression of miR-3677-5p or intervention of CXCL12 effectively inhibited the proliferation, migration, and invasion of SHI-1 cells. The luciferase assay showed that CXCL12 was the downstream target gene of miR-3677-5p. After overexpression of miR-3677-5p or intervention of CXCL12 in combination with Rk3, the inhibitory effect on the proliferation, migration, and invasion of SHI-1 cells was more obvious. Importantly, Rk3 significantly regulated the expression levels of miR-3677-5p, CXCL12, CXCR4, and EMI-related functional proteins including MMP2 and TIMP2. Overexpression of miR-3677-5p or intervention of CXCL12 also regulated the expression of MMP2 and TIMP2. Conclusions: The leukemia cells of M5 patients with EMI appeared to have low expression of miR-3677-5p and high expression of the mRNA of CXCL12 and CXCR4, which may be used as indicators of EMI and poor prognosis. Rk3 is effective in inhibiting the EMI of SHI-1 cells by targeting the miR-3677-5p/CXCL12 axis.

17.
Drug Des Devel Ther ; 16: 3957-3974, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36411859

RESUMO

Remimazolam (CNS7056) is a novel benzodiazepine for intravenous sedation; it has an ultra-short duration of action and was recently approved for use in procedural sedation and general anaesthesia. It acts on γ-aminobutyric acid type A receptors and is rapidly converted into an inactive metabolite by tissue esterase enzymes. Remimazolam has been successfully used in endoscopic inspection or surgery and general anaesthesia induction and maintenance with fast and predictable onset and recovery times, high procedure success rates, and minor respiratory and hemodynamic fluctuations and without serious drug-related adverse reactions. If needed, the effects of remimazolam can be reversed by flumazenil, which allows prompt termination of sedation. Although remimazolam has great potential for sedation in patients admitted to intensive care units, future studies are needed to evaluate its efficacy and safety in patients requiring sedation for a long period, and numerous studies are warranted to explore the optimal dose in different application scenarios. The review aimed to provide an introduction to the process of remimazolam synthesis and its current clinical uses and future clinical developments.


Assuntos
Anestésicos , Hipnóticos e Sedativos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Midazolam/uso terapêutico , Método Duplo-Cego , Benzodiazepinas/farmacologia , Anestesia Geral
18.
Front Immunol ; 13: 983502, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211339

RESUMO

Herpes simplex virus type 2 (HSV-2) is a prevalent human pathogen and the main cause of genital herpes. After initial infection, HSV-2 can establish lifelong latency within dorsal root ganglia by evading the innate immunity of the host. NF-κB has a crucial role in regulating cell proliferation, inflammation, apoptosis, and immune responses. It is known that inhibition of NF-κB activation by a virus could facilitate it to establish infection in the host. In the current study, we found that HSV-2 inhibited TNF-α-induced activation of NF-κB-responsive promoter in a dose-dependent manner, while UV-inactivated HSV-2 did not have such capability. We further identified the immediate early protein ICP22 of HSV-2 as a vital viral element in inhibiting the activation of NF-κB-responsive promoter. The role of ICP22 was confirmed in human cervical cell line HeLa and primary cervical fibroblasts in the context of HSV-2 infection, showing that ICP22 deficient HSV-2 largely lost the capability in suppressing NF-κB activation. HSV-2 ICP22 was further shown to suppress the activity of TNF receptor-associated factor 2 (TRAF2)-, IκB kinase α (IKK α)-, IKK ß-, IKK γ-, or p65-induced activation of NF-κB-responsive promoter. Mechanistically, HSV-2 ICP22 inhibited the phosphorylation and nuclear translocation of p65 by directly interacting with p65, resulting in the blockade of NF-κB activation. Furthermore, ICP22 from several alpha-herpesviruses could also inhibit NF-κB activation, suggesting the significance of ICP22 in herpesvirus immune evasion. Findings in this study highlight the importance of ICP22 in inhibiting NF-κB activation, revealing a novel mechanism by which HSV-2 evades the host antiviral responses.


Assuntos
Herpesvirus Humano 1 , Proteínas Imediatamente Precoces , Antivirais , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 2/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , NF-kappa B/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Virais/metabolismo
19.
Vaccines (Basel) ; 10(8)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36016177

RESUMO

Plasmid DNA (pDNA) represents a promising "genetic vaccine platform" capable of overcoming major histocompatibility complex barriers. We previously demonstrated that low-to-moderate doses of mucosae-associated epithelial chemokine (MEC or CCL28) as an immunomodulatory adjuvant can trigger effective and long-lasting systemic and mucosal HSV-2 gD-specific immune responses, whereas mice immunized with gD in combination with high-dose CCL28 showed toxicity and lost their immunoprotective effects after lethal HSV-2 challenge. The exact causes underlying high-dose, CCL28-induced lesions remain unknown. In an intramuscularly immunized mouse model, we investigated the immune-enhancement mechanisms of low-dose CCL28 as a molecular adjuvant combined with the relatively weak immunogen HSV-2 gB. Compared with the plasmid gB antigen group, we found that a low-dose of plasmid CCL28 (pCCL28) codelivered with pgB induced increased levels of gB-specific serum IgG and vaginal fluid IgA, serum neutralizing antibodies (NAb), Th1-polarized IgG2a, and cytokine IL-2 (>5-fold). Furthermore, low-dose pCCL28 codelivery with pgB enhanced CCL28/CCR10-axis responsive CCR10− plus CCR10+ B-cell (~1.2-fold) and DC pools (~4-fold) in the spleen, CCR10− plus CCR10+ T-cell pools (~2-fold) in mesenteric lymph nodes (MLNs), and the levels of IgA-ASCs in colorectal mucosal tissues, leading to an improved protective effect against a lethal dose of HSV-2 challenge. Findings in this study provide a basis for the development of CCL28-adjuvant vaccines against viral mucosal infections.

20.
ACS Sens ; 7(7): 1855-1866, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35775925

RESUMO

Bright monomeric near-infrared fluorescent proteins (NIR-FPs) are useful as markers for labeling proteins and cells and as sensors for reporting molecular activities in living cells and organisms. However, current monomeric NIR-FPs are dim under excitation with common 633/635/640 nm lasers, limiting their broad use in cellular/subcellular level imaging. Here, we report a bright monomeric NIR-FP with maximum excitation at 633 nm, named mIFP663, engineered from Xanthomonas campestris pv Campestris phytochrome (XccBphP). mIFP663 has high molecular brightness with a large extinction coefficient (86,600 M-1 cm-1) and a decent quantum yield (19.4%), and high cellular brightness that is 3-6 times greater than those of spectrally similar NIR-FPs in HEK293T cells in the presence of exogenous BV. Moreover, we demonstrate that mIFP663 is able to label critical cellular and viral proteins without perturbing subcellular localization and virus replication, respectively. Finally, with mIFP663, we engineer improved bimolecular fluorescence complementation (BiFC) and new bioluminescent resonance energy transfer (BRET) systems to detect protein-protein interactions in living cells.


Assuntos
Fitocromo , Células HEK293 , Células HeLa , Humanos , Proteínas Luminescentes/metabolismo , Microscopia de Fluorescência/métodos , Fitocromo/metabolismo
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