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Tuberculosis (TB) remains a threat to human health worldwide. Mycobacterium tuberculosis (Mtb) and other nontuberculous mycobacteria (NTM) can form biofilms, and in vitro and animal experiments have shown that biofilms cause serious drug resistance and mycobacterial persistence. Deeper investigations into the mechanisms of mycobacterial biofilm formation and, consequently, the exploration of appropriate antibiofilm treatments to improve the efficiency of current anti-TB drugs will be useful for curing TB. In this review, the genes and molecules that have been recently reported to be involved in mycobacterial biofilm development, such as ABC transporter, Pks1, PpiB, GroEL1, MprB, (p)ppGpp, poly(P), and c-di-GMP, are summarized. Biofilm-induced clinical problems, including biofilm-related infections and enhanced virulence, as well as their possible mechanisms, are also discussed in detail. Moreover, we also illustrate newly synthesized anti-TB agents that target mycobacterial biofilm, as well as some assistant methods with high efficiency in reducing biofilms in hosts, such as the use of nanoparticles.
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Antituberculosos , Biopelículas , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Humanos , Animales , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/fisiología , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , VirulenciaRESUMEN
The development of tissue adhesives with good biocompatibility and potent antimicrobial properties is crucial for addressing the high incidence of surgical site infections in emergency and clinical settings. Herein, an injectable hydrogel adhesive composed of chitosan biguanidine (CSG), oxidized dextran (ODex) and tannin (TA) was synthesized primarily through Schiff-base reactions, hydrogen bonding, and electrostatic interactions. TA was introduced into the CSG/ODex hydrogel to prepare a physicochemically double cross-linked hydrogel. The hydrogel formulation incorporating 2 wt% TA (CSG/ODex-TA2) exhibited rapid gelation, moderate mechanical properties, good tissue adhesion, and sustained release behavior of TA. Both in vitro and in vivo studies demonstrated that CSG/ODex-TA2 showed significantly enhanced adhesion and antibacterial effectiveness compared to the CSG/ODex hydrogel and commercial fibrin glue. Leveraging the positive charge of CSG, the CSG/ODex-TA2 hydrogel demonstrated a strong contact antibacterial effect, while the sustained release of TA provided diffusion antibacterial capabilities. By integrating contact and diffusion antibacterial mechanisms into the hydrogel, a promising approach was developed to boost antibacterial efficiency and accelerate the healing of wounds infected with methicillin-resistant Staphylococcus aureus (MRSA). The CSG/ODex-TA2 hydrogel has excellent biocompatibility, hemostatic properties, and antibacterial capabilities, making it a promising candidate for improving in vivo wound care and combating bacterial infections.
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Antibacterianos , Quitosano , Hidrogeles , Staphylococcus aureus Resistente a Meticilina , Adhesivos Tisulares , Cicatrización de Heridas , Quitosano/química , Quitosano/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Antibacterianos/farmacología , Antibacterianos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Ratones , Biguanidas/química , Biguanidas/farmacología , Dextranos/química , Dextranos/farmacología , Taninos/química , Taninos/farmacología , Humanos , Infecciones Estafilocócicas/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , MasculinoRESUMEN
Continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enhanced transmissibility, significant immune escape, and waning immunity call for booster vaccination. We evaluated the safety, immunogenicity, and efficacy of heterologous booster with a SARS-CoV-2 mRNA vaccine SYS6006 versus an active control vaccine in a randomized, open-label, active-controlled phase 3 trial in healthy adults aged 18 years or more who had received two or three doses of SARS-CoV-2 inactivated vaccine in China. The trial started in December 2022 and lasted for 6 months. The participants were randomized (overall ratio: 3:1) to receive one dose of SYS6006 (N = 2999) or an ancestral receptor binding region-based, alum-adjuvanted recombinant protein SARS-CoV-2 vaccine (N = 1000), including 520 participants in an immunogenicity subgroup. SYS6006 boosting showed good safety profiles with most AEs being grade 1 or 2, and induced robust wild-type and Omicron BA.5 neutralizing antibody response on Days 14 and 28, demonstrating immunogenicity superiority versus the control vaccine and meeting the primary objective. The relative vaccine efficacy against COVID-19 of any severity was 51.6% (95% CI, 35.5-63.7) for any variant, 66.8% (48.6-78.5) for BA.5, and 37.7% (2.4-60.3) for XBB, from Day 7 through Month 6. In the vaccinated and infected hybrid immune participants, the relative vaccine efficacy was 68.4% (31.1-85.5) against COVID-19 of any severity caused by a second infection. All COVID-19 cases were mild. SYS6006 heterologous boosting demonstrated good safety, superior immunogenicity and high efficacy against BA.5-associated COVID-19, and protected against XBB-associated COVID-19, particularly in the hybrid immune population.Trial registration: Chinese Clinical Trial Registry: ChiCTR2200066941.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2 , Vacunas de ARNm , Humanos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/virología , Adulto , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Femenino , Masculino , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , China , Persona de Mediana Edad , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Adulto Joven , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Adolescente , Eficacia de las Vacunas , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/efectos adversos , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Recent evidences highlight the potential impact of outdoor Light at Night (LAN) on executive function. However, few studies have investigated the association between outdoor LAN exposure and executive function. METHODS: We employed data from 48,502 Chinese children aged 5-12 years in a cross-sectional study conducted in Guangdong province during 2020-2021, to examine the association between outdoor LAN and executive function assessed using the validated parent-completed Behavior Rating Inventory of Executive Function. We assessed children's outdoor LAN exposure using the night-time satellite images based on the residential addresses. We used generalized linear mixed models to estimate the association between outdoor LAN exposure and executive function scores and executive dysfunction. RESULTS: After adjusting for potential covariates, higher quintiles of outdoor LAN exposure were associated with poorer executive function. Compared to the lowest quintile (Q1), all higher quintiles of exposure showed a significant increased global executive composite (GEC) score with ß (95% confidence intervals, CI) of 0.58 (0.28, 0.88) in Q2, 0.59 (0.28, 0.9) in Q3, 0.85 (0.54, 1.16) in Q4, and 0.76 (0.43, 1.09) in Q5. Higher quintiles of exposure were also associated with higher risks for GEC dysfunction with odd ratios (ORs) (95% CI) of 1.34 (1.18, 1.52) in Q2, 1.40 (1.24, 1.59) in Q3, 1.40 (1.23, 1.59) in Q4, and 1.39 (1.22, 1.58) in Q5. And stronger associations were observed in children aged 10-12 years. CONCLUSIONS: Our study suggested that high outdoor LAN exposure was associated with poor executive function in children. These findings suggested that future studies should determine whether interventions to reduce outdoor LAN exposure can have a positive effect on executive function.
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Función Ejecutiva , Humanos , Niño , Masculino , Femenino , Estudios Transversales , Preescolar , China , Exposición a Riesgos Ambientales , Luz , Iluminación/efectos adversos , Pueblos del Este de AsiaRESUMEN
BACKGROUND: In lung transplantation (LTx) surgery, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide mechanical circulatory support to patients with cardiopulmonary failure. However, the use of heparin in the administration of ECMO can increase blood loss during LTx. This study aimed to evaluate the safety of heparin-free V-A ECMO strategies. METHODS: From September 2019 to April 2022, patients who underwent lung transplantation at the First Affiliated Hospital of Guangzhou Medical University were retrospectively reviewed. A total of 229 patients were included, including 117 patients in the ECMO group and 112 in the non-ECMO group. RESULT: There was no significant difference in the incidence of thrombus events and bleeding requiring reoperation between the two groups. The in-hospital survival rate after single lung transplantation (SLTx) was 81.08%in the ECMO group and 85.14% in the Non-ECMO group, (P = 0.585). The in-hospital survival rate after double lung transplantation (DLTx) was 80.00% in the ECMO group and 92.11% in the Non-ECMO groups (P = 0.095). CONCLUSIONS: In conclusion, the findings of this study suggest that the heparin-free V-A ECMO strategy in lung transplantation is a safe approach that does not increase the incidence of perioperative thrombotic events or bleeding requiring reoperation.
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Oxigenación por Membrana Extracorpórea , Trasplante de Pulmón , Humanos , Estudios Retrospectivos , Heparina/uso terapéutico , CorazónRESUMEN
Sulfonamide antibiotics (SAs) have been widely used as antibacterial drugs for the prevention and treatment of livestock and poultry diseases, but they seriously threaten human health because they can accumulate in humans. Therefore, it is highly important to develop methods for monitoring sulfonamide residues in aquaculture and food. In this research, based on the generation of porous carbon (PC) by the pyrolysis of sodium citrate, magnetic porous carbon (PC@Fe3O4) was synthesized by a solvothermal method and used as an adsorbent for the magnetic solid-phase extraction of SAs. The effects of the proportion of PC in PC@Fe3O4, adsorbent dosage, adsorption time, eluent type, extraction pH, salt concentration and eluent dosage on the extraction efficiency were systematically studied. The adsorption performance and behavior of PC@Fe3O4 on SAs were evaluated using adsorption kinetics and adsorption isotherms, and the adsorption mechanism was preliminarily discussed. Under optimal conditions, combined with capillary electrophoresis diode array detection, a sensitive detection method for SAs was developed. The proposed method can be used for the determination of six SAs in fishpond water and milk samples, with a linear range of 0.5-200 ng mL-1, detection limits of 0.24-0.34 ng mL-1, and spiked recoveries of 85.9-109.0 %.
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Antibacterianos , Carbono , Electroforesis Capilar , Límite de Detección , Leche , Extracción en Fase Sólida , Sulfonamidas , Extracción en Fase Sólida/métodos , Electroforesis Capilar/métodos , Sulfonamidas/análisis , Sulfonamidas/aislamiento & purificación , Sulfonamidas/química , Adsorción , Porosidad , Carbono/química , Antibacterianos/análisis , Antibacterianos/aislamiento & purificación , Antibacterianos/química , Leche/química , Animales , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/aislamiento & purificación , Contaminantes Químicos del Agua/químicaRESUMEN
The emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs booster vaccination. We evaluated the long-term safety and immunogenicity of heterologous boosting with a SARS-CoV-2 messenger RNA vaccine SYS6006. A total of 1000 participants aged 18 years or more who had received two (Group A) or three (Group B) doses of SARS-CoV-2 inactivated vaccine were enrolled and vaccinated with one dose of SYS6006 which was designed based on the prototype spike protein and introduced mutation sites. Adverse events (AEs) through 30 days and serious AEs during the study were collected. Live-virus and pseudovirus neutralizing antibody (Nab), binding antibody (immunoglobulin G [IgG]) and cellular immunity were tested through 180 days. Solicited all, injection-site and systemic AEs were reported by 618 (61.8%), 498 (49.8%), and 386 (38.6%) participants, respectively. Most AEs were grade 1. The two groups had similar safety profile. No vaccination-related SAEs were reported. Robust wild-type (WT) live-virus Nab response was elicited with peak geometric mean titers (GMTs) of 3769.5 (Group A) and 5994.7 (Group B) on day 14, corresponding to 1602.5- and 290.8-fold increase versus baseline, respectively. The BA.5 live-virus Nab GMTs were 87.7 (Group A) and 93.2 (Group B) on day 14. All participants seroconverted for WT live-virus Nab. Robust pseudovirus Nab and IgG responses to wild type and BA.5 were also elicited. ELISpot assay showed robust cellular immune response, which was not obviously affected by virus variation. In conclusion, SYS6006 heterologous boosting demonstrated long-term good safety and immunogenicity in participants who had received two or three doses of SARS-CoV-2 inactivated vaccine.
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Vacunas contra la COVID-19 , COVID-19 , Inmunogenicidad Vacunal , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , China , COVID-19/prevención & control , Inmunoglobulina G , Vacunas de ARNm , Vacunas de Productos InactivadosRESUMEN
Continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants urges the development of new vaccines. We assessed the safety and immunogenicity of SYS6006.32, a bivalent vaccine (XBB.1.5/BQ.1), in healthy adults who had received SARS-CoV-2 primary vaccination. In a randomised, double-blinded, active-controlled trial, 200 participants were randomised to receive one dose of SYS6006.32 (N = 100) or a prototype-based, monovalent control vaccine SYS6006 (N = 100). Adverse events (AEs) were collected through the study. Immunogenicity was assessed by live-virus neutralising antibody (Nab) and pseudovirus Nab. 61 (61.0 %) and 60 (60.0 %) participants reported AE in the SYS6006.32 and SYS6006 groups, respectively. Most AEs were grade 1 or 2. Pain and fever were the most common injection-site and systemic AEs, respectively. No serious AEs were observed. SYS6006.32 heterologous boosting induced robust Nab responses against BA.5, XBB.1.5 and EG.5 with live-virus Nab geometric mean titres (GMTs) increased by 17.1-, 34.0-, and 48.0-fold, and pseudovirus Nab GMTs increased by 12.2-, 32.0-, and 35.1-fold, respectively, 14 days after vaccination. SYS6006.32 demonstrated a superior immunogenicity to SYS6006. SYS6006.32 also induced robust pseudovirus Nab responses against XBB.1.16, XBB.2.3, and BA.2.86, with GMTs 3- to 6-fold higher than those induced by SYS6006. In conclusion, SYS6006.32 showed good safety profile and superior immunogenicity to the monovalent vaccine SYS6006.
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Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , Vacunas contra la COVID-19/efectos adversos , SARS-CoV-2 , Vacunas de ARNm , COVID-19/prevención & control , Anticuerpos Bloqueadores , China , Inmunogenicidad Vacunal , Anticuerpos Antivirales , Anticuerpos Neutralizantes , Método Doble CiegoRESUMEN
Graphene has become an attractive material in the field of electrochemical detection owing to its unique electrical properties. Although the simple stacking structures of two-dimensional (2D) graphene sheets can provide excellent detection properties, a macroscopic three-dimensional (3D) structure needs to be constructed to enhance its functional properties. Graphene with a 3D structure has elegant functions, unlike graphene with a 2D structure. These properties include a large specific surface area, easy loading of nanomaterials with electrocatalytic and redox functions, and so on. Herein, we outline the preparation methods (self-assembly, chemical vapor deposition, templates, and 3D printing) for 3D graphene structures for obtaining excellent detection performance and applications in detecting biological molecules, bacteria, and cells. Furthermore, this review focuses on the improvement of the detection performance and enhancement of the applicability of graphene-based electrochemical sensors. We hope that this article will provide a reference for the future development of electrochemical sensors based on 3D graphene composites.
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Grafito , Nanoestructuras , Grafito/química , Técnicas Electroquímicas/métodos , Nanoestructuras/química , Oxidación-ReducciónRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine enables quick upgrade of antigen sequence to combat emerging new variants. In an observer-blinded, randomized, placebo-controlled phase 2 trial, immunologically naïve 300 adults and 150 older participants were enrolled and randomized (1:1:1) to receive two doses of 20 µg or 30 µg of a SARS-CoV-2 mRNA vaccine (SYS6006) or placebo. Adverse events (AEs) were recorded through 30 days after the second dose. Live virus neutralizing antibody (Nab), S1 protein-specific binding antibody (S1-IgG) and cellular immunity were tested. Results showed that robust wild-type Nab response was elicited with geometric mean titers of 91.3 and 84.9 in the adults, and 74.0 and 115.9 in the elders, 14 days following the second dose (Day 35) in the 20-µg and 30-µg groups, respectively. All seroconverted for wild-type Nab except two participants. Nab against Omicron BA.5 was mild. Robust wild-type S1-IgG response was induced with geometric mean concentrations of 2751.0 and 3142.2 BAU/mL in adults, and 2474.1 and 2993.5 BAU/mL in elders at Day 35 in the 20-µg and 30-µg groups, respectively. S1-IgG against Omicron BA.2 was induced. Cellular immunity was elicited, particularly in enzyme-linked immunospot assay. The most frequent AEs were injection-site pain and fever. Most reported AEs were grade 1 or grade 2. The AE incidences were similar following the first dose and second dose. No vaccination-associated serious AE was reported. In conclusion, two-dose vaccination with SYS6006 demonstrated good safety, tolerability and immunogenicity in immunologically naïve healthy participants aged 18 years or more.
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Vacunas contra la COVID-19 , COVID-19 , Adulto , Anciano , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , China , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Método Doble Ciego , Voluntarios Sanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Vacunas de ARNm , SARS-CoV-2RESUMEN
Hepatic encephalopathy (HE) is often associated with endogenous serotonin (5-HT) disorders. However, the reason for elevated brain 5-HT levels due to liver failure remains unclear. This study aimed to investigate the mechanism by which liver failure increases brain 5-HT levels and the role in behavioral abnormalities in HE. Using bile duct ligation (BDL) rats as a HE model, we verified the elevated 5-HT levels in the cortex but not in the hippocampus and striatum, and found that this cortical 5-HT overload may be caused by BDL-mediated inhibition of UDP-glucuronosyltransferase 1A6 (UGT1A6) expression and activity in the cortex. The intraventricular injection of the UGT1A6 inhibitor diclofenac into rats demonstrated that the inhibition of brain UGT1A6 activity significantly increased cerebral 5-HT levels and induced HE-like behaviors. Co-immunofluorescence experiments demonstrated that UGT1A6 is primarily expressed in astrocytes. In vitro studies confirmed that NH4Cl activates the ROS-ERK pathway to downregulate UGT1A6 activity and expression in U251 cells, which can be reversed by the oxidative stress antagonist N-acetyl-l-cysteine and the ERK inhibitor U0126. Silencing Hepatocyte Nuclear Factor 4α (HNF4α) suppressed UGT1A6 expression whilst overexpressing HNF4α increased Ugt1a6 promotor activity. Meanwhile, both NH4Cl and the ERK activator TBHQ downregulated HNF4α and UGT1A6 expression. In the cortex of hyperammonemic rats, we also found activation of the ROS-ERK pathway, decreases in HNF4α and UGT1A6 expression, and increases in brain 5-HT content. These results prove that the ammonia-mediated ROS-ERK pathway activation inhibits HNF4α expression to downregulate UGT1A6 expression and activity, thereby increasing cerebral 5-HT content and inducing manic-like HE symptoms. This is the first study to reveal the mechanism of elevated cortical 5-HT concentration in a state of liver failure and elucidate its association with manic-like behaviors in HE.
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Fallo Hepático , Serotonina , Animales , Ratas , Amoníaco/metabolismo , Conductos Biliares/cirugía , Conductos Biliares/metabolismo , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Fallo Hepático/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serotonina/metabolismoRESUMEN
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).
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Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease primarily affects populations in economically underdeveloped tropical regions, earning it the title of "neglected tropical disease". Schistosomiasis is difficult to eradicate globally if medication alone is used. One of the essential elements of thorough schistosomiasis prevention and control is the management and disruption of the life cycle of intermediate host snails. The key approach to controlling the transmission of schistosomiasis is to control the intermediate hosts of the schistosome to disrupt its life cycle. We believe that approaching it from the perspective of the intermediate host's immunity could be an environmentally friendly and potentially effective method. Currently, globally significant intermediate host snails for schistosomes include Oncomelania hupensis, Biomphalaria glabrata, and Bulinus truncatus. The immune interaction research between B. glabrata and Schistosoma mansoni has a history of several decades, and the complete genome sequencing of both B. glabrata and B. truncatus has been accomplished. We have summarized the immune-related factors and research progress primarily studied in B. glabrata and B. truncatus and compared them with several humoral immune factors that O. hupensis research focuses on: macrophage migration inhibitory factor (MIF), Toll-like receptors (TLRs), and thioredoxin (Trx). We believe that continued exploration of the immune interactions between O. hupensis and Schistosoma japonicum is valuable. This comparative analysis can provide some direction and clues for further in-depth research. Comparative immunological studies between them not only expand our understanding of the immune defense responses of snails that act as intermediaries for schistosomes but also facilitate the development of more comprehensive and integrated strategies for schistosomiasis prevention and control. Furthermore, it offers an excellent opportunity to study the immune system of gastropods and their co-evolution with pathogenic organisms.
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Biomphalaria , Schistosoma japonicum , Esquistosomiasis , Animales , Humanos , Schistosoma japonicum/genética , Esquistosomiasis/parasitología , Biomphalaria/parasitología , Bulinus , Schistosoma mansoniRESUMEN
Metformin plasma exposure is increased in rats with thioacetamide (TAA)-induced liver failure. The absorption, distribution, and excretion process of metformin is mainly mediated by organic cation transporters (OCTs) and multidrug and toxin extrusion transporters (MATEs). To investigate the mechanisms of the increase in TAA-induced metformin plasma exposure, we employed intestinal perfusion and urinary excretion assays to evaluate the changes in the absorption and excretion of metformin and used Western blotting to investigate the metformin-related transport proteins' expression changes and mechanisms. The results showed that neither intestinal OCT2 expression nor metformin intestinal absorption were significantly altered by TAA-induced liver failure, while significantly decreased expression and function of renal OCT2 and MATE1 as well as impaired metformin excretion were observed in TAA rats. HK-2 cells were used as an in vitro model to explore the mechanism of liver-failure-mediated downregulation in renal OCT2 and MATE1. The results demonstrated that among numerous abnormal substances that changed in acute liver failure, elevated estrogen levels and tumor necrosis factor-α were the main factors mediating the downregulation of OCT2 and MATE1. In conclusion, this study highlights the downregulation of renal OCT2 and MATE1 in liver injury and its regulatory mechanism and reveals its roles in the increase in TAA-mediated metformin plasma exposure.
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Purpose: This study aimed to compare the electrolyte balance efficacies of two Gelatin-Balanced Crystalloid in clinical applications. Methods: A multi-center, prospective, randomized, single-blind, parallel controlled study was conducted among non-cardiac surgery patients, with clinical registration number ChiCTR2200062999. They were randomized into Succinylated Gelatin, Multiple Electrolytes and Sodium Acetate Injection (SG-MESAI) group (experimental group) and Succinylated Gelatin Injection (SGI) infusion group (control group). The same anesthetic induction technique, anesthetic method, and calculation method for the volume of colloid infusion were used in the two groups. Between-group differences in the changes in base excess (BE), Chloride ion (Cl-), bicarbonate radical (HCO3â») and other parameters were recorded at 15 min, 30 min after the infusion relative to the baseline. Hemodynamic indicators were determined at 30 min after colloid infusion. Safety follow-up was conducted by administering the following tests within 48 h±12 h after surgery. Results: A total of 225 subjects (full analysis set) were finally enrolled, with 110 subjects in the experimental group and 115 subjects in the control group. The baseline data were comparable between the two groups. At 15 min after infusion, the mean changes in BE, Cl- and HCO3â» concentration in the experimental group were smaller than those of the control group (P<0.001). At 30 min after surgery, the mean changes in BE, Cl-, HCO3â»concentration and pH value were smaller in the experimental group than in the control group (P<0.05). The incidences of adverse events and adverse reactions in the experimental group was less than the control group, but the difference was not statistically significant (P≥0.05). Besides, no serious adverse events or adverse reactions were reported in any subjects. Conclusion: Succinylated Gelatin, Multiple Electrolytes and Sodium Acetate Injection maintained the balance of BE, Cl-, HCO3â» and pH value in a better way than Succinylated Gelatin Injection in non-cardiac surgery patients under general anesthesia.
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Vaccination plays a key role in preventing morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the safety and immunogenicity of a SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine SYS6006. In the two randomized, observer-blinded, placebo-controlled phase 1 trials, 40 adult participants aged 18-59 years and 40 elderly participants aged 60 years or more were randomized to receive two doses of SYS6006 or placebo (saline). Adverse events (AEs) were collected through 30 days post the second vaccination. Immunogenicity was assessed by live-virus neutralizing antibody (Nab), spike protein (S1) binding antibody (S1-IgG), and cellular immunity. The result showed that 7/15, 9/15 and 4/10 adult participants, and 9/15, 8/15 and 4/10 elderly participants reported at least one AE in the 20-µg, 30-µg and placebo groups, respectively. Most AEs were grade 1. Injection-site pain was the most common AE. Two adults and one elder reported fever. No vaccination-related serious AE was reported. SYS6006 elicited wild-type Nab response with a peak geometric mean titer of 232.1 and 130.6 (adults), and 48.7 and 66.7 (elders), in the 20-µg and 30-µg groups, respectively. SYS6006 induced moderate-to-robust Nab response against Delta, and slight Nab response against Omicron BA.2 and BA.5. Robust IgG response against wild type and BA.2 was observed. Cellular immune response was induced. In conclusion, two-dose primary vaccination with SYS6006 demonstrated good safety and immunogenicity during a follow-up period of 51 days in immunologically naive population aged 18 years or more. (Trial registry: Chictr.org.cn ChiCTR2200059103 and ChiCTR2200059104).
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Vacunas contra la COVID-19 , COVID-19 , Adulto , Anciano , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , China , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Método Doble Ciego , Inmunogenicidad Vacunal , Inmunoglobulina G , Vacunas de ARNm , ARN Mensajero , SARS-CoV-2 , Vacunación , Adolescente , Adulto Joven , Persona de Mediana EdadRESUMEN
Rabies, caused by the rabies virus (RABV), is the most fatal zoonotic disease. It is a neglected tropical disease which remains a major public health problem, causing approximately 59,000 deaths worldwide annually. Despite the existence of effective vaccines, the high incidence of human rabies is mainly linked to tedious vaccine immunisation procedures and the overall high cost of post-exposure prophylaxis. Therefore, it is necessary to develop an effective vaccine that has a simple procedure and is affordable to prevent rabies infection in humans. RABV belongs to the genus Lyssavirus and family Rhabdoviridae. Previous phylogenetic analyses have identified seven major clades of RABV in China (China I-VII), confirmed by analysing nucleotide sequences from both the G and N proteins. This study evaluated the immunogenicity and protective capacity of SYS6008, an mRNA rabies vaccine expressing rabies virus glycoprotein, in mice and cynomolgus macaques. We demonstrated that SYS6008 induced sufficient levels of rabies neutralising antibody (RVNA) in mice. In addition, SYS6008 elicited strong and durable RVNA responses in vaccinated cynomolgus macaques. In the pre-exposure prophylaxis murine model, one or two injections of SYS6008 at 1/10 or 1/30 of dosage provided protection against a challenge with a 30-fold LD50 of rabies virus (China I and II clades). We also demonstrated that in the post-exposure prophylaxis murine model, which was exposed to lethal rabies virus (China I-VII clades) before vaccination, one or two injections of SYS6008 at both 1/10 and 1/30 dosages provided better protection against rabies virus challenge than the immunization by five injections of commercial vaccines at the same dosage. In addition, we proved that SYS6008-induced RVNAs could neutralise RABV from the China I-VII clades. Finally, 1/10 of the dosage of SYS6008 was able to stimulate significant RABV-G specificity in the T cell response. Furthermore, we found that SYS6008 induced high cellular immunity, including RABV-G-specific T cell responses and memory B cells. Our results imply that the SYS6008 rabies vaccine, with a much simpler vaccination procedure, better immunogenicity, and enhanced protective capacity, could be a candidate vaccine for post-exposure prophylaxis of rabies infections.
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Vacunas Antirrábicas , Virus de la Rabia , Rabia , Humanos , Animales , Ratones , Rabia/prevención & control , Vacunas Antirrábicas/genética , Virus de la Rabia/genética , Profilaxis Posexposición/métodos , Modelos Animales de Enfermedad , Filogenia , Anticuerpos Antivirales , MacacaRESUMEN
Epidermal growth factor EGFR is an important target for non-small cell lung (NSCL) cancer, and inhibitors of the AKT protein have been used in many cancer treatments, including those for NSCL cancer. Therefore, searching small molecular inhibitors which can target both EGFR and AKT may help cancer treatment. In this study, we applied a ligand-based pharmacophore model, molecular docking, and MD simulation methods to search for potential inhibitors of EGFR and then studied dual-target inhibitors of EGFR and AKT by screening the immune-oncology Chinese medicine (TCMIO) database and the human endogenous database (HMDB). It was found that TCMIO89212, TCMIO90156, and TCMIO98874 had large binding free energies with EGFR and AKT, and HMDB0012243 also has the ability to bind to EGFR and AKT. These results may provide valuable information for further experimental study.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Simulación de Dinámica Molecular , Antineoplásicos/farmacología , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Inhibidores de Proteínas Quinasas/química , Receptores ErbB/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Microbial activity during spontaneous fermentation in alcoholic beverages have driven in developing the chemical and aromatic characteristic of products but not clear in apricot wines. We have characterised the composition of fungal communities and volatile metabolites in apricot wine spontaneous fermentation among two Shaanxi regions. Results showed that Aureobasidium, Alternaria, Pichia and Saccharomyces, were the dominant fungi in apricot wine fermentation. A total of 80 volatiles including esters, alcohols, acids and terpenes were detected from two apricot wines. Their correlations suggested that apricot wine aroma was mainly affected by Pichia kudriavzevii, rather than Saccharomyces cerevisiae we commonly considered. Furthermore, reinforced inoculation of P. kudriavzevii LQD20 has exhibited the commendable potential in enhancing sensory qualities. The results of this study provide fundamental information of the indigenous microbiota in microbial dynamic during apricot wine fermentation, which would be helpful in exploiting the strains with potential for industrial use as starter cultures.
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Type 2 diabetes (T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1 (RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde (Rald) levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liver-specific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis, and downregulated phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acid-treated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1/G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor α, as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D.