RESUMEN
INTRODUCTION: Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies. METHODS: A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay. RESULTS: Pharmacokinetic analysis of the drug concentration-time data showed that the mean maximum observed serum QX002N concentration (Cmax) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration-time curves from 0 to the time of the last quantifiable concentration (AUClast) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration-time curves from 0 to infinity (AUCinf) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%. CONCLUSIONS: Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects. TRIAL REGISTRATION: www.chinadrugtirals.org.cn , CTR20220430.
RESUMEN
To develop valuable applications for the invasive weed Palmer amaranth, we utilized it as a novel biochar source and explored its potential for methyl orange adsorption through the synthesis of chitosan-encapsulated Palmer amaranth biochar composite microspheres. Firstly, the prepared microspheres were characterized by scanning electron microscopy and Fourier transform infrared spectroscopy and were demonstrated to have a surface area of 19.6 m2/g, a total pore volume of 0.0664 cm3/g and an average pore diameter of 10.6 nm. Then, the influences of pH, dosage and salt type and concentration on the adsorption efficiency were systematically investigated alongside the adsorption kinetics, isotherms, and thermodynamics. The results reveal that the highest adsorption capacity of methyl orange was obtained at pH 4.0. The adsorption process was well fitted by a pseudo-second-order kinetic model and the Langmuir isotherm model, and was spontaneous and endothermic. Through the Langmuir model, the maximal adsorption capacities of methyl orange were calculated as 495.0, 537.1 and 554.3 mg/g at 25.0, 35.0 and 45.0 °C, respectively. Subsequently, the adsorption mechanisms were elucidated by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy investigations. It is indicated that electrostatic interactions, hydrogen bonding, π-π interactions and hydrophobic interactions between methyl orange and the composite microspheres were pivotal for the adsorption process. Finally, the regeneration studies demonstrated that after five adsorption-desorption cycles, the microspheres still maintained 93.6% of their initial adsorption capacity for methyl orange. This work not only presents a promising method for mitigating methyl orange pollution but also offers a sustainable approach to managing Palmer amaranth invasion.
RESUMEN
Nitrogen is an essential macronutrient for plant growth and development. Nitrate is the major form of nitrogen acquired by most crops and also serves as a vital signaling molecule. Nitrate is absorbed from the soil into root cells usually by the low-affinity NRT1 NO3 - transporters and high-affinity NRT2 NO3 - transporters, with NRT2s serving to absorb NO3 - under NO3 -limiting conditions. Seven NRT2 members have been identified in Arabidopsis, and they have been shown to be involved in various biological processes. In this review, we summarize the spatiotemporal expression patterns, localization, and biotic and abiotic responses of these transporters with a focus on recent advances in the current understanding of the functions of the seven AtNRT2 genes. This review offers beneficial insight into the mechanisms by which plants adapt to changing environmental conditions and provides a theoretical basis for crop research in the near future.
RESUMEN
AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.
Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Exenatida/efectos adversos , Voluntarios Sanos , Área Bajo la Curva , Prueba de Tolerancia a la Glucosa , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
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).
Asunto(s)
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
BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Método Doble Ciego , Pueblos del Este de Asia , Inmunogenicidad Vacunal , SARS-CoV-2 , Vacunas de ARNmRESUMEN
The emergence of tigecycline-resistant tet(X2/X3/X4/X5) genes poses a new threat to the efficacy of anti-infective therapy and the safety of our food and environment. To control the transfer of such genes, a sensitive and rapid molecular method is warranted to detect tet(X2/X3/X4/X5) genes in clinical isolates. Herein, we established a loop-mediated isothermal amplification (LAMP) assay to rapidly detect tet(X2/X3/X4/X5) genes, and the results were assessed by chromogenic visualization. The specificity and sensitivity of the primers during the LAMP assay for the simultaneous detection of tet(X2/X3/X4/X5) genes were determined in this study. All 48 clinical strains without tet(X2/X3/X4/X5) genes yielded negative results during the LAMP assay, substantiating the high specificity of the LAMP primers. The detection thresholds of this assay were 1.5 × 102 CFU/ml and 0.2 fg/uL corresponding to a 10 to 100-fold and 100-fold increase in sensitivity compared to polymerase chain reaction (PCR) assays. Out of 52 bacterial strains tested, using PCR as a reference, our research revealed that the LAMP assay demonstrated a sensitivity and specificity of 100%. To sum up, our novel approach has huge prospects for application in the simultaneous detection of tet(X2/X3/X4/X5) genes and can be applied to detect other drug-resistance genes.
Asunto(s)
Bacterias , Técnicas de Amplificación de Ácido Nucleico , Tigeciclina , Técnicas de Amplificación de Ácido Nucleico/métodos , Reacción en Cadena de la Polimerasa , Bacterias/genética , Antibacterianos , Pruebas de Sensibilidad Microbiana , PlásmidosRESUMEN
Purpose: This retrospective cohort study aimed to evaluate the clinical efficacy of ulinastatin (UTI) and azithromycin (AZM) combination therapy in treating severe pneumonia in children and its impact on inflammatory cytokines and oxidative stress. Patients and Methods: This retrospective cohort study was conducted from January 1, 2019, to January 1, 2021, involving pediatric patients diagnosed with severe mycoplasma pneumonia (SMPP). The pediatric patients were divided into two groups: those receiving UTI and AZM combination therapy (treatment group) and those receiving azithromycin alone (control group). We compared the two groups regarding clinical data, disease outcomes, inflammatory cytokines, and oxidative stress levels. Results: Baseline characteristics did not significantly differ between the two groups. UTI, in combination with AZM, significantly improved blood oxygen levels, inflammatory infection markers, and relevant clinical symptoms in patients with SMPP on the 3rd day of treatment. Additionally, it significantly reduced the levels of inflammatory cytokines TNF-a, IL-6, IL-1ß, and IL-10, as well as oxidative stress markers GSH and SOD. Conclusion: Combining UTI and AZM can rapidly alleviate clinical symptoms and effectively control the progression of patients with SMPP. Therefore, this treatment approach deserves consideration for clinical promotion and utilization.
RESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons in the brain and spinal cord. One important aspect of ALS pathogenesis is superoxide dismutase 1 (SOD1) mutant-mediated mitochondrial toxicity, leading to apoptosis in neurons. This study aimed to evaluate the neural protective synergistic effects of ginsenosides Rg1 (G-Rg1) and conditioned medium (CM) on a mutational SOD1 cell model, and to explore the underlying mechanisms. We found that the contents of nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor significantly increased in CM after human umbilical cord mesenchymal stem cells (hUCMSCs) were exposed to neuron differentiation reagents for seven days. CM or G-Rg1 decreased the apoptotic rate of SOD1G93A-NSC34 cells to a certain extent, but their combination brought about the least apoptosis, compared with CM or G-Rg1 alone. Further research showed that the anti-apoptotic protein Bcl-2 was upregulated in all the treatment groups. Proteins associated with mitochondrial apoptotic pathways, such as Bax, caspase 9 (Cas-9), and cytochrome c (Cyt c), were downregulated. Furthermore, CM or G-Rg1 also inhibited the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the phosphorylation of p65 and IκBα. CM/G-Rg1 or their combination also reduced the apoptotic rate induced by betulinic acid (BetA), an agonist of the NF-κB signaling pathway. In summary, the combination of CM and G-Rg1 effectively reduced the apoptosis of SOD1G93A-NSC34 cells through suppressing the NF-κB/Bcl-2 signaling pathway (Fig. 1 is a graphical representation of the abstract).
Asunto(s)
Esclerosis Amiotrófica Lateral , Ginsenósidos , Enfermedades Neurodegenerativas , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Ginsenósidos/farmacología , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Medios de Cultivo Condicionados/farmacología , Superóxido Dismutasa-1 , Neuronas/metabolismo , ApoptosisRESUMEN
BACKGROUND: The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and subsequent Coronavirus Disease 2019 (COVID-19) pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. Monoclonal antibodies (mAbs) are a potentially effective therapeutic option. We identified a potent antibody JMB2002 against the SARS-CoV-2 receptor binding domain. JMB2002 has demonstrated therapeutic efficacy in a SARS-CoV-2 infected rhesus macaque model. METHODS: We conducted a randomized, double-blind, phase 1 trial to evaluate the JMB2002's safety, tolerability, pharmacokinetics, and immunogenicity in healthy Chinese adults. Participants were randomly assigned to one of four cohorts with sequential dose, administrated intravenously with JMB2002 or placebo, and followed up for 85 ± 5 days. RESULTS: 40 participants were recruited and completed in the study. Eight (25.0%) participants experienced 13 treatment emergent adverse events (TEAEs) that were drug-related. No serious adverse events (SAEs), dose limiting events (DLTs), or adverse events of special interest (AESIs), such as infusion related/allergic reactions, were observed, and no drop out due to adverse events (AEs) occurred. There was no significant safety difference observed between JMB2002 and the placebo, suggesting it was well tolerated. The AUC0-∞, AUC0 - t of JMB2002 infusion increased dose-dependently from 5 mg/kg to 50 mg/kg while there is also a linear trend between doses and Cmax. CONCLUSION: Therefore, JMB2002 was well tolerated after administration of a single dose in the range of 5 mg/kg to 50 mg/kg in healthy Chinese adults. TRIAL REGISTRATION: ChiCTR2100042150 at https://www.chictr.org.cn/searchproj.aspx (14/01/2021).
Asunto(s)
COVID-19 , Animales , Humanos , Anticuerpos Antivirales , Método Doble Ciego , Pueblos del Este de Asia , Inmunogenicidad Vacunal , Macaca mulatta , SARS-CoV-2 , Voluntarios SanosRESUMEN
INTRODUCTION: Severe Coronavirus Disease 2019 (COVID-19) progresses with inflammation and coagulation, due to an overactive complement system. Complement component 5a (C5a) plays a key role in the complement system to trigger a powerful "cytokine and chemokine storm" in viral infection. BDB-001, a recombinant human immunoglobulin G4 (IgG4) that specially binds to C5a, has the potential to inhibit the C5a-triggered cytokine storm in treating COVID-19 patients and other inflammation diseases. Here, we have explored its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adults. This trial is registered with http://www.chinadrugtrials.org.cn/(CTR20200429 ). METHODS: Thirty-two enrolled participants were randomized into three single-dose cohorts (2, 4, and 8 mg/kg) and 1 multi-dose cohort (4 mg/kg), and received either BDB-001 or placebo (3:1) double-blindly. The safety and tolerability after administration were evaluated for 21 days for single-dose cohorts and 28 days for the multi-dose cohort. The pharmacokinetics of BDB-001 in plasma and pharmacodynamics as free C5a in plasma were analyzed. RESULTS: The incidence of drug-related adverse events (AEs) was low, and all AEs were mild or moderate: neither AEs ≥ 3 (NCI-Common Terminology Criteria For Adverse Events, CTCAE 5.0) nor serious adverse events (SAEs) were found. The area under the concentration-time curve from time zero to 480 h (AUC0-480h), that from time zero to infinity (AUCinf), and peak plasma concentration ©max) increased dose-dependently from 2 to 8 mg/kg in the single-dose cohorts and were characterized by a nonlinear pharmacokinetics of target-mediated drug disposal (TMDD). The accumulation index by AUC0-tau after five administrations (4 mg/kg) from the multi-dose cohort was 6.42, suggesting an accumulation effect. Furthermore, inhibition of C5a at the plasma level was observed. CONCLUSION: The results of this phase I study supported that BDB-001 is a potent anti-C5a inhibitor with safety, tolerability, and no immunogenicity. TRIAL REGISTRATION NUMBER: CTR20200429.
RESUMEN
BACKGROUND: Duplication of the common bile duct (CBD) is extremely rare among the anatomical variations in the biliary tract system, which presents a septum within the CBD or an accessory CBD. In our study, we report a rare case of duplication of the common bile duct combined congenital biliary dilatation.we present a rare case of a septum in the dilated biliary tract. CASE PRESENTATION: We reported a 5-year-old Asian girl who had history of repeated abdominal pain for 4 days and aggravated for 1 day. Magnetic resonance cholangiopancreatography (MRCP) examination revealed duplicated common bile duct (DCBD) malformation with congenital biliary dilatation and distal cholelithiasis. The patient underwent choledochal cyst resection and biliary tract reconstruction and abdominal cavity irrigation and drainage under general anesthesia. A septum was found within the common bile duct during the operation. The septum divided the extrahepatic bile duct into two parts connected to the left and right hepatic ducts respectively and the gallbladder is attached to the repeated right bile duct which was not previously reported in the literature. CONCLUSIONS: We complement and adjust the classification of common bile duct duplication by reviewing the literature.
Asunto(s)
Conductos Biliares Extrahepáticos , Procedimientos Quirúrgicos del Sistema Biliar , Sistema Biliar , Quiste del Colédoco , Femenino , Humanos , Preescolar , Quiste del Colédoco/diagnóstico por imagen , Quiste del Colédoco/cirugía , Conducto Colédoco/diagnóstico por imagen , Conducto Colédoco/cirugía , Conducto Colédoco/anomalías , Conductos Biliares Extrahepáticos/anomalías , Conductos Biliares Extrahepáticos/cirugíaRESUMEN
Vanillic acid, a phenolic compound mainly obtained from the foot of Picrorhiza scrophulariiflora Pennell, has been demonstrated to possess a cardiovascular-protective effect in previous studies. However, there is lack of research on vanillic acid protecting cardiomyocytes from oxidative stress injury by mediating mitophagy. In the present study, oxidative stress injury in the H9c2 cell line was induced by H2O2. Our results confirmed that vanillic acid mitigated apoptosis and injury triggered by oxidative stress, evidenced by the decline in production of reactive oxygen species and malondialdehyde and level of lactate dehydrogenase and the increase of superoxide dismutase and glutathione. The use of vanillic acid could also improve the polarization of mitochondrial membrane potential and decrease the cellular calcium level. After treatment by vanillic acid, impaired autophagy flux and mitophagy were improved, and the length of mitochondria was restored. Vanillic acid increased the expression of PINK1, Parkin, Mfn2, and the ratio of LC3-II/LC3-I and decreased the expression of p62. But, under the intervention of mitophagy inhibitor 3-MA, vanillic acid could not change the expression of PINK1/Parkin/Mfn2 and downstream genes to affect cell autophagy, mitophagy, and mitochondrial function. Our findings suggested that vanillic acid activated mitophagy to improve mitochondrial function, in which the PINK1/Parkin/Mfn2 pathway could be the potential regulatory mechanism.
RESUMEN
Wound healing is a complex and integrated process of the interaction of various components within the injured tissue. Accumulating evidence suggested that stem cell-derived exosomal transcriptomes could serve as key regulatory molecules in wound healing in stem cell therapy. Stem cell-derived exosomal transcriptomes mainly consist of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs) and messenger RNAs (mRNAs). In this article we presented a brief introduction on the wound repair process and exosomal transcriptomes. Meanwhile, we summarized our current knowledge of the involvement of exosomal transcriptomes in physiological and pathological wound repair process including inflammation, angiogenesis, and scar formation.
RESUMEN
BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 µg, 10 µg, 15 µg, 20 µg, and 25 µg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 µg group, 13 [65%] of 20 in the 10 µg group, 17 [85%] of 20 in the 15 µg group, 19 [95%] of 20 in the 20 µg group, 16 [100%] of 16 in the 25 µg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.
Asunto(s)
COVID-19 , SARS-CoV-2 , Adulto , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , China , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Pandemias/prevención & control , Glicoproteína de la Espiga del Coronavirus , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
The direct employment of polyfluoroarenes and gem-difluoroalkenes as building blocks is regarded as one of the most effective and straightforward strategies for the introduction of fluorine-containing moieties into organic skeletons. Accordingly, radical chemistry has gradually become a mild and powerful method for the activation of their C-F bonds. The radical-based transformations of polyfluoroarenes and gem-difluoroalkenes can be primarily categorized into three types based on the specific intermediates involved: (1) multifluoroaryl radical anions, (2) monofluoroalkenyl radicals and (3) other radicals. Compared with the more established multifluoroaryl radical anion pathway, the monofluoroalkenyl radical-involved cross-coupling reaction can proceed through C-radical cross-coupling, radical addition/elimination or the hydrogen atom transfer process. For the presented examples in this review, the typical reaction modes, substrate scope, radical-involved mechanisms, and late-stage applications in the modification of bioactive molecules are discussed, aiming to provide a comprehensive overview of the recent advances of the radical-based transformations of polyfluoroarenes and gem-difluoroalkenes.
RESUMEN
Atherosclerosis (AS) is a type of chronic vascular disease, and its etiology is not yet fully understood. AS is characterized by lipid deposition, atherosclerotic plaque formation, vascular stenosis or even complete blockage of the blood vessel wall. Clinical studies have shown that Danlou tablets (DLTs) can improve the heart function, quality of life, and prognosis of patients with coronary heart disease and myocardial infarction. However, its mechanism of action remains unknown. Our study revealed that DLTs ameliorated ApoE-/-AS mouse aortic atherosclerotic plaques [hematoxylin-eosin (HE) staining and small animal ultrasound] and reduced CD68+ macrophage infiltration, the expression of the inflammatory factor interferon-gamma (IFN-γ), vascular smooth muscle α-actin, and serum lipid levels. In vitro, in the macrophage foaming model, DLTs partially restored the activity of RAW264.7 cells, reduced the uptake of lipid droplets, and inhibited lipid droplet accumulation and apoptosis within BMDMs. We also found that Torin1, an autophagy agonist, reduced intracellular lipid deposition in BMDMs, as did DLTs. Moreover, DLTs upregulated the expression of the autophagy-related protein LC3II and decreased p62 accumulation in RAW264.7 cells. DLTs also inhibited the phosphorylation of p-PI3K, p-Akt, and p-mTOR, leading to upregulated autophagy in RAW264.7 cells. In summary, our results suggested that DLTs can promote autophagy in macrophages by inhibiting the PI3K/Akt/mTOR signaling pathway, thereby reducing foam cell formation and improving atherosclerosis.
RESUMEN
The beneficial effect of quercetin in rheumatic diseases is unclear. Studies have already confirmed that human umbilical cord mesenchymal stem cells (hUCMSCs) alleviate some symptoms of rheumatoid arthritis (RA) by their immunosuppressive capacities. This study explored whether there are additive effects of quercetin and hUCMSCs on peripheral blood mononuclear cells (PBMCs) under simulated rheumatic conditions. hUCMSCs were pretreated with quercetin (10 µM) before coculture with TNF-α/IFN-γ-stimulated PBMCs at a ratio of 1:1 for 3 days. PBMC proliferation was inhibited, and the proportion of Th17 cells was shifted. These effects may be related to the effect of quercetin on functional molecules in hUCMSCs, including nitric oxide (NO), indoleamine 2,3-dioxygenase (IDO), interleukin 6 (IL-6) and Toll-like receptor-3 (TLR-3) and the Akt/IκB pathways. These results suggest that quercetin effectively promoted the immunoregulatory effect of hUCMSCs by inhibiting the Akt/IκB pathway, activating the Toll-like receptor-3 pathway, and regulating downstream cytokines.
RESUMEN
Azilsartan (AZL), the active metabolite of azilsartan medoxomil, is the newest angiotensin receptor blocker that has been approved for the treatment of hypertension in 2012 in Japan. The present study aimed to evaluate the safety and pharmacokinetic properties of AZL in healthy Chinese subjects. We performed 2 phase 1 studies to investigate the pharmacokinetics and safety of AZL in healthy Chinese adults after a single dose (20 mg or 40 mg) or multiple doses of AZL (40 mg/d for 7 days; Study I) and after a single 40-mg dose under the fasted and fed conditions (Study II). Noncompartmental analysis and nonlinear mixed-effects modeling were used to analyze the pharmacokinetic properties of AZL. Twenty-seven healthy volunteers (14 men and 13 women) aged 20-32 years were enrolled and completed the study. During single dosing of AZL, the pharmacokinetics of AZL exhibited a linear profile between dosage and area under the concentration-time curve. There is no AZL accumulation after multiple doses. Food had no effect on the pharmacokinetic characteristics of AZL. AZL concentrations were best fit with a 2-compartment model, and the typical value of clearance was 1.63 L/h. Body weight had an impact on both the apparent clearance and peripheral volume of distribution. The pharmacokinetic parameters were consistent with previous studies in non-Chinese subjects. Model-based simulations indicated that a 45-kg subject would have approximately double the AZL exposure of a 90-kg subject. Whether the exposure difference has clinical significance needs to be confirmed in further studies among patients.
Asunto(s)
Antagonistas de Receptores de Angiotensina/administración & dosificación , Pueblo Asiatico , Bencimidazoles/administración & dosificación , Interacciones Alimento-Droga , Oxadiazoles/administración & dosificación , Adulto , Antagonistas de Receptores de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Modelos Biológicos , Oxadiazoles/efectos adversos , Oxadiazoles/farmacocinética , Distribución Tisular , Adulto JovenRESUMEN
Background: Donafenib is a novel compound similar to sorafenib that functions as a multikinase inhibitor. This phase 1b trial aimed to assess the safety, pharmacokinetics and efficacy of donafenib in treating Chinese patients with advanced hepatocellular carcinoma. Methods: From July 2014 to April 2015, 27 eligible advanced hepatocellular carcinoma patients were enrolled in the trial. They were randomly divided into 200 mg and 300 mg bid groups and received these oral doses of donafenib until the appearance of intolerance or disease progression. Results: Overall, donafenib was safe and well tolerated in the two groups, and most adverse events were grade 1 or 2. Elevated transaminase (n=19, 70.4 %), hypocalcemia (n=19, 70.4 %), and skin toxicity (n=17, 63.0 %) were the most frequently encountered adverse events. Donafenib exhibited high variability in pharmacokinetic parameters. Areas under the plasma concentration-time curve from 0-12 h increased disproportionally to the dose escalation. The treatment resulted in partial response in two patients and a stable disease status in 17 patients, and the median time to progression was 120 days for both groups. Conclusion: The results from this phase 1b trial indicate a favorable safety profile and notable anticancer efficacy of donafenib for treating advanced hepatocellular carcinoma. Comparable or better safety and efficacy were observed for a lower dosage of donafenib compared with sorafenib in the literature.