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The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.
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COVID-19 , SARS-CoV-2 , Animales , Ratones , Conejos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Macaca mulatta , Macrófagos , Nanovacunas , Fagocitosis , Lectinas Similares a la Inmunoglobulina de Unión a Ácido SiálicoRESUMEN
Various vaccine strategies have been proposed in response to the global COVID-19 pandemic, each with unique strategies for eliciting immune responses. Here, we developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (RBD) and/or heptad repeat (HR) subunits of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spike (S) protein. Compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing antibodies and cellular immune responses. RBD and RBD-HR nanoparticle vaccinated hACE2 transgenic mice vaccinated with RBD and/or RBD-HR nanoparticles exhibited reduced viral load in the lungs after SARS-CoV-2 challenge. RBD-HR nanoparticle vaccines also promoted neutralizing antibodies and cellular immune responses against other coronaviruses. The nanoparticle vaccination of rhesus macaques induced neutralizing antibodies, and T and B cell responses prior to boost immunization; these responses persisted for more than three months. RBD- and HR-based nanoparticles thus present a promising vaccination approach against SARS-CoV-2 and other coronaviruses.
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Proteínas Bacterianas/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Ferritinas/inmunología , Helicobacter pylori/metabolismo , Proteínas Recombinantes de Fusión/inmunología , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/inmunología , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Proteínas Bacterianas/química , Vacunas contra la COVID-19/química , Ferritinas/química , Humanos , Macaca mulatta , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Pandemias , Unión Proteica , Glicoproteína de la Espiga del Coronavirus/química , VacunaciónRESUMEN
Herein, we demonstrate a distinctive energy harvesting method that electricity can be generated from the ionic solution flowing through the interstices between packed three-dimensional graphene powders. A constructed electrokinetic nanogenerator with an effective flow area of â¼0.34 cm2can generate a large current of 91.33 nA under 10-6M NaCl solution with a flow rate of 0.4 ml min-1, corresponding to a maximum power density of 0.45µW m-2. Besides, it shows a good linear relationship between the streaming current and the flow rate, suggesting that it could be used as a self-powered micro-flowmeter. These results provide a convenient way for clean energy harvesting and show a bright future for self-powered systems.
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A series of biheterocyclic (1H-indole, benzofuran, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyrimidin-5(4H)-one, imidazo[2,1-b]thiazole and pyrazolo[5,1-b]thiazole) derivatives were synthesized and evaluated for their anti-tubercular activities. The imidazo[2,1-b]thiazoles 9a-c and pyrazolo[5,1-b]thiazoles 10a-c exhibited promising anti-tubercular activity in varying degrees. Especially, the 2,6-dimethylpyrazolo[5,1-b]thiazole 10a exhibited strong suppressing function against H37Ra strain with MIC value of 0.03µg/mL. Compound 10a also displayed good pharmacokinetic profiles with oral bioavailability (F) of 41.7% and a half-life of 13.4h. Furthermore, 10a significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model, suggesting its promising potential for development of anti-tubercular drugs.
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Antituberculosos/farmacología , Descubrimiento de Drogas , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Administración Oral , Animales , Antituberculosos/administración & dosificación , Antituberculosos/química , Disponibilidad Biológica , Chlorocebus aethiops , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Ratas , Relación Estructura-Actividad , Células VeroRESUMEN
Objective: To investigate the chemical constituents of Thalictrum fortunei. Methods: Compounds were separated and purified by chromatographic methods and the structures were identified by their physicochemical properties and spectroscopic data. Results: Ten compounds were isolated and identified as bergenin( 1),1-( 4-hydroxy-3-methoxy)-phenyl-2-[4-( 1,2,3-trihydroxypropyl)-2-methoxy]-phenoxym-1,3-propandiol( 2) ã4-( 2-hydroxyethyl)-2-methoxyphenyl-O-ß-D-glucopyranoside( 3),meliasendanin D( 4),2-( 4-hydroxy-3-methoxyphenyl)-ethyl-O-ß-D-glucopyranoside( 5),kizutasaponin C( 6),2-( 3-hydroxy-4-methoxyphenyl)-ethyl-O-ß-Dglucopyranoside( 7),ß-sitosterol( 8),3-O-ß-D-glucopyranosyl( 1â6)-ß-D-glucopyranosyl( 22 S,24Z)-cycloart-24-en-3ß,22,30-tetraol-26-O-ß-D-glucopyranoside( 9) and 3-O-ß-D-quinovopyranosyl( 1â6)-ß-D-glucopyranosyl( 1â4)-ß-D-fucopyranosyl( 22 S,24Z)-cycloart-24-en-3ß,22,26-triaol-26-O-ß-D-glucopyranoside( 10). Conclusion: Compounds 1 ~ 6 are isolated form this plant for the first time.
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Thalictrum , Cromatografía , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos VegetalesRESUMEN
OBJECTIVE: To study the protective effects of ginkgolide N against glutamte-induced injury in PC12 cells and its mechanisms. METHODS: The injury model was established by treating PC12 cells with glutamate, and PC12 cells were treated with different concentrations of ginkgolide N with ginkgolide B as control. The cells activity was analyzed by MTT assay. The apoptosis of PC12 cells were examined by acridine orange( AO) staining, the reactive oxygen species and mitochondrial membrane potential of PC12 cells were examined by flow cytometry. Western blot method was used to examine the expression of Cleaved Caspase-3 protein. RESULTS: Ginkgolides N of 2-8 µgmol/L inhibited PC12 cells apoptosis and ROS accumulation induced by glutamate,stabilized membrane potential of damaged PC12, and reduced the expression of Cleaved Caspase-3 protein. CONCLUSION: Ginkgolide N has a protective effect on PC12 cells injury induced by glutamate, and the mechanism may be associated with reducing ROS generation, stabilizing membrane potential and inhibiting the expression of Cleaved Caspase-3 protein.
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Ginkgólidos/farmacología , Ácido Glutámico/efectos adversos , Potencial de la Membrana Mitocondrial , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Apoptosis , Caspasa 3/metabolismo , Células PC12/efectos de los fármacos , RatasRESUMEN
Mitochondria and oxidative stress play important roles in neuronal cell death associated with cerebral ischemia. Elevated level of reactive oxygen species (ROS) and mitochondrial dysfunction are thought to be responsible for cerebral ischemia injury along with neural cells death through several apoptotic mechanisms. In this study, exposure of rat pheochromocytoma (PC12) cells to hydrogen peroxide (H2O2) at the concentration of 0.3 mM for 24 h caused significant loss of cell viability, lactate dehydrogenase (LDH) release from cells, ascent of ROS level and mitochondrial membrane potential (MMP) decrease. Moreover, the activities of caspase-9, caspase-8 and caspase-3 all were increased in H2O2-induced PC12 cells. However, pretreatment with ginkgolide K (GK) solutions of different concentrations (10, 50, 100 µM) for 24 h prior to exposuring to H2O2 significantly increased cells viability, suppressed LDH release, attenuated ROS level, prevented cytochrome c release from mitochondria and boosted MMP expression. In addition, ginkgolide K notably inhibited the caspase-3 and caspase-9 but not caspase-8 activities in exogenous H2O2-treated PC12 cells. These results demonstrated that ginkgolide K protected PC12 cells from H2O2-induced apoptosis by restoring MMP expression, ameliorating oxidative stress and subsequently leading to inhibit the activity of caspase-3 protein. Therefore, the present study supported that ginkgolide K may be a promising neuroprotective compound for cerebral ischemia treatment.
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Isquemia Encefálica , Supervivencia Celular/efectos de los fármacos , Ginkgo biloba/química , Ginkgólidos/farmacología , Lactonas/farmacología , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Caspasas/metabolismo , Citocromos c/metabolismo , Ginkgólidos/uso terapéutico , Peróxido de Hidrógeno , L-Lactato Deshidrogenasa/metabolismo , Lactonas/uso terapéutico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/fisiología , Fármacos Neuroprotectores/uso terapéutico , Células PC12 , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Microctis Folium, the leaves of Microcos paniculata L., is a commonly used herbal tea material. The methanol extract of Microctis Folium and its principle compounds vitexin (1), isovitexin (2) and isorhamnetin 3-O-ß-D-rutinoside (3) were investigated for their α-glucosidase inhibitory effects. The extract showed strong α-glucosidase inhibitory effect (IC50 = 61.30 µg/mL) and the three flavonoid glycosides 1-3 exerted satisfactory α-glucosidase inhibitory effects, with IC50 values of 244.0 µM, 266.2 µM and 275.4 µM, respectively. A simple and reliable HPLC-DAD method was developed for the quantification of the three flavonoid glycosides in Microctis Folium and applied successfully to determine contents of these components in samples collected from different locations. This study suggested that Microctis Folium may be a promising candidate for development of herbal antidiabetes drugs, and vitexin, isovitexin and isorhamnetin 3-O-ß-D-rutinoside can be the biomarkers and chemical markers for this plant substance.
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Flavonoides/farmacología , Inhibidores de Glicósido Hidrolasas , Glicósidos/farmacología , Poaceae/química , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Flavonoides/química , Glicósidos/química , Concentración 50 Inhibidora , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Reproducibilidad de los ResultadosRESUMEN
Ypsilandra thibetica belongs to the family Liliaceae. Its whole plant has the medicinal functions of heat-clearing and detoxifying, relieving congestion and other effects, and is used as the folk medicine to cure scrofula, dysuria embolism and other symptoms. Previous chemical studies revealed that its major and active ingredient is steroidal saponin. Up to now, more than fifty steroidal saponins, mainly composed of spirostan and furostanol types, have been described. Pharmacological and clinical studies have demonstrated that Y. thibetica has anti-tumor, uterine contractions, hemostatic and antibacterial activities, in particular for the treatment of a variety of gynecological hemorrhagic diseases. In an effort to provide references for the advanced research and development of this species, this paper summarized the research progress on its pharmacognosy, including botany and authentication, its isolated secondary metabolites, biological activities and pharmacological applications. In addition, some advantages of this species which could be potentially used as a substitute for Paridis Rhizoma, one of ingredients of the well-known drug "Yunnan Baiyao", together with the future prospect are also briefly included.
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Medicamentos Herbarios Chinos/química , Liliaceae/química , Plantas Medicinales/química , Animales , Medicamentos Herbarios Chinos/farmacología , Humanos , Estructura MolecularRESUMEN
Because of the rapid mutation and high airborne transmission of SARS-CoV-2, a universal vaccine preventing the infection in the upper respiratory tract is particularly urgent. Here, a mosaic receptor-binding domain (RBD) nanoparticle (NP) vaccine is developed, which induces more RBD-targeted type IV neutralizing antibodies (NAbs) and exhibits broad cross-protective activity against multiple SARS-CoV-2 sublineages including the newly-emerged BF.7, BQ.1, XBB. As several T-cell-reactive epitopes, which are highly conserved in sarbecoviruses, are displayed on the NP surface, it also provokes potent and cross-reactive cellular immune responses in the respiratory tissue. Through intranasal delivery, it elicits robust mucosal immune responses and full protection without any adjuvants. Therefore, this intranasal mosaic NP vaccine can be further developed as a pan-sarbecovirus vaccine to block the viral entrance from the upper respiratory tract.
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COVID-19 , Nanopartículas , Vacunas , Humanos , SARS-CoV-2 , COVID-19/prevención & control , Inmunidad MucosaRESUMEN
Two new cycloartane glycosides were isolated from the aerial parts of Thalictrum fortunei (Ranunculaceae). The chemical structures of these compounds were elucidated as 3-O-ß-D-glucopyranosyl (1 â 4)-ß-d-fucopyranosyl-(22S,24Z)-cycloart-24-en-3ß,22,26,30-tetraol 26-O-ß-D-glucopyranoside and 3-O-ß-D-glucopyranosyl (1 â 4)-ß-D-fucopyranosyl-(22S,24Z)-cycloart-24-en-3ß,22,26,29-tetraol 26-O-ß-D-glucopyranoside by extensive 1D and 2D NMR methods, HR-ESI-MS, and hydrolysis. Their cytotoxic activities toward human hepatoma Bel-7402 cells, human colon carcinoma LoVo cells, and human non-small-cell lung cancer NCIH-460 cells were evaluated by MTT assay, respectively.
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Antineoplásicos Fitogénicos/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Saponinas/aislamiento & purificación , Thalictrum/química , Triterpenos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Saponinas/química , Saponinas/farmacología , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
OBJECTIVE: To study the pharmacokinetics of ginkgolide B injection in Beagle dogs. METHODS: Determined the serum concentration of ginkgolide B by LC-MS and calculated its parameter of pharmacokinetics via DAS 2.0 software. RESULTS: After intravenous drips of 0.62, 2.07 and 10.35 mg/kg ginkgolide B, parameters of pharmacokinetics of ginkgolide B were as follows: Tmax were 0.444, 1, 1 h; Cmax were 0.764, 3.024, 11.013 mg/L; AUC(0-1) were 1.007, 3.644, 16.646 mg x h/Lo. CONCLUSION: Ginkgolide B has two compartment model in Beagle dogs.
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Cromatografía Líquida de Alta Presión/métodos , Ginkgo biloba/química , Ginkgólidos/farmacocinética , Lactonas/farmacocinética , Factor de Activación Plaquetaria/antagonistas & inhibidores , Factor de Activación Plaquetaria/farmacocinética , Animales , Área Bajo la Curva , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacocinética , Femenino , Fibrinolíticos/administración & dosificación , Ginkgólidos/administración & dosificación , Ginkgólidos/sangre , Inyecciones Intravenosas , Lactonas/administración & dosificación , Lactonas/sangre , Masculino , Modelos Animales , Factor de Activación Plaquetaria/administración & dosificación , Distribución Aleatoria , Factores de TiempoRESUMEN
OBJECTIVE: To study the pharmacokinetics of ginkgolide B for injection in rats. METHODS: The serum concentration of ginkgolide B was determined by LC-MS and calculate its parameter of pharmacokinetics via DAS2.0 software. RESULTS: After intravenous of 0.75, 3.75 and 14.0 mg/kg ginkgolide B, parameters of pharmacokinetics of ginkgolide B were: Tmax were all (0.083 +/- 0) h, Cmax were (422.312 +/- 14.203), (1608.467 +/- 226.677), (1987.036 +/- 237.202) microg/L, AUC0-1 were (533.833 +/- 114.943), (1786.029 +/- 137.066), (1943.44 +/- 415.892) microg x h/L. CONCLUSION: Ginkgolide B has three compartment model in rats.
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Cromatografía Líquida de Alta Presión/métodos , Fibrinolíticos/farmacocinética , Ginkgo biloba/química , Ginkgólidos/farmacocinética , Lactonas/farmacocinética , Animales , Área Bajo la Curva , Femenino , Fibrinolíticos/administración & dosificación , Fibrinolíticos/sangre , Ginkgólidos/administración & dosificación , Ginkgólidos/sangre , Inyecciones Intravenosas , Lactonas/administración & dosificación , Lactonas/sangre , Masculino , Espectrometría de Masas , Factor de Activación Plaquetaria/antagonistas & inhibidores , Distribución Aleatoria , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Purpose: This study examines the preferences for WeChat-based and hospital-based family intervention among caregivers of people living with schizophrenia (PLS) and identify correlates associated with these preferences. Patients and Methods: A cross-sectional study was conducted with 449 family caregivers of PLS. Face-to-face interviews were conducted to collect information on socio-demographics, preferences for WeChat-based and hospital-based family intervention, social support, and coping. Results: Over 72.16% of participants endorsed hospital-based family intervention, while 50.11% endorsed WeChat-based family intervention. Endorsement of WeChat-based family intervention was associated with younger age (OR=0.42, 95% CI: 0.22, 0.79), WeChat use (OR=12.90, 95% CI: 7.48, 22.23), and higher social support (OR=1.03, 95% CI: 1.01, 1.04). Endorsement of hospital-based family intervention was associated with lower education (OR=0.19-0.37, 95% CI: 0.07, 0.66) and WeChat use (OR=3.27, 95% CI: 1.91, 5.59). Conclusion: The studies showed a higher endorsement rate for hospital-based family intervention than WeChat-based family intervention and provide implications for developing targeted family intervention programs based on participants' own unique characteristics.
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Two previously undescribed triterpenoids (1-2), along with thirteen known compounds (3-15) were isolated from a CHCl3-soluble extract of the leaves of Cyclocarya paliurus. Their structures were established on the basis of chemical and spectroscopic approaches. These compounds were assessed for their therapeutic effects on diabetic nephropathy (DN)-evoked fibrosis through High-Glucose and transforming growth factor-ß1 (TGF-ß1) challenged HK-2 cells. Among them, compounds 3, 5 and 8 could remarkedly decrease the level of fibronectin to relieve DN with 27.66 ± 2.77%, 6.09 ± 0.57% and 17.74 ± 5.83% inhibition rate at 10 µM, 10 µM and 1 µM, respectively.
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Juglandaceae , Triterpenos , Juglandaceae/química , Extractos Vegetales/química , Hojas de la Planta/química , Triterpenos/químicaRESUMEN
Activation-induced cytidine deaminase (AID) initiates class-switch recombination and somatic hypermutation (SHM) in antibody genes. Protein expression and activity are tightly controlled by various mechanisms. However, it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works. Here, we demonstrated that a deubiquitinase USP10, which specifically stabilizes nuclear AID protein, can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain. Interestingly, the signals from BCR and TLR1/2 synergistically promoted this phosphorylation. The deficiency of USP10 in B cells significantly decreased AID protein levels, subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or human immunodeficiency virus type 1 (HIV-1) nanoparticle vaccines. Collectively, we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity. Its manipulation could be used for the development of vaccines and adjuvants.
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Vacunas contra el SIDA/inmunología , Factor Activador de Células B/inmunología , Vacunas contra la COVID-19/inmunología , Citidina Desaminasa/inmunología , VIH-1/inmunología , Nanopartículas , SARS-CoV-2/inmunología , Transducción de Señal/inmunología , Ubiquitina Tiolesterasa/inmunología , Ubiquitinación/inmunología , Vacunas contra el SIDA/genética , Animales , Factor Activador de Células B/genética , Vacunas contra la COVID-19/genética , Citidina Desaminasa/genética , Células HEK293 , VIH-1/genética , Humanos , Ratones , Ratones Noqueados , SARS-CoV-2/genética , Transducción de Señal/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Kelch superfamily involves a variety of proteins containing multiple kelch motif and is well characterized as substrate adaptors for CUL3 E3 ligases, which play critical roles in carcinogenesis. However, the role of kelch proteins in lung cancer remains largely unknown. In this study, the non-small cell lung cancer (NSCLC) patients with higher expression of a kelch protein, kelch domain containing 3 (KLHDC3), showed worse overall survival. KLHDC3 deficiency affected NSCLC cell lines proliferation in vitro and in vivo. Further study indicated that KLHDC3 mediated CUL2 E3 ligase and tumor suppressor p14ARF interaction, facilitating the N-terminal ubiquitylation and subsequent degradation of p14ARF. Interestingly, Gefitinib-resistant NSCLC cell lines displayed higher KLHDC3 protein levels. Gefitinib and Osimertinib medications were capable of upregulating KLHDC3 expression to promote p14ARF degradation in the NSCLC cell lines. KLHDC3 shortage significantly increased the sensitivity of lung cancer cells to epidermal growth factor receptor (EGFR)-targeted drugs, providing an alternative explanation for the development of Gefitinib and Osimertinib resistance in NSCLC therapy. Our works suggest that CRL2KLHDC3 could be a valuable target to regulate the abundance of p14ARF and postpone the occurrence of EGFR-targeted drugs resistance.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinib/farmacología , Gefitinib/uso terapéutico , Humanos , Secuencia Kelch , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteína p14ARF Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
Inoculation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing worldwide. However, the emergence of SARS-CoV-2 variants could cause immune evasion. We developed a bivalent nanoparticle vaccine that displays the receptor binding domains (RBDs) of the D614G and B.1.351 strains. With a prime-boost or a single-dose strategy, this vaccine elicits a robust neutralizing antibody and full protection against infection with the authentic D614G or B.1.351 strain in human angiotensin-converting enzyme 2 transgene mice. Interestingly, 8 months after inoculation with the D614G-specific vaccine, a new boost with this bivalent vaccine potently elicits cross-neutralizing antibodies for SARS-CoV-2 variants in rhesus macaques. We suggest that the D614G/B.1.351 bivalent vaccine could be used as an initial single dose or a sequential enforcement dose to prevent infection with SARS-CoV-2 and its variants.
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COVID-19/prevención & control , Protección Cruzada , SARS-CoV-2/inmunología , Vacunas Combinadas/uso terapéutico , Animales , Células CHO , Vacunas contra la COVID-19/síntesis química , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , Chlorocebus aethiops , Cricetulus , Protección Cruzada/inmunología , Femenino , Células HEK293 , Humanos , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Nanopartículas , Vacunación/métodos , Vacunas Combinadas/síntesis química , Vacunas Combinadas/inmunología , Células VeroRESUMEN
The SARS-CoV-2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first-generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS-CoV-2 variants as the major target. Here, receptor binding domain (RBD)-conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single-dose and a prime-boost strategy, these RBD-conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS-CoV-2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross-protective NAbs against almost all the notable SARS-CoV-2 variants including the Omicron variant in rhesus macaques by the third re-boost with trivalent vaccines is found. These results suggest that RBD-based monovalent or multivalent nanoparticle vaccines provide a promising second-generation vaccine strategy for SARS-CoV-2 variants.
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COVID-19 , Nanopartículas , Animales , Anticuerpos ampliamente neutralizantes , COVID-19/prevención & control , Macaca mulatta/metabolismo , Ratones , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas ConjugadasRESUMEN
Thalictrum fortunei S. Moore, a perennial plant distributed in the southeastern part of China, has been used in Traditional Chinese Medicine for thousands of years for its antitumor, antibacterial and immunoregulatory effects. In order to investigate the active components and the mechanism of the anti-tumor effects of Thalictrum fortunei, the growth inhibitory effects of eight triterpenoids isolated from the aerial parts of the plant on tumor cell lines were examined by 3-(4,5)-dimethylthiazoy1-3,5-diphenyltetrazolium bromide (MTT) assay. The MTT-assay results showed that the inhibitory activity of 3-O-ß-D-glucopyranosyl-(1â4)-ß-D-fucopyranosyl(22S,24Z)-cycloart-24-en-3ß,22,26-triol 26-O-ß-D-glucopyranoside (1) was stronger than that of the other seven tested triterpenoids on human hepatoma Bel-7402 cell line (Bel-7402), human colon lovo cells (LoVo), human non-small cells lung cancer NCIH-460 cells (NCIH-460) and human gastric carcinoma SGC-7901 cells (SGC-7901) after 48 h treatment in vitro, with the IC(50) values of 66.4, 84.8, 73.5, 89.6 µM, respectively. Moreover, the antitumor mechanism of compound 1 on Bel-7402 cell was explored through nucleus dyeing, fluorescence assay, flow cytometry and western blot. The flow cytometric analysis results revealed that compound 1 caused apoptosis and mitochondrial membrane potential (MMP) loss in Bel-7402 cells. A fluorescence assay indicated that intracellular reactive oxygen species (ROS) were markedly provoked by compound 1 treatment compared to control cells. Immunoblot results showed that compound 1 significantly increased the expression levels of cleaved caspase-3, P53 and Bax protein, and decreased the expression level of Bcl-2 protein. These findings indicate that compound 1 inhibits the growth activity of tumor cells, probably through the P53 protein-induced apoptosis pathway.