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1.
Cancer Immunol Immunother ; 73(9): 173, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953982

RESUMO

Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.


Assuntos
Imunoterapia Adotiva , Terapia Viral Oncolítica , Vírus Oncolíticos , Receptores de Antígenos Quiméricos , Animais , Camundongos , Terapia Viral Oncolítica/métodos , Humanos , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/genética , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Herpesvirus Humano 1/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Linfócitos T/imunologia , Feminino , Glioblastoma/terapia , Glioblastoma/imunologia
2.
J Environ Manage ; 353: 120158, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38271883

RESUMO

Granular sludge has been recognized as an effective method for the application and industrialization of the anammox-based process due to its good biomass retention capacity and environmental tolerance. In this study, a one-stage autotrophic nitrogen removal (ANR) dual-partition system with airlift internal circulation was implemented for 320 days. A high nitrogen removal efficiency of 84.6% was obtained, while the nitrogen removal rate reached 1.28 g-N/L/d. ANR granular sludge dominated by Nitrosomonas and Candidatus Brocadia was successfully cultivated. Results showed that activity and abundance of functional flora first increased with granulation process, but eventually declined slightly when particle size exceeded the optimal range. Total anammox activity was observed to be significantly correlated with protein content (R2 = 0.9623) and nitrogen removal performance (R2 = 0.8796). Correlation network revealed that AnAOB had complex interactions with other bacteria, both synergy for nitrogen removal and competition for substrate. Changes in abundances of genes encoding the Carbohydrate Metabolism, Energy Metabolism, and Membrane Transport suggested energy production and material transfer were possibly blocked with further sludge granulation. Formation of ANR granular sludge promoted the interactions and metabolism of functional microorganisms, and the complex nitrogen metabolic pathways improved the performance stability. These results validated the feasibility of granule formation in the airlift dual-partition system and revealed the response of the ANR system to sludge granulation.


Assuntos
Nitrogênio , Esgotos , Oxirredução , Nitrogênio/análise , Desnitrificação , Reatores Biológicos/microbiologia
3.
J Transl Med ; 21(1): 23, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36635683

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T cells and immune checkpoint blockades (ICBs) have made remarkable breakthroughs in cancer treatment, but the efficacy is still limited for solid tumors due to tumor antigen heterogeneity and the tumor immune microenvironment. The restrained treatment efficacy prompted us to seek new potential therapeutic methods. METHODS: In this study, we conducted a small molecule compound library screen in a human BC cell line to identify whether certain drugs contribute to CAR T cell killing. Signaling pathways of tumor cells and T cells affected by the screened drugs were predicted via RNA sequencing. Among them, the antitumor activities of JK184 in combination with CAR T cells or ICBs were evaluated in vitro and in vivo. RESULTS: We selected three small molecule drugs from a compound library, among which JK184 directly induces tumor cell apoptosis by inhibiting the Hedgehog signaling pathway, modulates B7-H3 CAR T cells to an effector memory phenotype, and promotes B7-H3 CAR T cells cytokine secretion in vitro. In addition, our data suggested that JK184 exerts antitumor activities and strongly synergizes with B7-H3 CAR T cells or ICBs in vivo. Mechanistically, JK184 enhances B7-H3 CAR T cells infiltrating in xenograft mouse models. Moreover, JK184 combined with ICB markedly reshaped the tumor immune microenvironment by increasing effector T cells infiltration and inflammation cytokine secretion, inhibiting the recruitment of MDSCs and the transition of M2-type macrophages in an immunocompetent mouse model. CONCLUSION: These data show that JK184 may be a potential adjutant in combination with CAR T cells or ICB therapy.


Assuntos
Proteínas Hedgehog , Neoplasias , Humanos , Animais , Camundongos , Avaliação Pré-Clínica de Medicamentos , Detecção Precoce de Câncer , Imunoterapia , Citocinas , Imunoterapia Adotiva/métodos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Microambiente Tumoral , Neoplasias/terapia
4.
BMC Nephrol ; 23(1): 175, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35524226

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is identified as the pneumonia and acute respiratory distress syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). The intravascular thrombotic phenomena related to the COVID-19 are emerging as an important complication that contribute to significant mortality. CASE PRESENTATION: We present a 62-year-old man with severe COVID-19 and type 2 diabetes. After symptomatic and supportive treatment, the respiratory function was gradually improved. However, the patient suddenly developed abdominal pain, and the enhanced CT scan revealed renal artery thrombosis. Given the risk of surgery and the duration of the disease, clopidogrel and heparin sodium were included in the subsequent treatment. The patient recovered and remained stable upon follow-up. CONCLUSIONS: Thrombosis is at a high risk in patients with severe COVID-19 pneumonia because of hypercoagulable state, blood stasis and endothelial injury. Thrombotic events caused by hypercoagulation status secondary to vascular endothelial injury deserves our attention. Because timely anticoagulation can reduce the risk of early complications, as illustrated in this case report.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Trombofilia , Trombose , COVID-19/complicações , Diabetes Mellitus Tipo 2/complicações , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , Artéria Renal/diagnóstico por imagem , SARS-CoV-2 , Trombose/diagnóstico por imagem , Trombose/etiologia
5.
J Environ Manage ; 254: 109830, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31733477

RESUMO

This study aims to enhance hydrolysis and anaerobic digestion of corn cob (CC) by using food waste (FW) pretreatment. FW, which tends to be acidification in fermentation, was applied in this process as an acid-like agent to accelerate lignocellulose hydrolysis, aiming to promote methane yield in further digestion process. The effect of FW pretreatment on pH, soluble chemical oxygen demand (SCOD), volatile fatty acids (VFAs), cellulose/hemicellulose contents and cellulose crystallinity are specially focused. FW:CC = 1:3 based on volatile solid (VS) was found to be the optimal mixing ratio in pretreatment and its hydrolysis efficiency was 28% higher than the control group. An increase of 13.2% in cellulose reduction and a decrease of 6.7% in cellulose crystallinity was achieved at this ratio. Supplementation of FW increased VFA concentrations in slurry mixture that directly change the activities of enzymes and microorganisms. In the stage of methane production, the digester A3 (FW:CC = 1:6 based on VS) with higher hydrolysis efficiency presented the best performance in methane production with a specific methane yield of 401.6 mL/g·VS, due to the recovery of the pH in this digester to the optimal pH range for methanogens' metabolism (pH 6.3-7.2). Kinetics studies of cellulose/hemicellulose degradation indicated that the pretreatment of FW could improve the degradation of cellulose. Three-dimensional excitation emission matrix (3DEEM) results further confirmed that FW play an important role in lignocellulose hydrolysis. In addition, variations of lignocellulosic textures during the pretreatment were also cleared by using field emission-scanning electron microscopy (FE-SEM) analysis.


Assuntos
Alimentos , Eliminação de Resíduos , Anaerobiose , Reatores Biológicos , Hidrólise , Lignina , Metano , Zea mays
6.
Mol Vis ; 20: 1109-21, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25324681

RESUMO

PURPOSE: Retinal vascular dysfunction caused by vascular endothelial growth factor (VEGF) is the major pathological change that occurs in diabetic retinopathy (DR). It has recently been demonstrated that G protein-coupled receptor 91 (GPR91) plays a major role in both vasculature development and retinal angiogenesis. In this study, we examined the signaling pathways involved in GPR91-dependent VEGF release during the early stages of retinal vascular change in streptozotocin-induced diabetes. METHODS: Diabetic rats were assigned randomly to receive intravitreal injections of shRNA lentiviral particles targeting GPR91 (LV.shGPR91) or control particles (LV.shScrambled). Accumulation of succinate was assessed by gas chromatography-mass spectrometry (GC-MS). At 14 weeks, the ultrastructure and function of the retinal vessels of diabetic retinas with or without shRNA treatment were assessed using hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), and Evans blue dye permeability. The expression of GPR91, extracellular signal-regulated kinases 1 and 2 (ERK1/2) and cyclooxygenase-2 (COX-2) were measured using immunofluorescence and western blotting. COX-2 and VEGF mRNA were determined by quantitative RT-PCR. Prostaglandin E2 (PGE2) and VEGF secretion were detected using an enzyme-linked immunosorbent assay. RESULTS: Succinate exhibited abundant accumulation in diabetic rat retinas. The retinal telangiectatic vessels, basement membrane thickness, and Evans blue dye permeability were attenuated by treatment with GPR91 shRNA. In diabetic rats, knockdown of GPR91 inhibited the activities of ERK1/2 and COX-2 as well as the expression of PGE2 and VEGF. Meanwhile, COX-2, PGE2, and VEGF expression was inhibited by ERK1/2 inhibitor U0126 and COX-2 inhibitor NS-398. CONCLUSIONS: Our data suggest that hyperglycemia causes succinate accumulation and GPR91 activity in retinal ganglion cells, which mediate VEGF-induced retinal vascular change via the ERK1/2/COX-2/PGE2 pathway. This study highlights the signaling pathway as a potential target for intervention in DR.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , Dinoprostona/metabolismo , Sistema de Sinalização das MAP Quinases , Receptores Acoplados a Proteínas G/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Ácido Succínico/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
7.
Chempluschem ; 89(7): e202300740, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38439199

RESUMO

So far, it is still extremely challenging to develop an efficient catalyst for deep oxidation of methanol at low temperature. Herein, we report the construction of the highly dispersed CuAg alloy on the surface of Ce0.90In0.10Oδ nanorods support for catalyzing methanol deep oxidation. The composition, structure and properties of catalysts were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), ultraviolet-visible (UV-vis) spectroscopy and X-ray photoelectron spectroscopy (XPS). The results show that the CuxAg100-x/Ce0.90In0.10Oδ alloy catalysts exhibit superior catalytic activity and stability compared to pure Ag/Ce0.90In0.10Oδ, with the highest activity observed for Cu40Ag60/Ce0.90In0.10Oδ, accompanied by the light-off temperature (T50) and full conversion temperature (T90) of 115 and 145 °C, respectively. This is attributed to the synergistic effect of CuAg alloy, which results in electron transfer, generating more Ag0, and enhanced interaction between CuAg alloy and the support, leading to increased Ce3+ content and higher oxygen vacancy concentration. This work successfully applies CuAg alloy catalysts in thermo-catalytic reaction, offering promising prospects for CuAg alloy catalysts in the methanol deep oxidation.

8.
Bioresour Technol ; 402: 130775, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38701984

RESUMO

Acidification recovery in anaerobic digestion of food waste is challenging. This study explored its in-situ recovery using a co-substrate of food waste and waste activated sludge. Fe3O4 and bentonite were used as conductor and carrier, respectively, to enhance AD performance under severe acidification. The application of Fe3O4-bentonite resulted in a 152% increase in cumulative methane in the Fe3O4-bentonite 10 digester, demonstrating its effectiveness in restoring the acidified AD system. In acidified systems, bentonite enhanced the diversity and richness of microbial communities due to its buffering capacity. The excessive non-conductive polysaccharides excreted by bacteria in extracellular polymeric substances reduced the possibility of electron transfer by Fe3O4. However, in the synergistic application of Fe3O4 and bentonite, this resistance was alleviated, increasing the possibility of direct interspecies electron transfer, and accelerating the consumption of volatile fatty acids. This approach of integrating carrier and conductive materials is significant for in-situ restoration of acidified systems.


Assuntos
Bentonita , Metano , Esgotos , Bentonita/química , Anaerobiose , Metano/metabolismo , Concentração de Íons de Hidrogênio , Alimentos , Ácidos Graxos Voláteis , Reatores Biológicos , Ácidos/química , Resíduos , Compostos Férricos/química , Perda e Desperdício de Alimentos
9.
Sci Total Environ ; 922: 171339, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38428595

RESUMO

Inappropriate sterilization strategies inhibit microalgal growth when culturing microalgae with anaerobic digestate. This study aimed to scientifically select a low-cost disinfection pretreatment of anaerobic digestate for large-scale microalgae cultivations. In this work, three different methods, including autoclaving, ultraviolet or NaClO treatments, were employed to sterilize the municipal anaerobic digestate. Scenedesmus quadricauda was then cultured in diluted liquid digestate for the simultaneous lipid production and nutrient removal. The results indicated that the growth of S. quadricauda was inhibited after NaClO treatment due to the residual free chlorine. The 15-min ultraviolet effectively mitigated microbial contamination and increasing nutrient availability, enhancing the electron transport of microalgal photosynthesis. After 6-days cultivation, the microalgal biomass concentration of the ultraviolet group was 1.09 g/L, comparable to that of the autoclaving group (1.15 g/L). High nutrient removal efficiency was observed: COD (93.30 %), NH4+-N (92.56 %), TN (85.82 %) and TP (95.12 %). Moreover, S. quadricauda outcompeted the indigenous microorganisms, contributing to its dominance in the culture system of ultraviolet group. The facultative anaerobe Comamonadaceae and aerobes Moraxellaceae, rather than strict anaerobe Paludibacteraceae and Bacteroidetes_vadinHA17, played vital roles in synergistic removal of contaminants by bacteria and algae. The potential competition for nitrogen and phosphorus by bacteria contributed to the ultraviolet group having the greatest lipid content (48.19 %). Therefore, this work suggested using 15-min ultraviolet treatment for anaerobic digestate in large-scale microalgae cultivation.


Assuntos
Microalgas , Scenedesmus , Raios Ultravioleta , Anaerobiose , Bactérias , Biomassa , Nitrogênio , Bacteroidetes , Lipídeos
10.
Transl Oncol ; 45: 101981, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38703658

RESUMO

The development of innovative therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) is a critical medical requirement. Antibody-drug conjugates (ADC) targeting tumor-specific surface antigens have demonstrated clinical effectiveness in treating hematologic and solid malignancies. Our investigation revealed high expression levels of SLC3A2 in HNSCC tissue and cell lines. This study aimed to develop a novel anti-SLC3A2 ADC and assess its antitumor effects on HNSCC both in vitro and in vivo. This study developed a potent anti-SLC3A2 ADC (19G4-MMAE) and systematically investigated its drug delivery potential and antitumor efficacy in preclinical models. This study revealed that 19G4-MMAE exhibited specific binding to SLC3A2 and effectively targeted lysosomes. Moreover, 19G4-MMAE induced a significant accumulation of reactive oxygen species (ROS) and apoptosis in SLC3A2-positive HNSCC cells. The compound demonstrated potent antitumor effects derived from MMAE against SLC3A2-expressing HNSCC in preclinical models, displaying a favorable safety profile. These findings suggest that targeting SLC3A2 with an anti-SLC3A2 ADC could be a promising therapeutic approach for treating HNSCC patients.

11.
Water Res ; 257: 121746, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38733966

RESUMO

Sewage sludge is promising for the recovery and utilisation of nutrient components, but its complex nature hinders the release of these components. The combination of pH and thermal modifications shows promise for the release of nutrient components from sludge. However, comprehensive studies on the full spectrum of pH levels and corresponding mechanisms of pH-varying thermal modification are lacking. In this study, the main nutrient components, physicochemical properties, molecular structure, and noncovalent interactions of sludge were comprehensively investigated through pH-varying thermal modification (within a pH range of 2.0 to 12.0 under the same thermal condition). The experimental results showed that the release of main organics, particularly nitrogen (N)-containing organics, was well-fitted, with a tick-like function (R2: 0.74-0.96). The thermal protons exhibited a notable accumulative mutagenic effect on the N-containing organics release, while the thermal hydroxyl ions had a more direct effect, as revealed by the changes in multivalent metals and molecular structures with the protonation-deprotonation of carboxyl groups. The driving force for the release of N-containing organics was identified as the fluctuation of electrostatic interactions at the solid-liquid interface of the sludge. However, the release of phosphorus (P)-containing substances exhibited a contrasting response to that of N-containing substances with varying pH, likely because the reaction sites of thermal protons and thermal hydroxyl ions for P-containing substances were different. Moreover, high concentrations of thermal protons and hydroxyl ions collapsed the Lifshitz-van der Waals interactions of sludge, resulting in a decrease in viscoelasticity and binding strength. These propositions were further confirmed through statistical analyses of the main indicators of the main nutrient components, physicochemical properties, and noncovalent interactions of sludge. These findings can provide a basis for optimising characteristic-specific methods to recovery nutrient components (N/P) from sludge.


Assuntos
Nitrogênio , Fósforo , Esgotos , Esgotos/química , Fósforo/química , Nitrogênio/química , Concentração de Íons de Hidrogênio , Eliminação de Resíduos Líquidos/métodos
12.
Nutr Diabetes ; 14(1): 53, 2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39004614

RESUMO

BACKGROUND: Limited studies have investigated the correlation between fat distribution and the risk of diabetic retinopathy (DR) in the general population with diabetes. The relationship between obesity and DR remains inconclusive, possibly due to using simple anthropometric measures to define obesity. This study investigates the relationships between the android-to-gynoid fat ratio (A/G ratio, measured using dual-energy X-ray absorptiometry) and DR within the US population with diabetes. METHODS: The study used a population-based, cross-sectional approach based on the 2003-2006 and 2011-2018 data of the National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression analyses were performed on participants with diabetes to evaluate the contribution of body mass index (BMI), waist-to-height ratio (WHtR), and A/G ratio to the prevalence of DR. RESULTS: The prevalence of DR was 22.2, 21.2, and 17.6% among participants with A/G ratios <1.0, 1.0-1.2, and ≥1.2, respectively. After adjusting sex, age, ethnicity, diabetes duration, hemoglobin A1c level, blood pressure level, and non-high-density lipoprotein cholesterol level, a higher A/G ratio (≥1.2) was independently associated with decreased odds of DR (odds ratio [OR], 0.565; 95% CI: 0.372-0.858) compared with the A/G ratio of 1.0-1.2. Associations between a higher A/G ratio and DR remained statistically significant after adjusting for BMI (OR, 0.567; 95% CI: 0.373-0.861) and WHtR (OR, 0.586; 95% CI: 0.379-0.907). Moreover, these associations remained statistically significant in analyses using the ethnic-specific tertiles for the A/G ratio. In sex-stratified models, these correlations remained in males. There was a significant inverse association between the A/G ratio and diabetes duration in males, which persisted after multivariable adjustments (p < 0.05). CONCLUSIONS: A novel finding indicates that a higher A/G ratio is associated with a reduced likelihood of DR in males with diabetes. The results from NHANES underscore the importance of considering imaging-based fat distribution as a critical indicator in clinical practice.


Assuntos
Absorciometria de Fóton , Distribuição da Gordura Corporal , Índice de Massa Corporal , Retinopatia Diabética , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/sangue , Estudos Transversais , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto , Prevalência , Idoso , Obesidade/epidemiologia , Fatores de Risco , Razão Cintura-Estatura , Diabetes Mellitus/epidemiologia
13.
Cancer Lett ; 585: 216660, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38266806

RESUMO

In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple myeloma cells highly expressed CD47 molecule and interact with the SIRPα ligand on the surface of macrophages, in which evade the clearance of macrophages through the activation of "don't eat me" signal. In this study, a BCMA-directed universal CAR-T cells, BC404-UCART, secreting a CD47-SIRPα blocker was developed using CRISPR/Cas9 gene-editing system. BC404-UCART cells significantly inhibited tumor growth and prolonged the survival of mice in the xenograft model. The anti-tumor activity of BC404-UCART cells was achieved via two mechanisms, on the one hand, the UCAR-T cells directly killed tumor cells, on the other hand, the BC404-UCART cells enhanced the phagocytosis of macrophages by secreting anti-CD47 nanobody hu404-hfc fusion that blocked the "don't eat me" signal between macrophages and tumor cells, which provides a potential strategy for the development of novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.


Assuntos
Mieloma Múltiplo , Neoplasias , Humanos , Camundongos , Animais , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Antígeno de Maturação de Linfócitos B , Antígeno CD47/genética , Receptores Imunológicos/genética , Linfócitos T , Antígenos de Diferenciação , Neoplasias/patologia , Fagocitose
14.
Adv Sci (Weinh) ; : e2400024, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39013083

RESUMO

Clinical trials of Chimeric Antigen Receptor T-cell (CAR-T) therapy have demonstrated remarkable success in treating both solid tumors and hematological malignancies. Nanobodies (Nbs) have emerged as promising antigen-targeting domains for CARs, owing to their high specificity, robust stability, and strong affinity, leading to significant advancements in the field of Nb-CAR-T. In the realm of T-cell acute lymphoblastic leukemia (T-ALL) targets, CD5 stands out as a potentially excellent candidate for T-cell-based CAR therapy, due to its distinct expression on the surface of malignant T-ALL cells. To mitigate graft-versus-host disease associated with allogeneic CAR-T, γδT cells are selected and stimulated from peripheral blood mononuclear cells, and γδT cells are engineered via CRISPR/Cas9 to eliminate fratricide, enabling the creation of fratricide-resistant CAR-γδTCD5- cells. In vitro transcribed (IVT) mRNA is used to construct CAR-T, presenting a safer, faster, and cost-effective method compared to traditional viral vector approaches. In this study, a CD5-VHH library is constructed, and specific CD5-nanobodies are screened for subsequent use in CD5-CAR-γδTCD5- therapy. IVT-mRNA-CD5-CAR-γδTCD5- cells exhibited favorable functional characteristics and demonstrated antitumor efficacy against malignant T cell lines, underlining the potential for advancing mRNA-CD5-CAR-γδTCD5- therapy.

15.
Cancer Lett ; 588: 216760, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38428724

RESUMO

Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and redirect cytotoxic T lymphocytes, enhancing the antitumor response. To take advantage of the specific infection capacity and carrying ability of exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-1dko-B7H3nb/CD3 or HSV-1dko-B7H3nb/mCD3, carrying a B7H3nb/CD3 or B7H3nb/mCD3 BsAb that replicates and expresses BsAb in tumor cells in vitro and in vivo. The new generation of oncolytic viruses has been genetically modified using CRISPR/Cas9 technology and the cre-loxp system to increase the efficiency of HSV genome editing. Additionally, we used two fully immunocompetent models (GL261 and MC38) to assess the antitumor effect of HSV-1dko-B7H3nb/mCD3. Compared with the HSV-1dko control virus, HSV-1dko-B7H3nb/mCD3 induced enhanced anti-tumor immune responses and T-cell infiltration in both GL261 and MC38 models, resulting in improved treatment efficacy in the latter. Furthermore, flow cytometry analysis of the tumor microenvironment confirmed an increase in NK cells and effector CD8+ T cells, and a decrease in immunosuppressive cells, including FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and CD206+ macrophages (M2). Overall, our study identified a novel camel B7H3 nanobody and described the genetic modification of the HSV-1 genome using CRISPR/Cas9 technology and the cre-loxp system. Our findings indicate that expressing B7H3nb/CD3 BsAb could improve the antitumor effects of HSV-1 based oncolytic virus.


Assuntos
Herpesvirus Humano 1 , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Herpesvirus Humano 1/genética , Linfócitos T CD8-Positivos , Vírus Oncolíticos/genética , Neoplasias/genética , Terapia Viral Oncolítica/métodos , Microambiente Tumoral
16.
Exp Eye Res ; 109: 31-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23379999

RESUMO

Recent research using a rat oxygen-induced retinopathy model has demonstrated that the G protein-coupled receptor 91 (GPR91) of retinal ganglion neurons is the principal respondent to succinate and consequently induces the release of angiogenic factor vascular endothelial growth factor (VEGF). The aim of this study was to determine whether GPR91 modulate the release of VEGF from retinal ganglion cells in a high-glucose model in vitro and to dissect the role of GPR91 in the pathogenesis of diabetic retinopathy. We constructed a lentiviral small hairpin RNA (shRNA) expression vector targeting GPR91 (LV.shGPR91) and infected the retinal ganglion cell line RGC-5 to obtain stably transduction system. The knockdown effect of GPR91 was detected by Western blotting. After incubation with succinate and various concentrations of glucose, the expression of VEGF in RGC-5 cells was evaluated by real-time PCR and Western blotting, and the release of VEGF protein was measured using an ELISA assay. Conditioned media were also collected, and the effects of proliferation and migration of RF/6A cells, a vascular endothelial cell line, were evaluated by CCK-8 and Transwell assays. The phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and c-Jun N-terminal kinase (JNK) in RGC-5 cells after exposure to high glucose were evaluated by Western blotting. Following a single exposure of RGC-5 cells to the encoding lentivirus, more than 80% of infected cells expressed GFP at 72 h, and the level of GPR91 protein was significantly downregulated. GPR91 shRNA inhibited the cell survival rates of RGC-5 cells incubated with high glucose (F = 21.36, P = 0.002). The mRNA and protein expression of VEGF in LV.shGPR91 RGC-5 cells decreased markedly compared to that of LV.shScrambled or untransduced control cells incubated with different concentrations of glucose or succinate (P < 0.01). The VEGF protein level in medium from RGC-5 cells treated with high glucose (F = 57.43, P = 0.000) or succinate (F = 241.91, P = 0.000) was also downregulated when transduced with GPR91 shRNA. The siRNA-mediated knockdown of GPR91 was also found to inhibit the proliferation of RF/6A cells in high glucose-stimulated (t = 8.21, P = 0.001) or succinate-stimulated (t = 3.36, P = 0.028) conditioned media. However, the siRNA-mediated knockdown of GPR91 suppressed the migration of RF/6A cells incubated with moderate levels of glucose (t = 2.97, P = 0.018). The exposure of RGC-5 cells to high glucose activated ERK1/2 and JNK MAPK signaling blocking by GPR91 shRNA (P < 0.01). These results indicate that GPR91 modulates the high glucose-induced VEGF release of RGC-5 cells, possibly by inhibiting ERK1/2 and JNK MAPK signaling.


Assuntos
Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Glucose/farmacologia , Receptores Acoplados a Proteínas G/genética , Células Ganglionares da Retina/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Transformada , Movimento Celular/fisiologia , Proliferação de Células , Sobrevivência Celular/fisiologia , Retinopatia Diabética/fisiopatologia , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Lentivirus/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Macaca mulatta , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Células Ganglionares da Retina/citologia , Vasos Retinianos/citologia , Vasos Retinianos/metabolismo
17.
Sci Total Environ ; 886: 164002, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37169196

RESUMO

In practice, the influent organic matter is often pre-treated to reduce the impact on partial nitritation-anammox (PNA) process. However, the influent organics may also drive the denitrification process and improve total nitrogen removal efficiency of the PNA process. Thus, we designed and operated a novel dissolved oxygen-differentiated airlift internal circulation PNA (PNA-DOAIC) system in this study at various influent C/N ratios of 0-4.0. Nitrogen removal performance, microbial activity and community, and metabolic pathways in response to varying organic matter stress were investigated via the continuous experiment combined with batch test. The results showed that the optimum influent C/N ratio was 2.0 in this system, and the efficient and stable operation was still maintained at the C/N ratios of 0-3. At this time, the TN removal efficiency and removal rate could reach 95.1 % and 0.93 kg-N/m3/d, respectively, while COD efficiency remained at 95.4 %. Efficient removal performance was achieved via the PNA coupled with denitrification. However, the anammox bacteria (AnAOB) activity and abundance declined persistently as the influent C/N ratio was further raised, and heterotrophic bacteria gradually replaced AnAOB as dominate genus. Meanwhile, metabolic functions involving the material exchange and organic degradation were significantly enhanced. Nitrogen removal pathways changed from PNA to the nitrification-denitrification process. This study provides deep insights into effects of organic matter on the PNA process and can expand the application scope of this novel PNA-DOAIC bioreactor.


Assuntos
Oxidação Anaeróbia da Amônia , Desnitrificação , Oxirredução , Nitrificação , Nitrogênio/metabolismo , Reatores Biológicos/microbiologia , Bactérias/metabolismo , Redes e Vias Metabólicas , Esgotos/microbiologia
18.
J Environ Public Health ; 2022: 2993982, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36034617

RESUMO

Under the network environment, mental health and safety work on college is related to national security and campus security. Moreover, it affects the healthy development of college students. In the era of ever-changing mobile Internet, colleges and universities must take practical countermeasures against the problems in mental health and safety education on college and improve the relevance and effectiveness of college students' network safety education. This paper first finds the problems of college students' mental health and safety through questionnaire survey and analyzes the current situation of college students' mental health and safety under the current networked environment. In response to the problems found, we propose complete and systematic educational countermeasures. At the same time, we need to firmly establish the strategic awareness of network security education and strengthen the construction of network security education in colleges and universities. We should strengthen the construction of network security education in colleges and universities, form a joint effort of schools, families, government, and society, and improve the quality and effectiveness of network security education.


Assuntos
Saúde Mental , Estudantes , Humanos , Instituições Acadêmicas , Inquéritos e Questionários , Universidades
19.
Water Res ; 220: 118653, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35635911

RESUMO

The bioconversion of waste activated sludge (WAS) into methane is usually limited by the poor hydrolysis of sludge and/or poor syntrophic methanogenesis during anaerobic digestion (AD). In this study, the underlying mechanism of MOF-808 enhancing hydrolysis and syntrophic methanogenesis during AD process of WAS was investigated. Experimentally, with the effects of MOF-808 (150 mg MOF-808/g Volatile Solid (VS)), the methane production and the proportion of methane in biogas increased by approximately 26.7% and 15.6%, respectively, and the lag phase of methanogenesis decreased by 50.8%, which indicate that MOF-808 enhanced the generation efficiency of methane. The changes in activities of main hydrolytic enzymes with and without MOF-808 (150 mg MOF-808/g VS) during AD process revealed that MOF-808 improved the enzymatic hydrolysis of sludge, and the abiotic hydrolysis of sludge extracellular organic substances by MOF-808 shows that the maximum proportion and the initial increasing rate of low-molecular weight fractions increased by 60% and 583.7%, respectively, indicating that MOF-808 can greatly enhance the hydrolysis degree and rate of sludge via abiotic effect. These demonstrate that MOF-808 enhanced both biological and abiotic hydrolysis of sludge during AD. In addition, changes in the concentrations of acetate kinase and volatile fatty acids (VFAs) with and without MOF-808 (150 mg MOF-808/g VS) during AD process showed that MOF-808 accelerated the bioconversion of VFAs to methane, suggesting MOF-808 has a positive effect on syntrophic metabolism for methanogenesis. Moreover, further analyses of the microbial community structure of sludge samples with and without MOF-808 (150 mg MOF-808/g VS) showed that MOF-808 enriched hydrogen-producing bacteria and mixotrophic methanogens (i.e. Methanosarcina), and changed the methanogenic pathway via accelerating proton transfer between syntrophic anaerobes, especially improving the reduction of CO2 to methane, and resulting in highly efficient syntrophic methanogenesis. These findings, however, may provide an important reference for enhancing AD efficiency of WAS based on MOF-like materials.


Assuntos
Reatores Biológicos , Esgotos , Anaerobiose , Bactérias Anaeróbias/metabolismo , Ácidos Graxos Voláteis , Metano/metabolismo , Esgotos/química , Eliminação de Resíduos Líquidos/métodos
20.
Environ Sci Pollut Res Int ; 29(49): 73935-73945, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35643995

RESUMO

In this paper, we prepared a series of Ce1-xTixO2 (x = 0-0.20) nanorods by hydrothermal method, which were used to construct the PdCu/Ce1-xTixO2 catalysts. The Ce1-xTixO2 and PdCu/Ce1-xTixO2 samples were characterized by transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), N2 adsorption-desorption, X-ray diffraction (XRD), inductively coupled plasma optical emission spectrometer (ICP-OES), etc. Catalytic activity, stability, and repeatability of the catalysts for methanol oxidation were investigated. The results show that doping a proper amount of titanium could strengthen the interaction between Ce1-xTixO2 support and PdCu nanoalloy, thus increasing the oxygen vacancy concentration and promoting Pd species with a higher oxidation state. These modified properties are beneficial for the deep oxidation of methanol. The light-off temperature (T50) and full-conversion temperature (T90) of methanol over the PdCu/CeO2 catalyst are 108 °C and 159 °C, respectively. The greatest activity improvement is found for PdCu/Ce0.9Ti0.1O2, which shows the lowest T50 of 88 °C and T90 of 138 °C. Furthermore, neither PdCu/CeO2 nor the modified PdCu/CeO2 catalyst produces by-products and exhibit excellent stability and repeatability throughout the whole test period. This study provides a reference for in-depth understanding and designing of efficient and stable CeO2-based oxidation catalysts.


Assuntos
Cério , Metanol , Catálise , Cério/química , Oxigênio/química , Titânio/química
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