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1.
Clin Cancer Res ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022322

RESUMO

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus induced immunotherapy. EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of recurrent glioblastoma (GBM) patients treated with oHSV was used to evaluate the effect of NOTCH signaling on virus induced immunotherapy. RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1 expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH activated macrophages increased the secretion of CCL2 which further amplified myeloid derived suppressor cells (MDSCs). CCL2 and IL-10 induction was also observed in serum of recurrent GBM patients treated with oHSV (rQnestin34.5) (NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV induced immunosuppressive TME and activated a CD8 dependent anti-tumor memory response, resulting in a therapeutic benefit. CONCLUSIONS: NOTCH induced immunosuppressive myeloid cell recruitment limited anti-tumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.

2.
Gastroenterology ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34999097

RESUMO

BACKGROUND & AIMS: Pancreatic cancer (PC) is the third leading cause of cancer-related death with a 5-year survival rate of approximately 10%. It typically presents as a late-stage incurable cancer and chemotherapy provides modest benefit. Here, we demonstrate the feasibility, safety, and potency of a novel human natural killer (NK) cell-based immunotherapy to treat PC. METHODS: The expression of prostate stem cell antigen (PSCA) was evaluated in primary PC at mRNA and protein levels. The processes of retroviral transduction, expansion, activation, and cryopreservation of primary human NK cells obtained from umbilical cord blood were optimized, allowing us to develop frozen, off-the-shelf, allogeneic PSCA chimeric antigen receptor (CAR) NK cells. The safety and efficacy of PSCA CAR NK cells also expressing soluble (s)IL-15 (PSCA CAR_s15 NK cells) were evaluated in vitro and in vivo. RESULTS: PSCA was elevated in primary human PC compared to the adjacent or other normal tissues. PSCA CAR_s15 NK cells displayed significant tumor-suppressive effects against PSCA(+) PC in vitro before and after one cycle of freeze-thaw. The viability of frozen PSCA CAR_s15 NK cells persisted more than 90 days in vivo following their last infusion and significantly prolonged the survival of mice engrafted with human PC. CONCLUSIONS: PSCA CAR_s15 NK cells showed therapeutic efficacy in human metastatic PC models without signs of systematic toxicity, providing a strong rationale to support clinical development.

3.
Spectrochim Acta A Mol Biomol Spectrosc ; 271: 120881, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35042042

RESUMO

Precise design of organic photosensitizers (PSs) promoted the technological innovation for multimodal imaging-guided synergistic therapy. Nonetheless, various group substitution could not only optimize the basic photophysical behavior, but possibly change the aggregate, which handicaps the deep understanding of the "Formula-Aggergete-Property" relationship. Bearing this in mind, herein two isomers, named 6-TDE and 7-TDE, were prepared via substituting position modification. Among them, 6-TDE exhibited the grid-like structure, while 7-TDE presented wavy-like structure. Despite the aggregates were different, 6-TDE and 7-TDE shared common features including partly twisted backbone and non-overlapped-orbit, hence resulting in similar optical physical behavior such as decent extinction coefficient, near-IR emission, large stockes shifts, etc. Meanwhile, though two PSs could both generated Type-I and Type-II ROS, 7-TDE possessed smaller singlet-triplet splitting (ΔEST), which exhibited favorable ROS as well as outstanding mitochondrial targeting, achieving efficient photodynamic therapy (PDT) effect. During this process, mitochondrial autophagy could be tracked and observed effectively and in real-time. Moreover, 7-TDE presented outstanding performance in multimodal imaging, including fluorescence imaging (FLI), photoacousticimaging (PAI) and photothermal imaging (PTI). This study enriches the strategy of precise molecular engineering to optimize theranostic agents.

4.
Infect Dis Ther ; 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35050490

RESUMO

INTRODUCTION: Pneumocystis pneumonia is a common opportunistic infection in patients with HIV/AIDS, and is a leading cause of death in this population. Early selection of effective treatment is therefore critical to reduce mortality. We conducted a clinical trial to compare the effectiveness and safety of three different antifungal treatment regimens in HIV-infected patients with moderate to severe PCP. METHODS: Our study was a multicenter, observational prospective clinical trial. We recruited 320 HIV-infected patients with moderate to severe PCP, and stratified these subjects into a trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy group, a TMP-SMX plus clindamycin group, and a TMP-SMX plus caspofungin group. Patients were invited to participate in 12 weeks of follow-up. Outcomes included the difference in overall mortality and the proportion of overall positive response to treatment in the three groups at weeks 4 and 12, the difference in treatment duration, and the proportion of adverse events among the three groups during the study period. RESULTS: The probability of survival not statistically different among three treatment groups. Mortality in the TMP-SMX monotherapy group (group 1) was 15/115 (13.04%) vs. 20/83 (24.10%) in the TMP-SMX plus clindamycin group (group 2) vs. 24/107 (22.43%) in the TMP-SMX plus caspofungin group (group 3) at week 12 (p = 0.092). The overall positive response rate to treatment in the three groups was 24.14%, 34.94%, and 38.32%, respectively, at week 4, and 33.91%, 38.55%, and 44.86%, respectively, at week 12. No significant difference in the overall positive response rate to treatment at either week 4 or week 12 was noted (p = 0.061, p = 0.246). Rates of changes to therapy were 6.50% (8/123) in group 1, 3.40% (3/87) in group 2, and 2.70% (3/110) in group 3, and did not differ significantly among the three groups (p = 0.376). There were also no significant differences in adverse events among the three treatment groups of patients with moderate to severe PCP. CONCLUSIONS: Our results indicate that there are no significant statistical differences among the three studied treatment regimens in terms of antifungal effectiveness in HIV-infected patients with moderate to severe PCP. TMP-SMX monotherapy is a convenient, cheap, and effective therapeutic drug regimen to treat HIV-infected patients with moderate to severe PCP, and is an appropriate treatment strategy in resource-limited settings. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov , ID: ChiCTR1900021195. Registered on February 1, 2019.

5.
Proc Natl Acad Sci U S A ; 119(3)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35027451

RESUMO

The axis of platelet-derived growth factor (PDGF) and PDGF receptor-beta (PDGFRß) plays prominent roles in cell growth and motility. In addition, PDGF-D enhances human natural killer (NK) cell effector functions when binding to the NKp44 receptor. Here, we report an additional but previously unknown role of PDGF-D, whereby it mediates interleukin-15 (IL-15)-induced human NK cell survival but not effector functions via its binding to PDGFRß but independent of its binding to NKp44. Resting NK cells express no PDGFRß and only a low level of PDGF-D, but both are significantly up-regulated by IL-15, via the nuclear factor κB signaling pathway, to promote cell survival in an autocrine manner. Both ectopic and IL-15-induced expression of PDGFRß improves NK cell survival in response to treatment with PDGF-D. Our results suggest that the PDGF-D-PDGFRß signaling pathway is a mechanism by which IL-15 selectively regulates the survival of human NK cells without modulating their effector functions.

6.
Nat Prod Res ; : 1-5, 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35045779

RESUMO

This study investigated the content and biological activity of three solvent extracts of Adonis ramosa Franch (AR), which contains 12 types of phytochemicals. The overall yield and total protein content of the aqueous extract were the highest, and it exhibited the highest hydroxyl and superoxide radical-scavenging abilities, copper chelating abilities, and cupric reducing antioxidant capacity. Ethanol extract had the highest total phenolic, flavonoid, and carbohydrate contents, and it showed the highest iron chelating activity, and HClO- and nitrite-scavenging abilities. Methanol AR extract contained the highest total steroid and tannin contents; it also demonstrated high radical- and reactive oxygen species-scavenging abilities and had the best ferric reducing antioxidant power, which allowed it to effectively prevent ß-carotene bleaching. Methanol extract also showed good stability and low toxicity. All tested solvent extracts of AR exhibited weak enzyme-inhibitory activities for four enzymes (α-glucosidase, α-amylase, acetylcholinesterase and butyrylcholinesterase). Overall, AR can serve as a natural antioxidant.

7.
Front Med (Lausanne) ; 8: 779181, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869498

RESUMO

Background: The optimal timing for initiation of antiretroviral therapy (ART) in HIV-positive patients with cryptococcal meningitis (CM) has not, as yet, been compellingly elucidated, as research data concerning mortality risk and the occurrence of immune reconstitution inflammatory syndrome (IRIS) in this population remains inconsistent and controversial. Method: The present multicenter randomized clinical trial was conducted in China in patients who presented with confirmed HIV/CM, and who were ART-naïve. Subjects were randomized and stratified into either an early-ART group (ART initiated 2-5 weeks after initiation of antifungal therapy), or a deferred-ART group (ART initiated 5 weeks after initiation of antifungal therapy). Intention-to-treat, and per-protocol analyses of data for these groups were conducted for this study. Result: The probability of survival was found to not be statistically different between patients who started ART between 2-5 weeks of CM therapy initiation (14/47, 29.8%) vs. those initiating ART until 5 weeks after CM therapy initiation (10/55, 18.2%) (p = 0.144). However, initiating ART within 4 weeks after the diagnosis and antifungal treatment of CM resulted in a higher mortality compared with deferring ART initiation until 6 weeks (p = 0.042). The incidence of IRIS did not differ significantly between the early-ART group and the deferred-ART group (6.4 and 7.3%, respectively; p = 0.872). The percentage of patients with severe (grade 3 or 4) adverse events was high in both treatment arms (55.3% in the early-ART group and 41.8% in the deferred-ART group; p=0.183), and there were significantly more grade 4 adverse events in the early-ART group (20 vs. 13; p = 0.042). Conclusion: Although ART initiation from 2 to 5 weeks after initiation of antifungal therapy was not significantly associated with high cumulative mortality or IRIS event rates in HIV/CM patients compared with ART initiation 5 weeks after initiation of antifungal therapy, we found that initiating ART within 4 weeks after CM antifungal treatment resulted in a higher mortality compared with deferring ART initiation until 6 weeks. In addition, we observed that there were significantly more grade 4 adverse events in the early-ART group. Our results support the deferred initiation of ART in HIV-associated CM. Clinical Trials Registration: www.ClinicalTrials.gov, identifier: ChiCTR1900021195.

8.
Front Cell Dev Biol ; 9: 773048, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34901018

RESUMO

Lung cancer is the leading cause of cancer death worldwide. Cisplatin is the major DNA-damaging anticancer drug that cross-links the DNA in cancer cells, but many patients inevitably develop resistance with treatment. Identification of a cisplatin sensitizer might postpone or even reverse the development of cisplatin resistance. Halofuginone (HF), a natural small molecule isolated from Dichroa febrifuga, has been found to play an antitumor role. In this study, we found that HF inhibited the proliferation, induced G0/G1 phase arrest, and promoted apoptosis in lung cancer cells in a dose-dependent manner. To explore the underlying mechanism of this antitumor effect of halofuginone, we performed RNA sequencing to profile transcriptomes of NSCLC cells treated with or without halofuginone. Gene expression profiling and KEGG analysis indicated that PI3K/AKT and MAPK signaling pathways were top-ranked pathways affected by halofuginone. Moreover, combination of cisplatin and HF revealed that HF could sensitize the cisplatin-resistant patient-derived lung cancer organoids and lung cancer cells to cisplatin treatment. Taken together, this study identified HF as a cisplatin sensitizer and a dual pathway inhibitor, which might provide a new strategy to improve prognosis of patients with cisplatin-resistant lung cancer.

9.
Ann Noninvasive Electrocardiol ; : e12905, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34741562

RESUMO

With the steadily increasing amount of leadless pacemaker implantations performed worldwide, it has called attention to the delivery difficulty in patients with severe large right heart. Nevertheless, limited studies have reported leadless pacemaker implantation in patients with tricuspid stenosis. Here, we report the successful implantation of leadless pacemaker in a 60-year-old female patient with giant right atrium and tricuspid valve stenosis. It is highlighted that leadless pacemaker should not be discouraged even if there are tricuspid valve stenosis and giant right atrium.

10.
J Invest Dermatol ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34774537

RESUMO

Cutaneous T cell lymphoma (CTCL) is characterized by a background of chronic inflammation, where malignant CTCL cells escape immune surveillance. To study how microRNAs (miRs) regulate T-cell exhaustion, we performed miR sequencing analysis, qRT-PCR, and in situ hybridization on 45 primary CTCL samples, three healthy skin samples, and CTCL cell lines, identifying miR-155-5p, miR-130b-3p, and miR-21-3p. Moreover, miR-155-5p, miR-130b-3p, and miR-21-3p positively correlated with immune checkpoint gene expression in lesional skin samples and were enriched in the IL-6/Jak/signal transducer and activator of transcription signaling pathway by gene set enrichment analysis. Further gene sequencing analysis showed decreased mRNA expression of the major negative regulators of Jak/signal transducer and activator of transcription signaling: SOCS, PIAS, and PTPN. Transfection of MyLa and HuT78 cells with anti-miR-155-5p, anti‒miR-21-3p, and anti‒miR-130b revealed a considerable increase in SOCS proteins along with a significant decrease in the levels of activated signal transducer and activator of transcription 3 and immune checkpoint surface protein expression as well as decreased cell proliferation. Downregulation of miR-155, miR-130, and miR-21 in CTCL cell lines decreased CTCL cell growth and facilitated CD8+ T-cell-mediated cytotoxic activity, with concordant production of IFN-γ and CD107a expression. Our results describe the mechanisms of miR-induced T-cell exhaustion, which provide a foundation for developing synthetic anti-miRs to therapeutically target the tumor microenvironment in CTCL.

11.
STAR Protoc ; 2(4): 100874, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34746857

RESUMO

Cytotoxic natural killer cells kill tumors and infected cells. We carried out CRISPR-based gene editing and transcriptional regulation in hard-to-manipulate NK-92 cells. NK-92-based therapies were found to be safe and efficacious in preclinical studies of cancers. Here, we have pioneered the generation and validation of NK-92 cells constitutively expressing Cas9 or dCas9 for knockout (CRISPRko), transcriptional activation (CRISPRa), or transcriptional repression (CRISPRi) of genes. Our CRISPR-engineered NK-92 cell platforms can be modified for research and off-the-shelf therapeutic applications.

12.
Medicine (Baltimore) ; 100(42): e27430, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34678871

RESUMO

ABSTRACT: This study aimed to compare between the clinical and laboratory characteristics of neurosyphilis and those of syphilis in human immunodeficiency virus (HIV) positive and explore the risk factors associated with the occurrence of neurosyphilis in the HIV infected.In-patients diagnosed with HIV and syphilis co-infection who underwent a lumbar puncture and completed cerebrospinal fluid (CSF) examination were divided into neurosyphilis group and syphilis group. The demographic characteristics, symptoms and signs, and laboratory tests of the 2 groups were comparatively analyzed. Logistic regression analysis was used to explore the risk factors associated with the occurrence of neurosyphilis.Among 81 patients, 33 patients were assigned to the neurosyphilis group, and 48 to the syphilis group. There were no significant differences in the age, gender, marital status, acquired immunodeficiency syndrome course, opportunistic infections, serum HIV viral load, and history of syphilis treatment. The difference in HIV transmission route between the 2 groups was statistically significant (P = .010), and the patients from the neurosyphilis group were mainly infected via heterosexual contact. The proportion of serum toludine red unheated serum test (TRUST) titer ≥1:16 in the neurosyphilis group were 78.8%, which was significantly higher compared to the syphilis group (48.9%). The level of CSF white blood cell count, CSF protein, and CSF HIV viral load in the neurosyphilis group were significantly higher than those of the syphilis group. The proportion of patients with neurological symptoms and signs in the neurosyphilis group was significantly higher compared to the syphilis group (P < .001). Multivariate logistic regression analysis showed that heterosexual contact transmission route, not received antiretroviral therapy, lower CD4 cell count and higher serum TRUST titer, untreated with syphilis, and neurological symptoms and signs were risk factors associated with the occurrence of neurosyphilis.The serum TRUST titer, CSF white blood cell count, CSF protein level, CSF HIV viral load, and the percentage of neurological symptoms and signs in the neurosyphilis group were higher. Heterosexual transmission route, not received antiretroviral therapy, and untreated with syphilis prompted the possibility of neurosyphilis occurrence.


Assuntos
Infecções por HIV/epidemiologia , Infecções por HIV/fisiopatologia , Neurossífilis/epidemiologia , Neurossífilis/fisiopatologia , Adulto , Fatores Etários , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , China , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Comportamento Sexual , Fatores Socioeconômicos , Carga Viral
13.
Artigo em Inglês | MEDLINE | ID: mdl-34603468

RESUMO

Objective: To explore the expression of helper T cells 17 (Th17)/regulatory T cells (Treg) in peripheral blood and related cytokines of patients with different types of ulcerative colitis (UC) and analyze their correlation with the disease. Methods: From January 2018 to December 2019, 53 patients diagnosed with UC in our hospital were selected. According to their medical syndromes, they were divided into the damp-heat internal accumulation group (n = 35) and the spleen-kidney yang deficiency group (n = 18). 21 healthy volunteers were selected as the control group. The Mayo scoring standard was used to determine the severity of the patient's condition. The expression levels of Th17/Treg cells and related cytokines in peripheral blood were compared between the groups. Pearson correlation was used to analyze the correlation between the ratio of Th17 and Treg cells in the peripheral blood of UC patients and the ratio of TH17/Treg with Mayo score. Results: The peripheral blood Th17 cell ratio and Th17/Treg ratio of the damp-heat internal accumulation and spleen-kidney yang deficiency group were higher than those of the control group; the Treg cell ratio was lower than that of the control group; the peripheral blood Th17 cell ratio and Th17/Treg ratio of the damp-heat internal accumulation group were higher those of the spleen-kidney yang deficiency group; and the proportion of Treg cells was lower than that of the spleen-kidney yang deficiency group (P < 0.05). The expression levels of serum IL-6, IL-17, IL-22, and TNF-α in the damp-heat internal accumulation and spleen-kidney yang deficiency group were higher than those of the control group; IL-10 and TGF-ß were lower than those of the control group; the levels of serum IL-6, IL-17, IL-22, and TNF-α in the damp-heat internal accumulation group were higher than those of the spleen-kidney yang deficiency group; and both IL-10 and TGF-ß were lower than those of the spleen-kidney yang deficiency group (P < 0.05). The peripheral blood Th17 cell ratio and Th17/Treg ratio in the moderately active period group and severely active period group were higher than those of the lightly active period group; the Treg cell ratio was lower than that of the lightly active period group; the peripheral blood Th17 cell ratio and Th17/Treg ratio in the severely active period group were higher than those in the moderately active period group; and the proportion of Treg cells was lower than that of the moderately active period group. Pearson correlation analysis showed that the proportion of Th17 cells and Th17/Treg in peripheral blood of UC patients were both positively correlated with Mayo score (r = 0.762, r = 0.777, P < 0.001). Treg was negatively correlated with Mayo score (r = -0.790, P < 0.001). Conclusion: There are differences in the expression of peripheral blood Th17/Treg cells and related cytokines among UC patients with different syndromes, and the damp-heat content is the most significant. The higher the ratio of Th17 cells in peripheral blood and the degree of Th17/Treg imbalance, the lower the ratio of Treg cells, and the more severe the condition of UC patients, which can provide a preliminary quantitative basis for the TCM classification and severity of the diagnosis of UC.

14.
Nat Commun ; 12(1): 5908, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625564

RESUMO

Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, represents an important immune checkpoint to inhibit phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(α)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.


Assuntos
Anticorpos/farmacologia , Glioblastoma/imunologia , Glioblastoma/terapia , Imunidade Inata , Vírus Oncolíticos/imunologia , Animais , Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Antígeno CD47 , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1/imunologia , Humanos , Imunoglobulina G , Imunoterapia , Células Matadoras Naturais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Terapia Viral Oncolítica/métodos , Fagocitose , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Clin Cancer Res ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645647

RESUMO

PURPOSE: mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the "don't eat me" pathway. However, this strategy is associated with severe toxicity. EXPERIMENTAL DESIGN: To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G4). RESULTS: Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47-SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. In vivo, these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection. CONCLUSIONS: Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.

16.
J Virol ; : JVI0096421, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34668775

RESUMO

A comprehensive analysis and characterization of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection model that mimics non-severe and severe coronavirus disease 2019 (COVID-19) in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2×103 and 2×104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lung, liver, and kidney, while lower doses (2×101 and 2×102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in post-mortem samples from COVID-19 patients. Finally, the mice that recovered from infection with a low dose of virus survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human post-mortem samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans being dose-dependent and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. Importance The pandemic of coronavirus disease 2019 (COVID-19) has reached nearly 240 million cases and caused nearly 5 million deaths worldwide as of October 2021, has raised an urgent need for the development of novel drugs and therapeutics to prevent the spread and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of anti-viral drugs and therapeutics.

17.
Acta Pharmacol Sin ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593973

RESUMO

The multi-generation heredity trait of hypertension in human has been reported, but the molecular mechanisms underlying multi-generational inheritance of hypertension remain obscure. Recent evidence shows that prenatal inflammatory exposure (PIE) results in increased incidence of cardiovascular diseases, including hypertension. In this study we investigated whether and how PIE contributed to multi-generational inheritance of hypertension in rats. PIE was induced in pregnant rats by intraperitoneal injection of LPS or Poly (I:C) either once on gestational day 10.5 (transient stimulation, T) or three times on gestational day 8.5, 10.5, and 12.5 (persistent stimulation, P). Male offspring was chosen to study the paternal inheritance. We showed that PIE, irrespectively induced by LPS or Poly (I:C) stimulation during pregnancy, resulted in multi-generational inheritance of significantly increased blood pressure in rat descendants, and that prenatal LPS exposure led to vascular remodeling and vasoconstrictor dysfunction in both thoracic aorta and superior mesenteric artery of adult F2 offspring. Furthermore, we revealed that PIE resulted in global alteration of DNA methylome in thoracic aorta of F2 offspring. Specifically, PIE led to the DNA hypomethylation of G beta gamma (Gßγ) signaling genes in both the F1 sperm and the F2 thoracic aorta, and activation of PI3K/Akt signaling was implicated in the pathologic changes and dysregulated vascular tone of aortic tissue in F2 LPS-P offspring. Our data demonstrate that PIE reprogrammed DNA methylome of cells from the germline/mature gametes contributes to the development of hypertension in F2 PIE offspring. This study broadens the current knowledge regarding the multi-generation effect of the cumulative early life environmental factors on the development of hypertension.

18.
mBio ; 12(5): e0233521, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34544279

RESUMO

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients. IMPORTANCE The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteases 3C de Coronavírus/metabolismo , Proteína DEAD-box 58/metabolismo , Receptores Imunológicos/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Células CACO-2 , Proteases 3C de Coronavírus/genética , Proteína DEAD-box 58/genética , Ensaio de Imunoadsorção Enzimática , Células HCT116 , Células HEK293 , Humanos , Imunidade Inata/genética , Imunidade Inata/fisiologia , Immunoblotting , Interferon Tipo I/metabolismo , Camundongos , Receptores Imunológicos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Ubiquitinação , Replicação Viral/genética , Replicação Viral/fisiologia
19.
Mol Ther Nucleic Acids ; 26: 388-400, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34552820

RESUMO

RNA-binding proteins (RBPs) are a set of proteins involved in many steps of post-transcriptional regulation to maintain cellular homeostasis. Ovarian cancer (OC) is the most deadly gynecological cancer, but the roles of RBPs in OC are not fully understood. Here, we reported that the RBP QKI5 was significantly negatively correlated with aggressive tumor stage and worse prognosis in serous OC patients. QKI5 could suppress the growth and metastasis of OC cells both in vitro and in vivo. Transcriptome analysis showed that QKI5 negatively regulated the expression of the transcriptional coactivator TAZ and its downstream targets (e.g., CTGF and CYR61). Mechanistically, QKI5 bound to TAZ mRNA and recruited EDC4, thus decreasing the stability of TAZ mRNA. Functionally, TAZ was involved in the QKI5-mediated tumor suppression of OC cells, and QKI5 expression was inversely correlated with TAZ, CTGF, and CYR61 expression in OC patients. Together, our study indicates that QKI5 plays a tumor-suppressive role and negatively regulates TAZ expression in OC.

20.
Int J Biol Sci ; 17(11): 2683-2702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345201

RESUMO

Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-α (TNF-α), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-α- mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-α activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-κB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells in vivo. We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3ß phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases.

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