RESUMO
Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
Assuntos
Peptídeo Natriurético Tipo C , Neovascularização Patológica , Microambiente Tumoral , Animais , Neovascularização Patológica/tratamento farmacológico , Peptídeo Natriurético Tipo C/farmacologia , Peptídeo Natriurético Tipo C/uso terapêutico , Camundongos , Humanos , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/irrigação sanguínea , Imunidade/efeitos dos fármacosRESUMO
Chemical pollution poses a significant threat to human health, with detrimental effects on various physiological systems, including the respiratory, cardiovascular, mental, and perinatal domains. While the impact of pollution on these systems has been extensively studied, the intricate relationship between chemical pollution and immunity remains a critical area of investigation. The focus of this study is to elucidate the relationship between chemical pollution and human immunity. To accomplish this task, this study presents a comprehensive review that encompasses in vitro, ex vivo, and in vivo studies, shedding light on the ways in which chemical pollution can modulate human immunity. Our aim is to unveil the complex mechanisms by which environmental contaminants compromise the delicate balance of the body's defense systems going beyond the well-established associations with defense systems and delving into the less-explored link between chemical exposure and various immune disorders, adding urgency to our understanding of the underlying mechanisms and their implications for public health.
Assuntos
Poluição Ambiental , Humanos , Poluição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Exposição Ambiental/efeitos adversos , Imunidade/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , AnimaisRESUMO
HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.
Assuntos
Infecções por HIV , Animais , Camundongos , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Emtricitabina/uso terapêutico , Emtricitabina/farmacologia , Antirretrovirais/uso terapêutico , Antirretrovirais/farmacologia , Modelos Animais de Doenças , Masculino , Tenofovir/uso terapêutico , Tenofovir/farmacologia , Tenofovir/análogos & derivados , Citocinas/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Camundongos Endogâmicos C57BL , Imunidade/efeitos dos fármacos , Alanina/análogos & derivados , Alanina/uso terapêutico , Alanina/farmacologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Amidas , PiridonasRESUMO
The Endoplasmic Reticulum (ER) is associated with many cellular functions, from post-transcriptional modifications to the proper folding of proteins, and disruption of these functions causes ER stress. Although the relationship between epileptic seizures and ER stress has been reported, the contribution of ER stress pathways to epileptogenesis is still unclear. This study aimed to investigate the possible effects of ER stress-related molecular pathways modulated by mild- and high-dose Thapsigargin (Tg) on absence epileptic activity, CACNA1H and immune responses in WAG/Rij rats. For this purpose, rats were divided into four groups; mild-dose (20 ng) Tg, high-dose (200 ng) Tg, saline, and DMSO and drugs administered intracerebroventriculary. EEG activity was recorded for 1 h and 24 h after drug administration following the baseline recording. In cortex and thalamus tissues, GRP78, ERp57, GAD153 protein changes (Western Blot), Eif2ak3, XBP-1, ATF6, CACNA1H mRNA expressions (RT-PCR), NF-κB and TNF-α levels (ELISA) were measured. Mild-dose-Tg administration resulted in increased spike-wave discharge (SWD) activity at the 24th hour compared to administration of saline, and high-dose-Tg and it also significantly increased the amount of GRP78 protein, the expression of Eif2ak3, XBP-1, and CACNA1H mRNA in the thalamus tissue. In contrast, high-dose-Tg administration suppressed SWD activity and significantly increased XBP-1 and ATF6 mRNA expression in the thalamus, and increased NF-κB and TNF-α levels. In conclusion, our findings indicate that Tg affects SWD occurrence by modulating the unfolded protein response pathway and activating inflammatory processes in a dose-dependent manner.
Assuntos
Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático , Tapsigargina , Resposta a Proteínas não Dobradas , Animais , Tapsigargina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ratos , Masculino , Resposta a Proteínas não Dobradas/efeitos dos fármacos , NF-kappa B/metabolismo , Imunidade/efeitos dos fármacos , Eletroencefalografia , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genéticaRESUMO
Pyroptosis, a new mode of regulatory cell death, holds a promising prospect in tumor therapy. The occurrence of pyroptosis can trigger the release of damage-associated molecular patterns (DAMPs) and activate the antitumor immune response. Moreover, enhancing intracellular reactive oxygen species (ROS) generation can effectively induce pyroptosis. Herein, an integrated nanoplatform (hCZAG) based on zeolitic imidazolate framework-8 (ZIF-8) with Cu2+ and Zn2+ as active nodes and glucose oxidase (GOx) loading is constructed to evoke pyroptosis. GOx can effectively elevate intracellular hydrogen peroxide (H2O2) levels to regulate the unfavorable tumor microenvironment (TME). Cu2+ can be reduced to Cu+ by endogenous overexpressed GSH and both Cu2+ and Cu+ can exert Fenton-like activity to promote ROS generation and amplify oxidative stress. In addition, the accumulation of Cu2+ leads to the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), thus resulting in cuproptosis. Notably, the outburst of ROS induced by hCZAG activates Caspase-1 proteins, leads to the cleavage of gasdermin D (GSDMD), and induces pyroptosis. Pyroptosis further elicits an adaptive immune response, leading to immunogenic cell death (ICD). This study provides effective strategies for triggering pyroptosis-mediated immunotherapy and achieving improved therapeutic effects.
Assuntos
Glucose Oxidase , Piroptose , Espécies Reativas de Oxigênio , Microambiente Tumoral , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Animais , Glucose Oxidase/metabolismo , Glucose Oxidase/química , Humanos , Camundongos , Cobre/química , Peróxido de Hidrogênio/química , Linhagem Celular Tumoral , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Nanopartículas/química , Imunidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , ImidazóisRESUMO
Cytokines mediate cell-cell communication in the immune system and represent important therapeutic targets1-3. A myriad of studies have highlighted their central role in immune function4-13, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine-cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1ß induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell-cell communication networks in any immune response.
Assuntos
Citocinas , Imunidade , Análise de Célula Única , Animais , Camundongos , Comunicação Celular/efeitos dos fármacos , Citocinas/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunidade/efeitos dos fármacos , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Células Matadoras Naturais/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , SoftwareRESUMO
The PD-1/PD-L1 checkpoint pathway is important for regulating immune responses and can be targeted by immunomodulatory drugs to treat a variety of immune disorders. However, the precise protein-protein interactions required for the initiation of PD-1/PD-L1 signaling are currently unknown. Previously, we designed a series of first-generation PD-1 targeting peptides based on the native interface region of programmed death ligand 1 (PD-L1) that effectively reduced PD-1/PD-L1 binding. In this work, we further characterized the previously identified lead peptide, MN1.1, to identify key PD-1 binding residues and design an optimized peptide, MN1.4. We show MN1.4 is significantly more stable than MN1.1 in serum and retains the ability to block PD-1/PD-L1 complex formation. We further characterized the immunomodulatory effects of MN1.4 treatment by measuring markers of T cell activation in a co-culture model with ovarian cancer cells and peripheral blood mononuclear cells. We found MN1.4 treatment reduced cytokine secretion and suppressed T cell responses in a similar manner as recombinant PD-L1. Therefore, the PD-L1 interface region used to design MN1.4 appeared sufficient to initiate PD-1 signaling and likely represents the minimum necessary region of PD-L1 required for PD-1 recognition. We propose a peptide agonist for PD-1, such as MN1.4, could have several applications for treating autoimmune disorders caused by PD-1 deficiencies such as type 1 diabetes, inflammatory arthritis, or autoimmune side effects arising from monoclonal antibody-based cancer immunotherapies.
Assuntos
Antígeno B7-H1 , Modelos Moleculares , Neoplasias , Transdução de Sinais , Humanos , Antígeno B7-H1/química , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Imunoterapia , Leucócitos Mononucleares/metabolismo , Neoplasias/tratamento farmacológico , Peptídeos/farmacologia , Receptor de Morte Celular Programada 1/agonistas , Receptor de Morte Celular Programada 1/química , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica , Mutação , Estrutura Quaternária de Proteína , Linhagem Celular Tumoral , Imunidade/efeitos dos fármacosRESUMO
Some chemoattractants and leukocytes such as M1 and M2 macrophages are known to be involved in the development of glomerulosclerosis during diabetic nephropathy (DN). In the course of diabetes, an altered and defective cellular metabolism leads to the increase in adenosine levels, and thus to changes in the polarity (M1/M2) of macrophages. MRS1754, a selective antagonist of the A2B adenosine receptor (A2BAR), attenuated glomerulosclerosis and decreased macrophage-myofibroblast transition in DN rats. Therefore, we aimed to investigate the effect of MRS1754 on the glomerular expression/secretion of chemoattractants, the intraglomerular infiltration of leukocytes, and macrophage polarity in DN rats. Kidneys/glomeruli of non-diabetic, DN, and MRS1754-treated DN rats were processed for transcriptomic analysis, immunohistopathology, ELISA, and in vitro macrophage migration assays. The transcriptomic analysis identified an upregulation of transcripts and pathways related to the immune system in the glomeruli of DN rats, which was attenuated using MRS1754. The antagonism of the A2BAR decreased glomerular expression/secretion of chemoattractants (CCL2, CCL3, CCL6, and CCL21), the infiltration of macrophages, and their polarization to M2 in DN rats. The in vitro macrophages migration induced by conditioned-medium of DN glomeruli was significantly decreased using neutralizing antibodies against CCL2, CCL3, and CCL21. We concluded that the pharmacological blockade of the A2BAR decreases the transcriptional expression of genes/pathways related to the immune response, protein expression/secretion of chemoattractants, as well as the infiltration of macrophages and their polarization toward the M2 phenotype in the glomeruli of DN rats, suggesting a new mechanism implicated in the antifibrotic effect of MRS1754.
Assuntos
Acetamidas , Antagonistas do Receptor A2 de Adenosina , Polaridade Celular , Fatores Quimiotáticos , Nefropatias Diabéticas , Glomérulos Renais , Macrófagos , Purinas , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Fatores Quimiotáticos/antagonistas & inibidores , Fatores Quimiotáticos/genética , Fatores Quimiotáticos/metabolismo , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Receptor A2B de Adenosina , Acetamidas/farmacologia , Purinas/farmacologia , Animais , Ratos , Movimento Celular/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Transcrição Gênica/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Imunidade/genéticaRESUMO
Immunotherapy has changed the treatment landscape for cancer over the past decade. Inhibitors of the immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset of patients with metastatic disease. However, these treatments can be limited by inflammatory toxicities that can affect any organ system in the body and in some cases can be life threatening. Considerable progress has been made in understanding the drivers of these toxicities as well as effective management strategies. Further research into understanding the molecular and cellular mechanisms that drive toxicity will enable better prediction of toxicity and development of optimized therapies for these toxicities that avoid interfering with antitumor immunity. In this review, we discuss our current understanding of the inflammatory toxicities from immune checkpoint inhibitors (ICIs) and propose optimal treatment strategies for these toxicities.
Assuntos
Inibidores de Checkpoint Imunológico , Imunoterapia , Inflamação , Neoplasias , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Humanos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Imunidade/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/prevenção & controleRESUMO
Autologous stem cell transplantation (ASCT) with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma, and a subset of patients achieve durable progression-free survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears to be a potent inhibitor of myeloma-specific immunity and represents a promising new checkpoint target. Here we demonstrate high expression of TIGIT on activated CD8+ T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical anti-TIGIT antibodies that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8+ T cell-dependent, antimyeloma efficacy. Analysis of bone marrow (BM) CD8+ T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after ASCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Lenalidomida , Mieloma Múltiplo , Receptores Imunológicos , Animais , Camundongos , Imunidade/efeitos dos fármacos , Imunidade/genética , Lenalidomida/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia , Receptores de IgG , Transplante de Células-Tronco/efeitos adversos , Transplante Autólogo , Microambiente Tumoral , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismoRESUMO
Immune checkpoint inhibitors (ICIs) are essential components of the cancer therapeutic armamentarium. While ICIs have demonstrated remarkable clinical responses, they can be accompanied by immune-related adverse events (irAEs). These inflammatory side effects are of unclear etiology and impact virtually all organ systems, with the most common being sites colonized by the microbiota such as the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint inhibition unleashes commensal-specific inflammatory T cell responses. These aberrant responses were dependent on production of IL-17 by commensal-specific T cells and induced pathology that recapitulated the cutaneous inflammation seen in patients treated with ICIs. Importantly, aberrant T cell responses unleashed by ICIs were sufficient to perpetuate inflammatory memory responses to the microbiota months following the cessation of treatment. Altogether, we have established a mouse model of skin irAEs and reveal that ICIs unleash aberrant immune responses against skin commensals, with long-lasting inflammatory consequences.
Assuntos
Dermatite , Inibidores de Checkpoint Imunológico , Microbiota , Animais , Dermatite/imunologia , Dermatite/microbiologia , Modelos Animais de Doenças , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunidade/efeitos dos fármacos , Interleucina-17/metabolismo , Camundongos , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus epidermidis/imunologia , Simbiose/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human T-lymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell RNA sequencing (scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of COVID-19 patients revealed a marked increase in HPSE gene expression in CD68+ macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of COVID-19 and the expression of inflammatory cytokine genes, including IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory cytokines in human macrophages challenged with SARS-CoV-2 S1 protein. Treatment with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-mediated inflammatory cytokine release from human macrophages, through disruption of NF-κB signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory cytokine production during S1 protein challenge. Taken together, this study provides a proof of concept that heparanase is a target for SARS-CoV-2-mediated pathogenesis and that Roneparstat may serve as a dual-targeted therapy to reduce viral infection and inflammation in COVID-19. IMPORTANCE The complex pathogenesis of COVID-19 consists of two major pathological phases: an initial infection phase elicited by SARS-CoV-2 entry and replication and an inflammation phase that could lead to tissue damage, which can evolve into acute respiratory failure or even death. While the development and deployment of vaccines are ongoing, effective therapy for COVID-19 is still urgently needed. In this study, we explored HPSE blockade with Roneparstat, a phase I clinically tested HPSE inhibitor, in the context of COVID-19 pathogenesis. Treatment with Roneparstat showed wide-spectrum anti-infection activities against SARS-CoV-2, HTLV-1, and HIV-1 in vitro. In addition, HPSE blockade with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-induced inflammatory cytokine release from human macrophages through disruption of NF-κB signaling. Together, this study provides a proof of principle for the use of Roneparstat as a dual-targeting therapy for COVID-19 to decrease viral infection and dampen the proinflammatory immune response mediated by macrophages.
Assuntos
Tratamento Farmacológico da COVID-19 , Heparina/análogos & derivados , Linhagem Celular , Citocinas/metabolismo , Fenofibrato , Técnicas de Silenciamento de Genes , Glucuronidase/genética , Glucuronidase/metabolismo , Heparina/uso terapêutico , Humanos , Imunidade/efeitos dos fármacos , Inflamação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , NF-kappa B , SARS-CoV-2RESUMO
Wild pigs usually showed high tolerance and resistance to several diseases in the wild environment, suggesting that the gut bacteria of wild pigs could be a good source for discovering potential probiotic strains. In our study, wild pig feces were sequenced and showed a higher relative abundance of the genus Lactobacillus (43.61% vs. 2.01%) than that in the domestic pig. A total of 11 lactic acid bacteria (LAB) strains including two L. rhamnosus, six L. mucosae, one L. fermentum, one L. delbrueckii, and one Enterococcus faecalis species were isolated. To investigate the synergistic effects of mixed probiotics strains, the mixture of 11 LAB strains from an intestinal ecology system was orally administrated in mice for 3 weeks, then the mice were challenged with Escherichia coli ATCC 25922 (2 × 109 CFU) and euthanized after challenge. Mice administrated with LAB strains showed higher (p < 0.05) LAB counts in feces and ileum. Moreover, alterations of specific bacterial genera occurred, including the higher (p < 0.05) relative abundance of Butyricicoccus and Clostridium IV and the lower (p < 0.05) abundance of Enterorhabdus in mice fed with mixed LAB strains. Mice challenged with Escherichia coli showed vacuolization of the liver, lower GSH in serum, and lower villus to the crypt proportion and Claudin-3 level in the gut. In contrast, administration of mixed LAB strains attenuated inflammation of the liver and gut, especially the lowered IL-6 and IL-1ß levels (p < 0.05) in the gut. Our study highlighted the importance of gut bacterial diversity and the immunomodulation effects of LAB strains mixture from wild pig in gut health.
Assuntos
Infecções por Escherichia coli/terapia , Enteropatias/terapia , Lactobacillales/fisiologia , Probióticos/farmacologia , Animais , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Enteropatias/imunologia , Enteropatias/metabolismo , Enteropatias/microbiologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Lactobacillales/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/uso terapêutico , Sus scrofaRESUMO
Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.
Assuntos
Envelhecimento/imunologia , Antígenos/imunologia , Imunidade , Tolerância a Antígenos Próprios/imunologia , Linfócitos T/imunologia , Animais , Antioxidantes/farmacologia , Apolipoproteínas B/metabolismo , Atrofia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Catalase/metabolismo , Suplementos Nutricionais , Imunidade/efeitos dos fármacos , Epitopos Imunodominantes/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/imunologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Tolerância a Antígenos Próprios/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/enzimologia , Linfócitos T/efeitos dos fármacos , Timo/patologiaRESUMO
Although checkpoint inhibitors (CPIs) have changed the paradigm of cancer therapy, low response rates and serious systemic adverse events remain challenging. In situ vaccine (ISV), intratumoral injection of immunomodulators that stimulate innate immunity at the tumor site, allows for the development of vaccines in patients themselves. K3-SPG, a second-generation nanoparticulate Toll-like receptor 9 (TLR9) ligand consisting of K-type CpG oligodeoxynucleotide (ODN) wrapped with SPG (schizophyllan), integrates the best of conventional CpG ODNs, making it an ideal cancer immunotherapy adjuvant. Focusing on clinical feasibility for pancreaticobiliary and gastrointestinal cancers, we investigated the antitumor activity of K3-SPG-ISV in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). K3-SPG-ISV suppressed tumor growth more potently than K3-ISV or K3-SPG intravenous injections, prolonged survival, and enhanced the antitumor effect of CPIs. Notably, in PDAC model, K3-SPG-ISV alone induced systemic antitumor effect and immunological memory. ISV combination of K3-SPG and agonistic CD40 antibody further enhanced the antitumor effect. Our results imply that K3-SPG-based ISV can be applied as monotherapy or combined with CPIs to improve their response rate or, conversely, with CPI-free local immunotherapy to avoid CPI-related adverse events. In either strategy, the potency of K3-SPG-based ISV would provide the rationale for its clinical application to puncturable pancreaticobiliary and gastrointestinal malignancies.
Assuntos
Antineoplásicos Imunológicos , Vacinas Anticâncer , Carcinoma Ductal Pancreático , Neoplasias Colorretais , Receptor Toll-Like 9 , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Carcinoma Ductal Pancreático/terapia , Neoplasias Colorretais/terapia , Ensaios de Seleção de Medicamentos Antitumorais , Imunidade/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptor Toll-Like 9/agonistas , Glucanos/farmacologia , Glucanos/uso terapêuticoRESUMO
Polyetheretherketone (PEEK) is a potential substitute for conventional metallic biomedical implants owing to its superior mechanical and chemical properties, as well as biocompatibility. However, its inherent bio-inertness and poor osseointegration limit its use in clinical applications. Herein, thin titanium films were deposited on the PEEK substrate by plasma sputtering, and porous nanonetwork structures were incorporated on the PEEK surface by alkali treatment (PEEK-TNS). Changes in the physical and chemical characteristics of the PEEK surface were analyzed to establish the interactions with cell behaviors. The osteoimmunomodulatory properties were evaluated using macrophage cells and osteoblast lineage cells. The functionalized nanostructured surface of PEEK-TNS effectively promoted initial cell adhesion and proliferation, suppressed inflammatory responses, and induced macrophages to anti-inflammatory M2 polarization. Compared with PEEK, PEEK-TNS provided a more beneficial osteoimmune environment, including increased levels of osteogenic, angiogenic, and fibrogenic gene expression, and balanced osteoclast activities. Furthermore, the crosstalk between macrophages and osteoblast cells showed that PEEK-TNS could provide favorable osteoimmunodulatory environment for bone regeneration. PEEK-TNS exhibited high osteogenic activity, as indicated by alkaline phosphatase activity, osteogenic factor production, and the osteogenesis/osteoclastogenesis-related gene expression of osteoblasts. The study establishes that the fabrication of titanate nanonetwork structures on PEEK surfaces could extract an adequate immune response and favorable osteogenesis for functional bone regeneration. Furthermore, it indicates the potential of PEEK-TNS in implant applications.
Assuntos
Benzofenonas/farmacologia , Fatores Imunológicos/farmacologia , Nanopartículas/química , Osteogênese , Polímeros/farmacologia , Titânio/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Forma Celular/efeitos dos fármacos , Forma Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Células RAW 264.7 , Propriedades de SuperfícieRESUMO
Immunogenic cell death (ICD) can engage a specific immune response and establish a long-term immunity in hepatocellular carcinoma (HCC). Herein, we design and synthesize a series of Pt(II)-N-heterocyclic carbene (Pt(II)-NHC) complexes derived from 4,5-diarylimidazole, which show strong anticancer activities in vitro. Among them, 2c displays much higher anticancer activities than cisplatin and other Pt(II)-NHC complexes, especially in HCC cancer cells. In addition, we find that 2c is a type II ICD inducer, which can successfully induce endoplasmic reticulum stress (ERS) accompanied by reactive oxygen species (ROS) generation and finally lead to the release of damage-associated molecular patterns (DAMPs) in HCC cells. Importantly, 2c shows a great anti-HCC potential in a vaccination mouse model and leads to the in vivo immune cell activation in the CCl4-induced liver injury model.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Complexos de Coordenação/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Calreticulina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Células Dendríticas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/uso terapêutico , Imunidade/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Platina/química , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/metabolismoRESUMO
A series of 2-phenylthiazole analogues were designed and synthesized as potential histone deacetylase 6 (HDAC6) inhibitors based on compound 12c (an HDAC6/tubulin dual inhibitor discovered by us recently) and CAY10603 (a known HDAC6 inhibitor). Among them, compound XP5 was the most potent HDAC6 inhibitor with an IC50 of 31 nM and excellent HDAC6 selectivity (SI = 338 for HDAC6 over HDAC3). XP5 also displayed high antiproliferative activity against various cancer cell lines including the HDACi-resistant YCC3/7 gastric cancer cells (IC50 = 0.16-2.31 µM), better than CAY10603. Further, XP5 (50 mg/kg) exhibited significant antitumor efficacy in a melanoma tumor model with a tumor growth inhibition (TGI) of 63% without apparent toxicity. Moreover, XP5 efficiently enhanced the in vivo antitumor immune response when combined with a small-molecule PD-L1 inhibitor, as demonstrated by the increased tumor-infiltrating lymphocytes and reduced PD-L1 expression levels. Taken together, the above results suggest that XP5 is a promising HDAC6 inhibitor deserving further investigation.
Assuntos
Antineoplásicos/uso terapêutico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Imunidade/efeitos dos fármacos , Melanoma/tratamento farmacológico , Tiazóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/toxicidade , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/uso terapêutico , Ácidos Hidroxâmicos/toxicidade , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Masculino , Melanoma/terapia , Camundongos , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/toxicidadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Coronavirus and influenza virus infection seriously threaten human health. Cangma Huadu Granules (CMHD) is an in-hospital preparation composed of eight traditional Chinese medicines (TCM), which has been clinically used against COVID-19 in China and may be a promising candidate for the treatment of influenza. However, the role of its treatment urgently needs to be studied. AIM OF THE STUDY: To evaluate the therapeutic effects of CMHD on pneumonia induced by coronavirus (HCoV-229E) and influenza A virus (H1N1/FM1) in mice and explore its mechanism of anti-infection. MATERIALS AND METHODS: Mice were infected with HCoV-229E or H1N1/FM1 virus through the nasal cavity. CMHD (12.1, 6.05 and 3.03 g/kg/d) or the positive control drugs were administered intragastrically. The lung index and histopathological changes were used to evaluate the therapeutic effect of CMHD. The expression of TNF-α, IL-1ß, IL-6 and IL-4 in Serum and the proportion of CD4+ and CD8+ T lymphocytes in peripheral blood were detected to evaluate the anti-inflammatory and immune regulation effects of CMHD, respectively. Furthermore, the levels of p-NF-κBp65/ NF-κB p65, which was the key targets of the NF-κB pathway was analyzed. RESULTS: In HCoV-229E-induced pneumonia, the lung index was markedly reduced, and lung pathology was improved in mice that treated with CMHD (12.1, 6.05 g/kg/d). Meanwhile, the expression of TNF-α, IL-6 were obviously inhibited, but the expression of IL-4 was significantly increased in CMHD groups. Compared with the model group, CMHD could also markedly upregulate the level of CD4+ and CD8+. Furthermore, CMHD has a markedly effect on inhibit the expression of p-NF-κB p65/NF-κB p65 in the lung. In H1N1-induced pneumonia, the lung index of mice in the CMHD (12.1 g/kg/d) treatment group was lower than that in the model group, and less inflammatory infiltration could be seen in the lung pathological. Moreover, CMHD could also obviously decrease the expression of TNF-α, IL-1ß, IL-6, but significantly increase the expression of IL-4. Except for that, CMHD could also markedly downregulate the level of CD4+ and upregulate the level of CD8+ compared with the model group. In addition, CMHD has a markedly effect on inhibit the expression of p-NF-κB p65/NF-κB p65 in the lung. CONCLUSION: CMHD can significantly combats viral infections caused by HCoV-229E and H1N1, and the mechanism may be related to its multiple functions of anti-inflammatory, immunity regulating and inhibiting NF-κB signal transduction pathway.
Assuntos
Anti-Inflamatórios/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Medicina Tradicional Chinesa/métodos , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Coronavirus Humano 229E/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Imunidade/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Linfócitos T/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
Cancer is a leading cause of death worldwide. Recent research studies have revealed that GM3 derivatives have considerable promise as potential therapeutic agents for cancer. To discover novel GM3 derivatives as potential antitumor agents, a one-pot enzymatic synthesis was established, yielding 14 GM3 derivatives in high total yields (22-41%). Subsequently, the inhibitory activities of GM3 derivatives were assessed by wound-healing assays and Transwell assays and tumor-bearing animal models. Among all the GM3 derivatives, N-12 showed excellent migration and invasion inhibitory effects in cells and marked antitumor activity in C57BL/6 mice. The subsequent analysis of cancer tissues and serum samples revealed that N-12 induces tumor inhibition, which was closely related to immune response. Taken together, N-12 can be further developed as an effective therapeutic for the treatment of cancer. An RNA-sequencing (RNA-seq) analysis was then performed and indicated that the antitumor mechanism of N-12 involved focal adhesion and ECM-receptor interaction signaling pathways.