RESUMO
Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible Src homology 2-containing (CIS) protein, a key negative regulator of interleukin 15 (IL-15) signaling, with fourth-generation "armored" chimeric antigen receptor (CAR) engineering of cord blood-derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell antitumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15-secreting armored CAR-NK cells by promoting their metabolic fitness and antitumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.
Assuntos
Sangue Fetal/citologia , Imunoterapia Adotiva , Interleucina-15/genética , Células Matadoras Naturais/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Supressoras da Sinalização de Citocina/antagonistas & inibidores , Aerobiose , Animais , Antígenos CD19/imunologia , Linfoma de Burkitt/patologia , Linfoma de Burkitt/terapia , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Glicólise , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/transplante , Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptores de Antígenos Quiméricos , Transdução de Sinais/fisiologia , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: There are a growing number of studies on the effect of acupuncture on glial cells in the central nervous system; however, there are few related bibliometric analyses in this area. Therefore, the purpose of this bibliometric study was to visualize the literature on acupuncture-regulated glial cells. METHODS: On November 23, 2022, regular and review articles on acupuncture and glial cell-related research were retrieved from the Web of Science Core Collection database. The R package "bibliometrix" was used to summarize the main findings, count the occurrences of the top keywords, visualize the international collaboration network, and generate a 3-field plot. The VOSviewer software was used to conduct both co-authorship and co-occurrence analyses. CiteSpace was used to identify the best references and keywords with the highest citation rates. RESULTS: Overall, 348 publications on acupuncture and glial cells were included. The publications were primarily from China, Korea, and the United States of America. The majority of publications were found in relevant journals. Apart from "acupuncture" and "glial cells," the most frequently used keywords were "neuroinflammation," "hyperalgesia," and "pain." CONCLUSION: This bibliometric study mapped a fundamental knowledge structure comprising countries, institutions, authors, journals, and articles in the research fields of acupuncture and glial cells over the last 3 decades. These results provide a comprehensive perspective on the wider landscape of this research area.
Assuntos
Terapia por Acupuntura , Bibliometria , Neuroglia , Humanos , Terapia por Acupuntura/estatística & dados numéricos , Terapia por Acupuntura/métodos , Pesquisa Biomédica/estatística & dados numéricosRESUMO
Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3Z creates a platform that recruits critical kinases, such as LCK and ZAP70, initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy.
RESUMO
Numerous studies have demonstrated that multiple intrinsic and extrinsic factors shape the structure and composition of gut microbiota in a host. The disorder of the gut microbiota may trigger various host diseases. Here, we collected fecal samples from wild-caught Japanese geckos (Gekko japonicus) and captive conspecifics fed with mealworms (mealworm-fed geckos) and fruit flies (fly-fed geckos), aiming to examine the dietary and sexual correlates of the gut microbiota. We used 16S rRNA gene sequencing technology to determine the composition of the gut microbiota. The dominant phyla with a mean relative abundance higher than 10% were Verrucomicrobiota, Bacteroidota, and Firmicutes. Gut microbial community richness and diversity were higher in mealworm-fed geckos than in wild geckos. Neither community evenness nor beta diversity of gut microbiota differed among wild, mealworm-fed, and fly-fed geckos. The beta rather than alpha diversity of gut microbiota was sex dependent. Based on the relative abundance of gut bacteria and their gene functions, we concluded that gut microbiota contributed more significantly to the host's metabolic and immune functions. A higher diversity of gut microbiota in mealworm-fed geckos could result from higher chitin content in insects of the order Coleoptera. This study not only provides basic information about the gut microbiota of G. japonicus but also shows that gut microbiota correlates with dietary habits and sex in the species.
RESUMO
COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.
Assuntos
COVID-19 , Interleucina-6 , Animais , Camundongos , Interleucina-6/metabolismo , COVID-19/metabolismo , SARS-CoV-2 , Neutrófilos/metabolismo , Síndrome da Liberação de Citocina , Macrófagos/metabolismo , NF-kappa B/metabolismoRESUMO
The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. Neural release of neurotransmitters and neuropeptides allows fast communication with immune cells and their recruitment. In addition to maintaining homeostasis and fighting infections, neuroimmune interactions are also implicated in several chronic inflammatory conditions such as atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), and asthma.