[摘 要] 自2017年以来，已有12款嵌合抗原受体基因修饰T淋巴细胞（CAR-T细胞）产品相继被批准用于血液系统恶性肿瘤的治疗，包括复发性/难治性急性B淋巴细胞白血病、特定亚型B细胞淋巴瘤和多发性骨髓瘤。然而，CAR-T细胞疗法在应用过程中面临诸多挑战，如在治疗血液系统肿瘤中的抵抗、生产周期长、个体化/价格昂贵，在实体瘤中的肿瘤异质性强/抗原逃逸、浸润能力不足、免疫抑制微环境和反应性差等问题。随着肿瘤免疫学研究的深入和基因工程技术的发展，尝试了众多新策略来提升CAR-T细胞疗法的疗效和普适性。作者根据自身对该领域研究的认知，针对CAR-T细胞疗法的临床关键问题及其应对解决策略进行述评，为未来CAR-T细胞疗法的基础研究和临床转化提供重要思路。

Lung cancer is the malignant tumor with the highest incidence and mortality rates globally. Current treatment methods for lung cancer primarily include surgery， chemotherapy， targeted therapy， and immunotherapy. However， the main limitations of these treatments are their side effects， the drug resistance， and the economic burden they impose. As a critical cancer pathway， the Janus kinase （JAK）/signal transducer and activator of transcription （STAT） signaling pathway regulates tumor occurrence and development through multiple mechanisms by influencing various downstream targets. Consequently， the JAK/STAT signaling pathway offers a promising avenue for lung cancer treatment research. Numerous studies have demonstrated that the JAK/STAT signaling pathway plays a key role in the proliferation and growth of lung cancer cells， angiogenesis， epithelial-mesenchymal transition （EMT）， metabolic alterations， remodeling of the immune microenvironment， and the development of treatment resistance. Traditional Chinese medicine （TCM） has garnered increasing attention due to its minimal side effects， low economic burden， and its potential to enhance efficacy and reduce toxicity when used in conjunction with Western medicine. In addition to traditional Chinese medicine compounds， a growing number of Chinese medicine monomers have come into the spotlight because of their more targeted effects. Numerous studies investigating the regulation of the JAK/STAT signaling pathway by TCM in the treatment of lung cancer have demonstrated that TCM can inhibit the proliferation and invasion of lung cancer cells， tumor angiogenesis， and EMT， improve the inflammatory and immunosuppressive microenvironments， and enhance treatment sensitivity by intervening in the JAK/STAT signaling pathway， thereby impeding the progression of lung cancer. In recent years， the research on the regulation of this pathway by TCM in the treatment of lung cancer has been updated rapidly. However， the summary of these studies has not been updated in time. This review summarizes and reflects on the recent research findings regarding the regulation of the JAK/STAT signaling pathway by TCM to intervene in lung cancer from three aspects， introducing the JAK/STAT pathway， elaborating the mechanism of this pathway in lung cancer， and exploring the intervention of TCM in the treatment of lung cancer through this pathway， to provide more reference for the treatment of lung cancer in the future.

Stroke is the main cause of death and disability among adults in China and is characterized by high incidence， disability， mortality， and recurrence rates. The combination of traditional Chinese and Western medicine has great potential in treating stroke and its sequelae. The classic traditional Chinese medicine prescription Da Chengqitang （DCQT） has a long history and proven efficacy in treating stroke. Clinically， DCQT is often used to treat stroke and its sequelae. However， the number and quality of clinical trials of DCQT in treating stroke need to be improved. Because of the insufficient basic research， the active ingredients and multi-target mechanism of action of DCQT remain unclear. Our research group has previously confirmed that DCQT can effectively reverse neurological damage， reduce iron deposition， and downregulate the levels of pro-inflammatory cytokines in the rat model of hemorrhagic stroke. The treatment mechanism is related to the nuclear factor erythroid 2-related factor 2 （Nrf2）-mediated signaling pathway and p38 mitogen-activated protein kinase （MAPK） signaling-mediated microglia activation. To clarify the pharmacodynamic basis and anti-stroke mechanism of DCQT， this article reviews the research progress in the treatment of stroke with DCQT in terms of clinical trials， pharmacodynamic material basis， safety evaluation， and mechanisms of absorbed components. This article summarizes 45 major phytochemical components of DCQT， 11 of which are currently confirmed absorbed components. Among them， emodin， rhein， chrysophanol， aloe-emodin， synephrine， hesperidin， naringin， magnolol， and honokiol can be used as quality markers （Q-markers） of DCQT. The mechanism of DCQT in treating stroke is complex， involving regulation of inflammatory responses， neuronal damage， oxidative stress， blood-brain barrier， brain-derived neurotrophic factor， and anti-platelet aggregation. This article helps to deeply understand the pharmacodynamic basis and mechanism of DCQT in treating stroke and provides a theoretical basis for the clinical application of DCQT in treating stroke and the development of stroke drugs.

Objective:This study aims to evaluate the clinical utility of total IgE （tIgE） and specific IgE （sIgE） levels in nasal secretions for diagnosing allergic rhinitis. The investigation is enhanced through an improved method of nasal secretion collection and advanced quantum dot immunofluorescence detection technology. Methods:A total of 88 subjects were enrolled in this study, and demographic data and clinical characteristics were collected through standardized questionnaires. Anterior rhinoscope was used to check the local condition of the nasal cavity. Each participant underwent skin prick test（SPT）. The total IgE（tIgE） and sIgE in nasal secretions were quantitatively analyzed by improved nasal secretion collection strategy and quantum dot immunofluorescence method, and the correlation between them and clinical symptoms and signs was discussed. The receiver operating characteristic curve（ROC） was used to calculate the optimum threshold and detection efficiency of total IgE and sIgE in nasal secretions. Results:The improved method successfully collected nasal secretions from all subjects. Based on SPT results, participants were categorized into three groups: normal control （20 cases）, non-allergic rhinitis （22 cases）, and allergic rhinitis （46 cases）. Analysis showed that both tIgE and sIgE levels in nasal secretions correlated with nasal symptoms and signs. A tIgE level of ≥9.42 IU/mL was identified as a cut-off for allergic rhinitis diagnosis, demonstrating an 85.37% agreement with SPT results. Furthermore, cut-off values for house dust mite sIgE （≥0.34 IU/mL） and dermatophagoides Farinae sIgE （≥0.41 IU/mL） yielded a diagnostic agreement of 97.56% with SPT. Notably, two patients in the non-allergic rhinitis group tested negative for SPT but positive for dust mite sIgE in nasal secretions and exhibited positive results in the nasal provocation test, indicating potential local allergic rhinitis. Conclusion:The assessment of tIgE and mite-specific IgE levels in nasal secretions presents a rapid, reliable, and non-invasive approach for diagnosing allergic rhinitis, particularly in cases of local allergic rhinitis.
Humans ; Immunoglobulin E/analysis* ; Quantum Dots ; Male ; Female ; Adult ; Young Adult ; Middle Aged ; Rhinitis, Allergic/immunology* ; Adolescent ; Fluorescent Antibody Technique/methods* ; Case-Control Studies ; Nasal Mucosa/immunology*

OBJECTIVES: To explore the effect of A. muciniphila gavage on intestinal microbiota and gut-brain interaction disorders (DGBIs) in gp120tg transgenic mouse models of HIV-associated neurocognitive disorder (HAND). METHODS: Intestinal microbiota was detected by 16S rRNA gene sequencing in 6-, 9-, and 12-month-old wild-type (WT) mice and gp120tg transgenic mice. The 12-month-old WT and transgenic mice were divided into 2 groups for daily treatment with PBS or A.muciniphila gavage (2×10⁸ CFU/mouse) for 6 weeks. After the treatment, immunohistochemistry, ELISA and qPCR were used to detect changes in colonic expression levels of glycosylated mucins, MBP and IL-1β, eosinophil infiltration, serum lipopolysaccharide (LPS) levels, and colonic expressions of occludin, ZO-1, IL-10, TNF-α and INF-γ mRNA. Morris water maze test and immunofluorescence assay were used to assess learning and spatial memory abilities and neuronal damage of the mice. RESULTS: Compared with WT mice, the transgenic mice exhibited significantly lowered Simpson's diversity of the intestinal microbiota with reduced abundance of Akkermansia genus, increased serum LPS levels and decreased colonic expression of glycosylated mucin. A.muciniphila gavage obviously ameliorated the reduction of glycosylated mucin in the transgenic mice without causing significant changes in body weight. The 12-month-old gp120tg mice had significantly decreased cdonic expressions of Occludin and ZO-1 with increased eosinophil infiltration and TNF-β, INF-γ and IL-1β levels and obviously lowered IL-10 level; all these changes were significantly mitigated by A.muciniphila gavage, which also improved cognitive impairment and neuronal loss in the hippocampus and cortex of the transgenic mice. CONCLUSIONS The gp120tg mice have lower intestinal microbiota richness and diversity than WT mice. The 12-month-old gp120tg mice have significantly reduced Akkermansia abundance with distinct DGBIs-related indexes, and A. muciniphila gavage can reduce intestinal barrier injury, colonic inflammation and eosinophil activation, cognitive impairment and brain neuron injury in these mice.
Animals ; Mice, Transgenic ; Gastrointestinal Microbiome ; Mice ; Brain ; HIV Envelope Protein gp120/genetics* ; Akkermansia ; Disease Models, Animal

The efficient production of L-glutamate is dependent on the product's rapid efflux, hence researchers have recently concentrated on artificially modifying its transport system and cell membrane wall structure. Considering the unique composition and structure of the cell wall of Corynebacterium glutamicum, we investigated the effects of CmpLs on L-glutamate synthesis and transport in SCgGC7, a constitutive L-glutamate efflux strain. First, the knockout strains of CmpLs were constructed, and it was confirmed that the deletion of CmpL1 and CmpL4 significantly improved the performance of L-glutamate producers. Next, temperature-sensitive L-glutamate fermentation with the CmpL1 and CmpL4 knockout strains were carried out in 5 L bioreactors, where the knockout strains showcased temperature-sensitive characteristics and enhanced capacities for L-glutamate production under high temperatures. Notably, the CmpL1 knockout strain outperformed the control strain in terms of L-glutamate production, showing production and yield increases of 69.2% and 55.3%, respectively. Finally, the intracellular and extracellular metabolites collected at the end of the fermentation process were analyzed. The modification of CmpLs greatly improved the L-glutamate excretion and metabolic flux for both L-glutamate production and transport. Additionally, the CmpL1 knockout strain showed decreased accumulation of downstream metabolites of L-glutamate and intermediate metabolites of tricarboxylic acid (TCA) cycle, which were consistent with its high L-glutamate biosynthesis capacity. In addition to offering an ideal target for improving the stability and performance of the industrial strains for L-glutamate production, the functional complementarity and redundancy of CmpLs provide a novel target and method for improving the transport of other metabolites by modification of the cell membrane and cell wall structures in C. glutamicum.
Corynebacterium glutamicum/genetics* ; Glutamic Acid/biosynthesis* ; Fermentation ; Metabolic Engineering ; Bacterial Proteins/metabolism* ; Bioreactors/microbiology* ; Gene Knockout Techniques

Tumor cells adapt their metabolism to meet the demands for energy and biosynthesis.Mitochondria,pivotal organelles in the metabolic reprogramming of tumor cells,contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells.Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation,proliferation,and differentiation of immune cells.The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics,thereby facilitating the establishment of a tumor immunosuppressive microenvironment.Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals,including cGAS-STING,TLR9,and NLRP3.Moreover,mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy.Additionally,mitochondrial reactive oxygen species,a crucial factor in tumorigenesis,drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment.This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles.We explore the core role of mitochondria in the dynamic interplay between the tumor and the host to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

Tumor cells adapt their metabolism to meet the demands for energy and biosynthesis.Mitochondria,pivotal organelles in the metabolic reprogramming of tumor cells,contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells.Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation,proliferation,and differentiation of immune cells.The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics,thereby facilitating the establishment of a tumor immunosuppressive microenvironment.Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals,including cGAS-STING,TLR9,and NLRP3.Moreover,mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy.Additionally,mitochondrial reactive oxygen species,a crucial factor in tumorigenesis,drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment.This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles.We explore the core role of mitochondria in the dynamic interplay between the tumor and the host to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

Tumor cells adapt their metabolism to meet the demands for energy and biosynthesis.Mitochondria,pivotal organelles in the metabolic reprogramming of tumor cells,contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells.Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation,proliferation,and differentiation of immune cells.The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics,thereby facilitating the establishment of a tumor immunosuppressive microenvironment.Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals,including cGAS-STING,TLR9,and NLRP3.Moreover,mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy.Additionally,mitochondrial reactive oxygen species,a crucial factor in tumorigenesis,drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment.This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles.We explore the core role of mitochondria in the dynamic interplay between the tumor and the host to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

Tumor cells adapt their metabolism to meet the demands for energy and biosynthesis.Mitochondria,pivotal organelles in the metabolic reprogramming of tumor cells,contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells.Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation,proliferation,and differentiation of immune cells.The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics,thereby facilitating the establishment of a tumor immunosuppressive microenvironment.Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals,including cGAS-STING,TLR9,and NLRP3.Moreover,mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy.Additionally,mitochondrial reactive oxygen species,a crucial factor in tumorigenesis,drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment.This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles.We explore the core role of mitochondria in the dynamic interplay between the tumor and the host to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.