Upregulation of PGC-1α expression by pioglitazone mediates prevention of sepsis-induced acute lung injury

Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.

Research progress in the mechanisms of γδT cells recognition / 中国肿瘤生物治疗杂志

@#[摘 要] γδT细胞在肿瘤免疫治疗中具有重要潜力，其识别抗原的特异性和MHC非依赖性使其成为治疗的有力工具。然而，γδT细胞在肿瘤发生发展过程中发挥着复杂多样的双向作用，包括产生促进肿瘤生长的IL-17。近期的研究进一步揭示了γδT细胞的识别机制，包括Vγ9Vδ1 TCR对EphA2的识别机制、Vγ9Vδ2 T细胞激活依赖于磷酸抗原（pAg）介导的BTN2A1-BTN3A1蛋白相互作用，以及TCR链介导的Vδ3亚群识别机制。这些发现为肿瘤免疫治疗提供了新思路，例如通过促进EphA2的表达来增强Vδ1T细胞的杀伤作用，通过干预BTN3A1-BTN2A1相互作用来控制Vγ9Vδ2 T细胞的异常活化等。随着对γδT细胞识别机制研究的不断深入，将为深入理解它们在免疫监视中的角色、优化肿瘤免疫治疗策略提供了新视角和有力支持。

Safety of allogeneic γδT cell immunotherapy for advanced hepatocellular carcinoma and its effect on patients' immune function / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨使用同种异体Vγ9Vδ2 T细胞回输治疗晚期肝细胞癌（HCC）患者的安全性及治疗后患者免疫功能的变化。方法：选择2021年10月至2022年10月珠海市人民医院收治的4例晚期HCC患者，从健康供体获取外周血单个核细胞（PBMC）后经刺激扩增培养获得Vγ9Vδ2 T细胞，经质控放行后予以回输治疗，回输细胞剂量为5×108个/次，每两周一次，回输次数9次以上，治疗后检测患者αβT细胞、B细胞、NK细胞、γδT细胞各亚群比例，转氨酶、肌酐、肌酸激酶等肝、肾、心功能生化标志物，以及血常规三系（白细胞系统、红细胞系统和血小板系统）细胞数量的变化。结果：4例患者在回输治疗后均显示出对异体Vγ9Vδ2 T细胞良好的耐受性；转氨酶、肌酐、肌酸激酶等肝、肾、心功能生化标志物以及血常规三系细胞数量在回输前后均无明显变化；患者的Tfh1、Tc1、CD127+TEM、HLADR+CD8+ T细胞、CD27- B细胞比例有升高趋势，提示特异性免疫功能的增强。结论：同种异体Vγ9Vδ2 T细胞治疗晚期HCC有较好的安全性并可在一定程度上改善患者的免疫功能。

Major progress made in γδT cell-based tumor immunotherapy in 2023 / 中国肿瘤生物治疗杂志

@#[摘 要] γδT细胞是一类表达γδTCR异源二聚体的特殊固有免疫T细胞。过去，缺乏对其全面系统的基础研究，在其发育、分化、增殖、活化、效应和耗竭等所有环节仍有很多问题尚不清楚。然而，因为成熟的γδT细胞优势定植于皮肤、消化道、呼吸道、生殖道等肿瘤高发的黏膜组织，能以MHC非限制性的方式直接识别和杀伤多种肿瘤细胞，在肿瘤免疫治疗领域具有不可替代的优势，近年来其应用异军突起，发展迅速，也因此反过来促进了基础研究的深入，取得了一些亮眼的进展。本文对2023年γδT细胞在肿瘤免疫治疗领域的重大进展进行述评，主要集中在γδT细胞肿瘤抗原识别机制、肿瘤微环境中γδT细胞的功能调控、γδT细胞抗肿瘤细胞毒活性的机制、新型基于γδT细胞的肿瘤免疫治疗协同增效策略四个方面，以期推动γδT细胞在肿瘤免疫治疗领域的进一步发展，为临床γδT细胞应用协同增效的策略提供新的思路。

Establishment and observation of a mouse model of cytokine release syndrome induced by recombinant mouse IFN-γ adenovirus / 中国肿瘤生物治疗杂志

@#目的：通过向C57Bl/6J小鼠腹腔注射IFN-γ腺病毒（Ad-mIFN-γ）建立细胞因子释放综合征（CRS）的动物模型。方法：构建Ad-mIFN-γ及对照Ad-lacZ腺病毒载体，分别以MOI=100体外转染小鼠腹腔巨噬细胞，流式细胞术检测其对细胞mIFN-γ分泌的影响。将40只雌性C57Bl/6J小鼠按随机数字表法分为对照组、载体对照组、病毒低、中、高剂量组（每组8只），分别向各组小鼠腹腔注射PBS（200 μL）、Ad-lacZ（2×107 PFU/只）、Ad-mIFN-γ（5×106 PFU/只）、Ad-mIFN-γ（1.5×107 PFU/只）和Ad-mIFN-γ（2×107 PFU /只）。每日观测小鼠的体质量及生存情况；第3天时采用流式细胞术检测小鼠外周血和脾内单核细胞（CD11b+）、巨噬细胞（CD11b+/CD86+）比例，免疫荧光染色法检测脾内CD11b+的单核细胞比例；第9天时采用流式细胞术检测小鼠血清中细胞因子的分泌水平；第14天，采用颈椎脱臼法处死小鼠，H-E染色法观察小鼠肝、脾、肺和肾的病理和组织学变化。结果： Ad-mIFN-γ体外感染小鼠腹腔巨噬细胞，在第3天检测到巨噬细胞分泌mIFN-γ达到峰值（118.34±2.90）pg/mL，并在一周内持续高分泌mIFN-γ，Ad-lacZ对照组IFN-γ分泌水平较低后，第3天时为（0.17±0.08）pg/mL。小鼠腹腔注射Ad-mIFN-γ后，在14 d内病毒低、中剂量组无小鼠死亡，病毒高剂量组小鼠体质量持续减轻（P<0.001）；第3天，病毒高剂量组小鼠外周血和脾组织内单核细胞、巨噬细胞比例较对照组和中剂量组均显著增加（P<0.05或P<0.01）；第9天，病毒低、中、高剂量组小鼠血清中mIFN-γ、IL-6、单核细胞趋化蛋白-1（MCP-1）、IL-1、TNF-α等细胞因子的水平均显著升高（P<0.001）；10 d内病毒高剂量组小鼠死亡率达100%。组织病理检测可见病毒高剂量组小鼠的肝、脾、肺、肾组织有明显损伤。结论： Ad-mIFN-γ体外感染小鼠原代腹腔巨噬细胞后，可以快速分泌mIFN-γ；腹腔注射高剂量（2×107 PFU/只）Ad-mIFN-γ导致小鼠出现CRS典型表现，可作为CAR-T细胞治疗诱发CRS的动物模型。

Potential efficacy and mechanism of eight mild-natured and bitter-flavored TCMs based on gut microbiota: A review / 中草药·英文版

The mild-natured and bitter-flavored traditional Chinese medicines (MB-TCMs) are an important class of TCMs that have been widely used in clinical practice and recognized as safe long-term treatments for chronic diseases. However, as an important class of TCMs, the panorama of pharmacological effects and the mechanisms of MB-TCMs have not been systemically reviewed. Compelling studies have shown that gut microbiota can mediate the therapeutic activity of TCMs and help to elucidate the core principles of TCM medicinal theory. In this systematic review, we found that MB-TCMs commonly participated in the modulation of metabolic syndrome, intestinal inflammation, nervous system disease and cardiovascular system disease in association with promoting the growth of beneficial bacteria Bacteroides, Akkermansia, Lactobacillus, Bifidobacterium, Roseburia as well as inhibiting the proliferation of harmful bacteria Helicobacter, Enterococcus, Desulfovibrio and Escherichia-Shigella. These alterations, correspondingly, enhance the generation of protective metabolites, mainly including short-chain fatty acids (SCFAs), bile acid (BAs), 5-hydroxytryptamine (5-HT), indole and gamma-aminobutyric acid (GABA), and inhibit the generation of harmful metabolites, such as proinflammatory factors trimethylamine oxide (TAMO) and lipopolysaccharide (LPS), to further exert multiplicative effects for the maintenance of human health through several different signaling pathways. Altogether, this present review has attempted to comprehensively summarize the relationship between MB-TCMs and gut microbiota by establishing the TCMs-gut microbiota-metabolite-signaling pathway-diseases axis, which may provide new insight into the study of TCM medicinal theories and their clinical applications.

Toll-like receptor 2-mediated downstream cytokine levels as determinant of malaria pathogenesis

Background & objectives: Toll-like receptors (TLRs) are transmembrane proteins that recognize specific molecular patterns and activate downstream cytokine production usually for the eradication of invading pathogens. The objective of this study was to evaluate the genetic polymorphism of TLR2 Arg753Gln (rs 5743708) and soluble cytokines and TLR2 expression levels in malaria disease cases. Methods: The study included prospectively collected 2 ml blood samples from 153 individuals clinically suspected for malaria and confirmed by microscopy and RDT from Assam. Stratification of the study groups was done as healthy control (HC, n=150), uncomplicated malaria (UC-M, n=128) and severe malaria (SM, n=25). The PCR-restriction fragment length polymorphism (RFLP) method was applied for the analysis of TLR2 Arg753Gln polymorphism and following the ELISA for soluble serum TLR2 (sTLR2) and its associated downstream cytokines, viz. tumour necrosis factor (TNF)-? and interferon (IFN)-? levels. Results: Variation in TLR2 Arg753Gln gene showed no association with the susceptibility and the severity of malarial infection. Soluble TLR2 expression was significantly higher in uncomplicated malaria (UC-M) cases compared to healthy controls (P=0.045) and in terms of SM cases, the expression was also found to be higher in UC-M cases (P=0.078). The TNF-? expression was significantly higher in SM cases compared to both UC-M and control (P=0.003 and P=0.004). Similarly, significantly elevated expression of IFN-? was noted in SM cases compared to both UC-M (P=0.001) and healthy controls (P<0.001). Interpretation & conclusions: The present study suggests the association of deregulated TLR2 pathway that leads to the deleterious downstream immune response in the development of malarial pathogenicity.

Interferon-gamma gene diplotype (AA-rs2069716 / AG-rs2069727) may play an important role during secondary outcomes of severe dengue in Brazilian patients

ABSTRACT Dengue is a global and growing health threat, especially in Southeast Asia, West Pacific and South America. Infection by the dengue virus (DENV) results in dengue fever, which can evolve to severe forms. Cytokines, especially interferons, are involved in the immunopathogenesis of dengue fever, and so may influence the disease outcomes. The aim of this study was to investigate the association between severe forms of dengue and two single nucleotide polymorphisms (SNPs) in the interferon-gamma gene (IFNG): A256G (rs2069716) and A325G (rs2069727). We included 274 patients infected with DENV serotype 3: 119 cases of dengue without warning signs (DWoWS), and 155 with warning signs (DWWS) or severe dengue (SD). DNA was extracted, and genotyped with Illumina Genotyping Kit or real time PCR (TaqMan probes). We estimated the adjusted Odds Ratios (OR) by multivariate logistic regression models. When comparing with the ancestral AA/AA diplotype (A256G/A325G), we found a protective association of the AA/AG against DWWS/SD among patients with secondary dengue (OR 0.51; 95% IC 0.24-1.10, p = 0.085), adjusting for age and sex. The variant genotype at locus A325G of the IFNG, in combination with the ancestral genotype at locus A256G, can protect against severe clinical forms of secondary dengue in Brazilian DENV3-infected patients.

Relationship between IL-17, TNF-α, IL-10, IFN-γ, and IL-18 polymorphisms with the outcome of hepatitis B virus infection in the Turkish population

SUMMARY OBJECTIVE: Hepatitis B virus is a global threat that can lead to liver cirrhosis and hepatocellular carcinoma. For the treatment of chronic hepatitis B virus, polymorphisms might be an option for gene treatments. This study aimed to investigate the effects of IL-17, TNF-α, IL-10, IFN-γ, and IL-18 gene polymorphisms on hepatitis B virus infection in the Turkish population. METHODS: The genotypes and allele distribution of 75 patients exposed to hepatitis B virus and 50 healthy control individuals were analyzed. The real-time polymerase chain reaction method was used for identification. RESULTS: A correlation was observed between susceptibility to hepatitis B virus infection and IL-17 Exon 3/3'UTR (rs1974226) C, IL-17 Exon 3 (rs763780) A, IL-18 (-607) (rs1946518) A alleles, and IL-17 Exon 3 (rs763780) AA genotype (p=0.006, p=0.009, p=0.025, and p=0.008, respectively). Furthermore, IL-18 (-137) (rs187238) TT genotype and TNF-α-308 (rs1800629) G and A alleles, were associated with protection against hepatitis B virus infection (p=0.0351 and p=0.032, respectively). CONCLUSION: This study demonstrated that TNF-α (-308), IL-17 (Exon 3/3' UTR), IL-17 (Exon 3), and IL-18 (-607) polymorphisms are associated with hepatitis B virus infection. Therefore, these may serve as potential therapeutic targets for chronic viral hepatitis in the Turkish population.

Análisis no-lineal de la onda gamma del electroencefalograma en una prueba de atención e inhibición / Non-linear analysis of the electroencephalogram gamma wave in an attention and inhibition test

Introducción: Durante las últimas décadas se ha estudiado la señal del electroencefalograma desde una perspectiva de matemática no-lineal. Esto permite entender la actividad eléctrica cerebral como un sistema dinámico complejo. Objetivo: Evaluar los exponentes de Hurst y sus correlaciones en la onda gamma durante una tarea de atención alternante e inhibición de la interferencia en estudiantes universitarios. Métodos: La muestra se constituyó por 14 alumnos de educación física. Para evaluar la actividad eléctrica cerebral se utilizó el dispositivo cerebro-interfaz Emotiv Epoc®. La atención alternante se estimó con el test de símbolos y dígitos, mientras que para la inhibición de la interferencia se empleó la prueba de palabras y colores de Stroop. Resultados: En la prueba de atención alternante, cuatro individuos revelaron mayor propensión al caos en el hemisferio derecho, uno presentó más tendencia en el hemisferio izquierdo y dos no tuvieron una predisposición definida. Por otra parte, durante la prueba de inhibición de la interferencia, cinco presentaron variaciones de las medias de Hurst entre las tres láminas del efecto Stroop, sobre todo de la región temporal. Los exponentes Hurst en ambas pruebas fueron inferiores a 0,5. Conclusiones: Durante la prueba de atención se observó un mayor caos de la actividad eléctrica cerebral, sin existir correlaciones entre las regiones estudiadas. Durante la prueba de inhibición las modificaciones de los exponentes de Hurst no presentaron patrones definidos hacia el orden o caos(AU)

Introduction: During the last decades the electroencephalogram signal has been studied from a nonlinear mathematical perspective. This allows understanding brain electrical activity as a complex dynamical system. Objective: To evaluate Hurst exponents and their correlations in the gamma wave during an alternating attention and interference inhibition task in university students. Methods: The sample consisted of 14 physical education students. The Emotiv Epoc® brain-interface device was used to evaluate brain electrical activity. Alternating attention was estimated with the symbols and digits test, while the Stroop words and colors test was used for interference inhibition. Results: In the alternating attention test, four individuals revealed a greater propensity to chaos in the right hemisphere, one showed a greater tendency in the left hemisphere and two had no defined predisposition. On the other hand, during interference inhibition, variations of Hurst average values between the three Stroop effect slices were determined in five subjects, especially in the temporal region. Hurst exponents in both tests were found to be less than 0.5. Conclusions: During the attention test, a greater chaos of brain electrical activity is observed, with no correlations between the regions studied. During the inhibition test, the modifications of the Hurst exponents do not present defined patterns towards order or chaos(AU)

The gamma-glutamyl transpeptidase to platelet ratio (GPR) and the gammaglutamyl transpeptidase to albumin (GAR) versus fibroscan as indicators of hepatic fibrosis in Non-Alcoholic Fatty Liver Disease Patients

Background: Identifying patients at risk with Non-alcoholic fatty liver disease (NAFLD) related fibrosis is crucial. Many noninvasive fibrosis markers were developed recently in chronic hepatitis C and B patients, but a few were evaluated in NAFLD. Aim: to assess the accuracy of the gamma-glutamyl transpeptidase and the other noninvasive markers gamma-glutamyl transpeptidase-to-platelet ratio and gammaglutamyl transpeptidase-to-albumin ratio (GPR and GAR) versus fibroscan as indicators of hepatic fibrosis in NAFLD patients. Patients and Methods: A total of 100 NAFLD patients were examined by abdominal ultrasound and then fibroscan to assess liver steatosis and fibrosis. They were grouped into the early fibrosis group and the advanced fibrosis group. Demographic data and laboratory investigation were collected. GPR and GAR were calculated. The correlation between them and liver stiffness measurement (LSM) was reported. The accuracy of predicting liver fibrosis was assessed. Results: There was a significant positive correlation between GPR and GAR and the degree of fibrosis. GPR (P <0.001*) and GAR (P <0.001*) were independent predictors for advanced hepatic fibrosis by multiple linear regression analysis. Fibrosis score was used as the dependent variable, with the other studied biomarkers as independent variables. The AUCs of GPR and GAR were 0.790 and 0.949 in assessing liver fibrosis, respectively. Conclusion: GPR and GAR were positively correlated with hepatic fibrosis and may be used as a novel, simple, accurate, and low-cost parameter for diagnosing hepatic fibrosis in NAFLD patients.

Gamma-glutamyl transpeptidase and indirect bilirubin may participate in systemic inflammation of patients with psoriatic arthritis

Abstract Background Previous studies have suggested that systemic metabolic abnormalities are closely related to psoriatic arthritis (PsA). Gamma-glutamyl transpeptidase (GGT) and indirect bilirubin (IBIL), two essential active substances in hepatic metabolism that have been demonstrated as an oxidative and anti-oxidative factor respectively, have been proved to be involved in oxidative stress damage and inflammation in several human diseases. However, their role in PsA remains unclear. Methods In this retrospective comparative cohort study, a case group of 68 PsA patients and a control group of 73 healthy volunteers from the Third Hospital of Hebei Medical University were enrolled. Serum GGT, IBIL, GGT/IBIL ratio and C-reactive protein (CRP), a well applied bio-marker of systemic inflammatory in PsA, were compared between the two groups. Furthermore, the relationship of GGT, IBIL and GGT/IBIL with CRP were explored in PsA patients. Finally, the patients were divided into high inflammation group and low inflammation group according to the median value of CRP. Multivariate logistic regression analyses were used for the association of systemic inflammation level with GGT, IBIL and GGT/IBIL. Results Compared with healthy controls, PsA patients exhibited significantly higher serum GGT, GGT/IBIL, and CRP levels and lower IBIL levels. Serum GGT and GGT/IBIL were positively correlated with CRP, whereas IBIL were negatively correlated with CRP. Binary logistic regression analysis revealed that serum GGT was a risk factor for high CRP in PsA, whereas IBIL was a protective factor. Furthermore, GGT/IBIL was a better indicator of high CRP condition in PsA patients than either GGT or IBIL alone, as determined by the receiver operating characteristic curves. Conclusion GGT and IBIL may participate in the pathogenesis of PsA. Additionally, GGT, IBIL and the balance of the two may reflect systemic inflammation mediated by oxidative stress events related to metabolic abnormalities to a certain extent.

Avances en tuberculosis en el 54° Congreso Chileno de enfermedades respiratorias. 3a parte: Prevención de la tuberculosis activa mediante el tratamiento de la tuberculosis latente / Advances in tuberculosis at the 54th Chilean Congress of Respiratory Diseases. Part 3: prevention of active tuberculosis by treating latent tuberculosis

La infección tuberculosa latente (ITL) es un estado asintomático de la infección por Mycobacterium tuberculosis incapaz de transmitir la infección a otros, pero con el potencial de originar una tuberculosis (TBC) activa en el infectado, especialmente ante la presencia de factores de riesgo inmunológico. Es importante en personas de riesgo de desarrollar TBC reconocer la ITL utilizando test como la reacción a la tuberculina (PPD o TST) y los ensayos de liberación de Interferón-γ (IGRAs). Sin embargo, estos tests tienen limitaciones en su capacidad de predicción de riesgo de evolución de infección a enfermedad lo que conlleva a tener que tratar muchas personas para evitar algún caso de enfermedad. Nuevos tests se encuentran en desarrollo para mejorar la sensibilidad de reconocimiento de la ITL, distinguir infecciones recientes (que tienen el mayor riesgo de progresión a enfermedad) e incluso con la capacidad de detectar enfermedad subclínica o inicial. Para reducir la probabilidad de enfermar por TBC se utilizan tratamientos preventivos con fármacos, pero la cobertura mundial de esta terapia es reducida y la adherencia a terapias auto-administradas, como en el caso del uso de isoniazida diaria oral, es también baja. Otro problema de esta terapia son los riesgos de reacciones adversas (hepatitis, erupciones cutáneas) aunque no frecuentes. La recomendación de terapia actual de la ITL incluye el uso de rifamicinas y sus derivados. La asociación de isoniazida con rifapentina en una dosis semanal durante tres meses, administrada bajo supervisión, es la terapia de primera línea para mayores de 2 años, mostrando menos riesgo de hepatotoxicidad y mayor adherencia.

Latent Tuberculosis infection (LTBI) is the asymptomatic state of infection caused by Mycobacterium tuberculosis. Although untransmissible, LTBI can progress to active tuberculosis (TB), especially in people with immune risk factors. It is important to recognize LTBI in people at risk of developing TB; tuberculin skin test (PPD or TST) or interferon-γ release assays (IGRAs) are current diagnostic tests. However, these tests have limitations in their ability to predict subjects who will evolve from infection to disease; consequently, a large number of people with LTBI need treatment to avoid a reduced number of future TB disease cases. Newer tests are under development to improve the sensitivity in recognizing LTBI, distinguish recent infections with highest risk of progression to disease, and even be able to detect initial subclinical disease. Antimicrobial preventive treatment effectively reduces the probability of getting sick with TB, but worldwide availability of TB preventive therapy is limited, and adherence to self-administered therapies, as in the case of the use of daily oral isoniazid, is low. Adverse reactions risk (hepatitis, skin rash) although infrequent, is another problem with these therapies. Currently, LTBI management guidelines include regimens with use of rifamycins and their derivatives. The combination of isoniazid and rifapentine in a weekly dose for three months administered under supervision is the first line choice for LTBI therapy in those over 2 years of age, showing less hepatoxicity risk and greater adherence.

Icariin Ameliorates Efferocytosis Dysfunction of Alveolar Macrophages Stimulated by Cigarette Smoke Extract via PPARγ Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of icariin in ameliorating efferocytosis dysfunction and inflammatory response of alveolar macrophages induced by cigarette smoke extract via the peroxisome proliferator-activated receptor gamma （PPARγ） signaling pathway. MethodThe untreated rat alveolar macrophages （NR8383） were taken as the blank group. The NR8383 cells treated with 10% cigarette smoke extract were divided into model， low-， medium-， and high-dose （10， 20， 40 μmol·L-1） icariin， PPARγ inhibitor， and PPARγ inhibitor + low-， medium-， and high-dose icariin groups. Alamar blue colorimetry was employed to examine the proliferation and toxicity of icariin on NR8383 cells. The efferocytosis rate of NR8383 cells was detected by flow cytometry. Enzyme-linked immunosorbent assay was employed to measure the levels of tumor necrosis factor-alpha （TNF-α）， transforming growth factor-β1 （TGF-β1）， and milk fat globule-epidermal growth factor 8 （MFG-E8）. Western blot and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） were employed to determine the protein and mRNA levels， respectively， of PPARγ， CD36， and RAS-related C3 botulinum toxin substrate 1 （Rac1）. ResultThe efferocytosis dysfunction model of NR8383 was established with the cigarette smoke extract. Compared with the blank control group， the model group showed decreased efferocytosis rate （P<0.05）， elevated TNF-α level （P<0.05）， lowered TGF-β1 and MFG-E8 levels （P<0.01）， and down-regulated mRNA and protein levels of PPARγ， CD36， and Rac1 （P<0.05， P<0.01）. Compared with the model group， the treatment with icariin increased the efferocytosis rate （P<0.05， P<0.01）， lowered the TNF-α level （P<0.01）， elevated TGF-β1 and MFG-E8 levels （P<0.05）， and up-regulated the protein and mRNA levels of PPARγ， CD36， and Rac1 （P<0.05， P<0.01）. Compared with icariin alone， PPARγ inhibitor + icariin decreased the efferocytosis rate （P<0.05） and down-regulated the protein and mRNA levels of PPARγ （P<0.05， P<0.01）. In addition， PPARγ inhibitor + low-dose icariin down-regulated the protein level of CD36 （P<0.01） and PPARγ inhibitor + low-/medium-dose icariin up-regulated the protein level of Rac1 （P<0.05）. ConclusionIcariin ameliorates the cigarette smoke extract-induced efferocytosis dysfunction of alveolar macrophage by regulating the PPARγ signaling pathway and cytoskeletal structure rearrangement.

Variation of amniotic fluid γ-glutamyl transferase level at 19-23 +6 gestational weeks in normal pregnancies / 中华围产医学杂志

Objective:To detect the levels of γ-glutamyl transferase (GGT) in the amniotic fluid of normal pregnancies at 19-23 +6 gestational weeks and to analyze the changes in GGT level with gestational age. Methods:This study retrospectively collected the amniotic fluid supernatant from 383 singleton pregnant women (102, 103, 82, 68 and 28 cases at 19-19 +6, 20-20 +6, 21-21 +6, 22-22 +6, 23-23 +6 weeks of gestation, respectively) who underwent amniocentesis for prenatal diagnosis but had normal genetic diagnosis results in Cheeloo Hospital of Shandong University from January 2021 to September 2022. The levels of GGT in the amniotic fluid supernatant were tested and the statistical parameters including xˉ± s, min-max, median ( M), P1, P2.5, P5, P95, P97.5 and P99 values of GGT levels at each gestational week were calculated. GGT were non-normal data and converted into natural logarithms (lnGGT), and a least square linear regression equation was established to analyze the relationship between lnGGT and gestational week. Results:At 19-19 +6, 20-20 +6, 21-21 +6, 22-22 +6, and 23-23 +6 gestational weeks, the xˉ± s of amniotic fluid GGT were (385.8±235.7), (331.8±219.4), (253.7±197.9), (226.7±166.4), and (155.3±96.8) U/L, and the weekly declines were 14.0%, 23.5%, 10.6%, and 31.5%, respectively; the M values were 311.0, 288.0, 199.0, 160.5, and 105.5 U/L, and the weekly declines were 7.4%, 30.9%, 19.3%, and 34.3%, respectively; the P1- P99 were 67.1-1 404.5, 63.2-1 189.1, 36.0-849.8, 44.0-787.3, and 32.0-375.6 U/L, respectively. lnGGT was negatively correlated with gestational age ( R 2=0.148, P<0.001). Conclusions:In normal pregnancies at 19-23 +6 gestational weeks, GGT levels in amniotic fluid decrease with gestational age. Therefore, gestational age should be considered when establishing the reference value for amniotic fluid GGT in normal pregnancies.

Progress of cyclic adenosine monophosphate responsive element binding protein in the pathogenesis of drug-resistant epilepsy / 中华神经科杂志

Recent studies have found that in the development of epilepsy, cyclic adenosine monophosphate response element binding protein (CREB) may cause recurrent epilepsy by inhibiting the expression of γ-aminobutyric acid, resulting in neuron damage and weakened effect of antiepileptic drug targets. Antiepileptic drugs can not control the extent or frequency of seizures, and then the patients are in a persistent state, hence the development of drug-resistant epilepsy. Therefore, the mechanism of CREB leading to drug-resistant epilepsy was reviewed in this paper, hoping to provide ideas for the treatment of drug-resistant epilepsy patients.

Role of PIAS-regulated SUMOylation of PPARγ in endogenous protective mechanism against endotoxin-induced acute lung injury in mice / 中华麻醉学杂志

Objective:To evaluate the role of small ubiquitin-associated modifier (SUMO) E3 ligase (PIAS)-regulated SUMOylation of peroxisome proliferator-activated receptor γ (PPARγ) in the endogenous protective mechanism against endotoxin-induced acute lung injury (ALI) in mice.Methods:Experiment Ⅰ Twenty-four clean-grade wild type male C57BL/6 mice, aged 6-8 weeks, weighing 18-22 g, were divided into 4 groups ( n=6 each) using a random number table method: control group (C group), ALI group, ALI+ PPARγ inducer TZD group (ALI+ T group) and ALI+ TZD+ SUMOylation inhibitor anacardic acid group (ALI+ T+ A group). Lipopolysaccharide (LPS) 15 mg/kg was injected into the tail vein to develop the ALI model. In ALI+ T+ A group, anacardic acid 5 mg/kg was intraperitoneally injected at 1 h before LPS administration. In ALI+ T group and ALI+ T+ A group, TZD 50 mg/kg was intraperitoneally injected at 30 min before LPS administration. The mice were sacrificed at 12 h after LPS administration, and the lung tissues were obtained to examine the pathological changes which were scored and to determine the wet/dry (W/D) weight ratio, and expression of PIAS1, PIAS2, PIAS3 and PIASy protein and mRNA (by Western blot or polymerase chain reaction). Experiment Ⅱ Mouse alveolar macrophages (MH-S cells) were cultured in vitro and divided into 4 groups ( n=5 each) using a random number table method: control group (C group), LPS group, LPS+ PIAS2 siRNA group (L+ P group) and LPS+ Con siRNA group (L+ C group). Cells were routinely cultured in group C. Cells were stimulated with 10 μg/ml LPS to develop the model of endotoxin challenge. PIAS2 siRNA 50 nmol/L and Con siRNA 50 nmol/L were transfected at 48 h before LPS was added in L+ P group and L+ C group, respectively. The cells were collected at 24 h of incubation with LPS to determine the cell viability, levels of M1 and M2 alveolar macrophages (by flow cytometry), expression of PIAS2 and PPARγ (by Western blot), co-expression of PPARγ-SUMO1 (by immunoprecipitation) and expression of tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) mRNA (by polymerase chain reaction). The ratio of M1/M2 was calculated. Results:Experiment Ⅰ Compared with C group, the lung injury scores and W/D ratio were significantly increased, and the expression of PIAS2 protein and mRNA was up-regulated in the other three groups ( P<0.05). Compared with ALI group, the lung injury scores and W/D ratio were significantly decreased, and the expression of PIAS2 protein and mRNA was up-regulated in ALI+ T group and ALI+ T+ A group ( P<0.05). Compared with ALI+ T group, the lung injury scores and W/D ratio were significantly increased, and the expression of PIAS2 protein and mRNA was down-regulated in ALI+ T+ A group ( P<0.05). There was no significant difference in the expression of PIAS1, PIAS3 and PIASy protein and mRNA in lung tissues among the four groups ( P>0.05). Experiment Ⅱ Compared with C group, the cell viability was significantly decreased, the expression of PPARγ and co-expression of PPARγ-SUMO1 was up-regulated, the levels of M1 and M2 macrophages and M1/M2 ratio were increased, the expression of TNF-α mRNA was up-regulated, and the expression of IL-10 mRNA was down-regulated in the other three groups, and PIAS2 expression was significantly up-regulated in L group and L+ C group ( P<0.05). Compared with L group, the cell viability was significantly decreased, the expression of PIAS2 and PPARγ and PPARγ-SUMO1 co-expression were down-regulated, the M1 macrophage level and M1/M2 ratio were increased, TNF-α mRNA expression was up-regulated, and the expression of IL-10 mRNA was down-regulated in L+ P group ( P<0.05), and no significant change was found in the parameters mentioned above in L+ C group ( P>0.05). Compared with L+ C group, the cell viability was significantly decreased, the expression of PIAS2 and PPARγ and co-expression of PPARγ-SUMO1 were down-regulated, the level of M1 alveolar macrophages and M1/M2 ratio were increased, the expression of TNF-α mRNA was down-regulated, and the expression of IL-10 mRNA was up-regulated in L+ P group ( P<0.05). Conclusions:PIAS2-regulated SUMOylation of PPARγ is the endogenous protective mechanism against endotoxin-induced ALI in mice, which may be related to inhibition of macrophage polarization into M1 type and alleviation of inflammatory responses.

Applying an ArcCHECK detector to the dose verification for ultra-long target volumes of cervical cancer / 中华放射医学与防护杂志

Objective:To explore the feasibility of applying an ArcCHECK detector to the dose verification for ultra-long target volumes of cervical cancer.Methods:This study retrospectively selected patients suffering from cervical cancer with ultra-long target volumes (lengths: ≥ 26 cm; 50 cases; the ultra-long target volume group) and conventional target volumes (lengths: < 26 cm; 50 cases; the conventional target volume group). Subsequently, this study designed treatment plans using the Volumetric Modulated Arc Therapy (VMAT) technique and then collected and verified doses using an ArcCHECK detector. The dose detection for the conventional target volume group was performed at the central point of the detector (marked by iso and Short-0 cm). Then, the detector was moved for 5 cm along the bed exit direction (marked by iso 1), followed by the dose verification of the ultra-long target volume group (marked by Long-5 cm) and conventional target volume group (marked by Short-5 cm). The geometric parameters (the length and volume of a target volume), mechanical parameters (machine hop count and the duration of irradiation), and gamma pass rates (GPRs) under different detection conditions of each group were analyzed.Results:The target lengths, target volumes, machine hop counts, and irradiation durations of the ultra-long target group were higher than those of the conventional target group ( t = 2.61-18.56, P < 0.05). For the conventional target group, the GPRs at iso 1 were significantly lower than those at iso ( t = 2.14-8.17, P < 0.05). Meanwhile, the GPRs at iso 1 of the ultra-long target volume group were significantly lower than those of the conventional target volume group ( t = -4.70 to -2.73, P < 0.01). The GPRs of each group met clinical requirements for criteria of both 3%/3 mm and 3%/2 mm. Conclusions:The deviation of the positioning center and the length of the target volume serve as primary factors affecting the dose verification result of cervical cancer. For ultra-long target volumes, dose verification can be performed by moving the positioning center, thus ensuring treatment accuracy for cervical cancer patients.

Radiomics-based prediction of gamma pass rates for different intensity-modulated radiation therapy techniques for pelvic tumors / 中华放射医学与防护杂志

Objective:To explore the feasibility of a classification prediction model for gamma pass rates (GPRs) under different intensity-modulated radiation therapy techniques for pelvic tumors using a radiomics-based machine learning approach, and compare the classification performance of four integrated tree models.Methods:With a retrospective collection of 409 plans using different IMRT techniques, the three-dimensional dose validation results were adopted based on modality measurements, with a GPR criterion of 3%/2 mm and 10% dose threshold. Then prediction were built models by extracting radiomics features based on dose documentation. Four machine learning algorithms were used, namely random forest (RF), adaptive boosting (AdaBoost), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM). Their classification performance was evaluated by calculating sensitivity, specificity, F1 score, and AUC value. Results:The RF, AdaBoost, XGBoost, and LightGBM models had sensitivities of 0.96, 0.82, 0.93, and 0.89, specificities of 0.38, 0.54, 0.62, and 0.62, F1 scores of 0.86, 0.81, 0.88, and 0.86, and AUC values of 0.81, 0.77, 0.85, and 0.83, respectively. XGBoost model showed the highest sensitivity, specificity, F1 score, and AUC value, outperforming the other three models. Conclusions:To build a GPR classification prediction model using a radiomics-based machine learning approach is feasible for plans using different intensity-modulated radiotherapy techniques for pelvic tumors, providing a basis for future multi-institutional collaborative research on GPR prediction.

Prediction of radiomics-based machine learning in dose verification of intensity-modulated pelvic radiotherapy / 中华放射医学与防护杂志

Objective:Based on radiomics characteristics, different machine learning classification models are constructed to predict the gamma pass rate of dose verification in intensity-modulated radiotherapy for pelvic tumors, and to explore the best prediction model.Methods:The results of three-dimensional dose verification based on phantom measurement were retrospectively analyzed in 196 patients with pelvic tumor intensity-modulated radiotherapy plans. The gamma pass rate standard was 3%/2 mm and 10% dose threshold. Prediction models were constructed by extracting radiomic features based on dose documentation. Four machine learning algorithms, random forest, support vector machine, adaptive boosting, and gradient boosting decision tree were used to calculate the AUC value, sensitivity, and specificity respectively. The classification performance of the four prediction models was evaluated.Results:The sensitivity and specificity of the random forest, support vector machine, adaptive boosting, and gradient boosting decision tree models were 0.93, 0.85, 0.93, 0.96, 0.38, 0.69, 0.46, and 0.46, respectively. The AUC values were 0.81 and 0.82 for the random forest and adaptive boosting models, respectively, and 0.87 for the support vector machine and gradient boosting decision tree models.Conclusions:Machine learning method based on radiomics can be used to construct a prediction model of gamma pass rate for specific dosimetric verification of pelvic intensity-modulated radiotherapy. The classification performance of the support vector machine model and gradient boosting decision tree model is better than that of the random forest model and adaptive boosting model.