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关键词： 帕金森病   睡眠障碍   安神交泰益智汤   同型半胱氨酸   白细胞介素-1β   多导睡眠监测  

摘要： 目的：研究安神交泰益智汤治疗帕金森病睡眠障碍临床效果及对患者同型半胱氨酸（homocysteine， Hcy）、白细胞介素-1β（Interleukin—1β，IL-1β）水平影响。方法：选取2021年1月～2022年12月于河北省中医院治疗的帕金森病合并睡眠障碍患者110例，按照随机数字表法均分为两组、各55例，对照组患者进行西医治疗，观察组患者采用西医联合安神交泰益智汤治疗，治疗2周后比较两组患者的临床疗效、睡眠质量、睡眠结构指标、相关因子水平及不良反应。结果：观察组总有效率高于对照组，96.36% vs83.64%（P＜0.05）。爱泼沃斯嗜睡量表（Epworth Sleepiness Scale，ESS）评分：治疗2周后观察组（7.92±1.83）分显著低于对照组（9.14±2.11）分（P＜0.05）。治疗前两组睡眠结构各指标差异均无统计学意义（P＞0.05），治疗2周后观察组睡眠效率、睡眠潜伏期、觉醒次数、呼吸暂停低通气指数（Apnea-Hypopnea Index， AHI）、最低氧饱和度显著优于对照组[（78.89±6.20）%、（23.10±4.08）min、（1.97±0.56）次、（9.08±1.03）、（89.15±5.80）% vs （73.39±6.14）%、（27.82±5.26）min、（2.75±0.67）次、（11.71±1.34）、（86.30±5.52）%]（P＜0.05）。治疗前两组血清Hcy、IL-1β可比（P＞0.05），治疗2周后观察组低于对照组[（1.01±0.06）mg/L、（8.90±1.85）pg/mL vs （1.20±0.06）mg/L、（10.13±1.91）pg/mL]（P＜0.05）。观察组、对照组不良反应发生率14.55%、10.91%（P＞0.05）。结论：安神交泰益智汤治疗帕金森病睡眠障碍临床效果更佳，能够显著改善睡眠状态、调节脑内神经免疫炎症反应，是安全有效的治疗方案，值得应用。

关键词： SMAD family member 4   Asthma   Ferroptosis   Interleukin-17A  

摘要： BackgroundThe TGF-beta/SMAD signaling pathway is crucial in the pathogenesis of asthma. However, SMAD family member 4 (SMAD4), a key mediator of TGF-beta, its roles and underlying mechanisms in asthma remain *** in vivo and in vitro roles of SMAD4 in asthma were investigated through an ovalbumin (OVA)-induced mouse model and an interleukin-13 (IL-13)-induced cell model. The molecular mechanism of SMAD4 influenced asthma was examined using transcriptome sequencing, followed by feedback experiments involving recombinant human interleukin 17 A (rhIL-17 A), an IL-17 A signaling pathway ***4 was highly expressed in the asthma models. SMAD4 silencing alleviated damage to lung tissue and decreased inflammatory infiltration. Expression levels of Caspase-3, IgG, and inflammatory factors were reduced after silencing SMAD4. Silencing SMAD4 suppressed ferroptosis. Silencing SMAD4 also enhanced IL-13-induced BEAS-2B cell proliferation and suppressed apoptosis. Furthermore. IL-17 A signaling pathway was promoted in the asthma models, as evidenced by elevated IL-17RA, IL-17 A, and Act1 protein levels. SMAD4 silencing inhibited the expression levels of these IL-17 A pathway-associated proteins. Moreover, rhIL-17 A treatment notably reversed the impacts of SMAD4 silencing on asthma in the IL-13-induced cell model and OVA-induced mouse model, indicating that silencing SMAD4 inhibited inflammation and ferroptosis in asthma by blocking the IL-17 A signaling *** SMAD4 prevents inflammation and ferroptosis in asthma by inhibiting the IL-17 pathway, which provides a novel potential approach for asthma therapy.

摘要： Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)-21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-gamma, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.

关键词： premature ovarian insufficiency   IL-33   soluble ST2   inflammation   predictor   ovarian reserve   embryo development   embryo quality  

摘要： Background: Premature ovarian insufficiency (POI) is a common reproductive disease that is associated with chronic inflammation in ovaries. Interleukin 33 (IL-33) is a pro-inflammatory IL-1 family cytokine, and functions as an alarmin reflecting inflammatory reaction. Our study aimed to investigate levels of IL-33 and its soluble receptor (sST2) in both follicular fluid (FF) and paired serum during different stages of POI, and evaluate their predictive potentials for POI. Furthermore, we attempted to determine whether IL-33 and sST2 were associated with embryo quality. Methods: A total of 148 women, including 50 patients with biochemical POI (bPOI) (10 IU/L < follicle-stimulating hormone (FSH) <= 25 IU/L), 46 patients with POI (25 IU/L Results: FF IL-33 levels were significantly increased in bPOI and POI patients compared to controls. They exhibited positive associations with FSH and luteinizing hormone (LH), whereas negative correlations with anti-M & uuml;llerian hormone (AMH), estradiol (E2), testosterone (T) and antral follicle count (AFC). Receiver operating characteristic (ROC) curve analysis showed that for POI prediction, FF IL-33 had a better predictive accuracy (AUC 0.901) with high sensitivity (82.61%) and good specificity (84.62%) than those for bPOI prediction. IL-33 levels in paired serum did not differ among three groups. Regarding sST2, its levels in FF declined with POI progression. Contrarily, they showed negative associations with FSH and LH, but positive correlations with AMH, E2, T and AFC. ROC analysis revealed that FF sST2 had comparatively weak potentials for both bPOI and POI prediction compared to those of FF IL-33. Similarly, there was no significant alteration of sST2 in paired serum among three groups. Additionally, Spearman's correlation analysis revealed that FF IL-33 levels were negatively associated with the rates of Day-3 good-quality embryos (r=-0.206, P=0.012), whereas FF sST2 did not. Conclusion: Our study revealed an increased a

关键词： Low molecular weight heparin   Multiple heart cut   Two-dimensional liquid chromatography   Glycan mapping   Structural analysis  

摘要： In this work, a synthetical glycan fingerprinting strategy using a multiple heart-cut two-dimensional liquid chromatography system linked to mass spectrometry (MHC 2D LC-MS) was developed to analyze enoxaparin, a widely used low molecular weight heparin (LMWH). Glycans from an enoxaparin standard were prepared offline based on size, and the derived tetra-, hexa-, octa- and decasaccharides were profiled using a qualitative analytical platform. Strong anion exchange chromatography (SAX) was employed as the first-dimensional chromatography (1D) to separate glycans of the same size but with different charges or sequences, while size exclusion chromatography (SEC) was used in the second dimension (2D) for desalting before MS analysis. The retention times (RTs), accurate masses and structural compositions of the glycans were fully characterized. Real samples were analyzed using the same platform but with 1 D and 2 D exchanged: SEC was used to separate enoxaparin glycans by size, followed by SAX using the same parameters as in the qualitative platform to separate glycans by charge or sequence. Glycans in real samples were identified by matching their RTs to those assigned in the qualitative analysis and semi-quantitated after normalization of peaks in each SAX chromatogram of glycans of different sizes. The analyses were performed automatically and robustly using this synthetical platform, enabling the fingerprinting and differentiation of enoxaparins from various sources. This platform could serve as a powerful tool for structural analysis, quality control, and heparin-related drug development.

关键词： 配伍   增效作用   类风湿关节炎   抗炎   凋亡  

摘要： 目的:揭示中医治疗类风湿关节炎的传统药对“附子-白芍”中主要活性成分附子总生物碱和白芍总苷配伍治疗类风湿关节炎的潜在分子机制。方法:采用CCK-8法筛选有毒成分附子总生物碱对MH7A细胞模型的安全给药剂量。采用Western Blot、免疫荧光、ELISA分析附子总生物碱和白芍总苷对NF-κB信号通路蛋白表达及下游部分细胞因子的影响,评估其抗炎作用。采用Western Blot和流式细胞术分析附子总生物碱和白芍总苷对线粒体凋亡信号通路蛋白表达及细胞凋亡率和细胞周期的影响。结果:与模型组比较,附子总生物碱具有抑制细胞增殖的作用。附子总生物碱和白芍总苷配伍,能通过降低p-IKBα、p-IKKβ、P65蛋白表达,抑制IL-1β、IL-6、MMP-1、MMP-3、PGE2、TGF-β、VEGF的生成;通过升高Bax、Caspase-3蛋白表达,降低Bcl-2蛋白表达,促进细胞凋亡;并阻滞细胞周期停留于G0/G1期。结论:附子总生物碱和白芍总苷通过作用于NF-κB和线粒体凋亡信号通路,发挥抗炎和促细胞凋亡作用;并参与细胞周期调节,抑制细胞增殖。附子总生物碱和白芍总苷配伍抗类风湿关节炎的协同作用可能与二者治疗靶点部分重叠有关。

关键词： silicosis   silica nanoparticles   IL-10   Stat3   SR-A/CD204   autoregulatory loop  

摘要： Inhalation of silica dust in the workplace has been addressed as a serious occupational pulmonary disease subsequently leading to inflammation and fibrosis. Enhanced expression of IL-10 significantly contributes to the disease etiology, along with an elevated Th2-type paradigm. Previously, we showed that the exaggerated Th2-type response was also associated with consistent upregulation of Stat3 in mouse airways stimulated with silica microparticles. However, a precise understanding of silicosis in light of the IL-10/Stat3 immune axis is required. We, therefore, aimed to determine the regulatory role of IL-10 in nanosized silica (nSiO2)-induced pulmonary fibrosis in association with Stat3. Herein, we report that amorphous nSiO2 could induce pulmonary fibrosis with consistent and concomitant upregulation of IL-10, Stat3, and SR-A/CD204. Following exogenous administration of siStat3 and rIL-10, the study further confirmed that Stat3 mediates the regulation of IL-10 and SR-A/CD204 and that IL-10 could regulate its own expression in an autoregulatory loop. The ChIP assay highlighted the localization of Stat3 over two putative binding sites in the IL-10 promoter region, which subsequently resulted in the overexpression of SR-A/CD204. Conclusively, Stat3-mediated transregulation of IL-10 through an autoregulatory loop in silicosis could offer novel molecular targets for therapeutic interventions.

关键词： Multiple sclerosis   Neuroinflammation   Cytokines   Autoantibodies   TWEAK  

摘要： Multiple sclerosis (MS) is a complex, chronic inflammatory disease of the central nervous system, where immune dysregulation plays a critical role. We sought to explore the modulation of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF alpha) and TNF-like weak inducer of apoptosis (TWEAK), along with their respective autoantibodies, TNAb and TWAb, and to decipher potential associations between these and clinical characteristics which could assist personalized therapy in MS. We also assessed the complementarity to leading candidate biomarkers in MS patient monitoring, namely, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL). Serum levels of these cytokines and their autoantibodies were measured in 150 MS patients and 186 healthy controls (HC) by ELISA. We found that sTWEAK levels were significantly higher, while sTNF alpha levels were lower in MS patients compared to HC. Additionally, we detected TWAb in 10% of MS patients, a prevalence significantly higher than in HC (4%) and TNAb in only one patient. TWAb-positive patients were significantly younger, had lower EDSS scores, a shorter disease duration, and predominantly presented with the relapsing-remitting form of MS. Together, these results provide new actors to be considered in the development of a biomarker profiling panel to be used in MS patient management. Further research is warranted to elucidate the clinical significance of these autoantibodies and their role in MS neuroinflammatory modulation.

关键词： 裴氏升血颗粒   5-氟尿嘧啶   T细胞亚群   IL-2  

摘要： 目的:研究裴氏升血颗粒（PG）联合5-氟尿嘧啶（5-Fu）对荷H22瘤小鼠肿瘤生长情况、免疫器官指数、T细胞亚群和IL-2的影响。方法:建立荷H22（肝癌）瘤小鼠模型后,将50只小鼠随机分为5组,包括模型组、5-Fu组和裴氏升血颗粒小、中、大剂量联合5-Fu组,每组10只,造模次日除模型组给予蒸馏水外其余各组开始进行药物干预,共10天。停药次日眼球取血处死小鼠,用瘤体质量计算裴氏升血颗粒联合5-Fu对荷瘤小鼠抑瘤率的影响;胸腺、脾脏称重计算胸腺指数（TI）和脾脏指数（SI）;用流式细胞法检测小鼠外周血中CD3+、CD4+、CD8+的量,用放免法检测小鼠血清中IL-2的含量。结果:裴氏升血颗粒联合5-Fu组抑瘤率较5-Fu组明显提高,其中PG大剂量+5-Fu组的抑瘤率为72.4%。PG+5-Fu组的TI及SI均高于5-Fu组,PG大剂量+5-Fu组TI为14.2 mg/10 g、SI为52.4 mg/10 g,统计学意义显著。PG+5-Fu组CD3+、CD4+和CD4+/CD8+均升高,CD8+降低;其中CD4+/CD8+分别为5.9、6.4、5.2,与5-Fu组相比差异具有统计学意义（P<0.05）。PG中剂量+5-Fu组IL-2的含量为1.18 ng/mL,较5-Fu组显著升高（P<0.05）。结论:裴氏升血颗粒能增加5-Fu抑瘤率,PG大剂量组作用明显;PG中剂量可上调CD3+、CD4+及IL-2的表达,下调CD8+的表达。PG通过调节荷H22瘤小鼠机体的免疫功能,改善机体的反应性,达到增效减毒的作用。