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HIV/AIDS pandemic remains the world's most severe public health challenge, especially for HIV/AIDS immunological nonresponders (HIV/AIDS-INRs), who tend to have higher mortality. Due to the advantages in promoting patients' immune reconstitution, Traditional Chinese medicine (TCM) has become one of the mainstays of complementary treatments for HIV/AIDS-INRs. Given that effective TCM treatments largely depend on precise syndrome differentiation, there is an increasing interest in exploring biological evidence for the classification of TCM syndromes in HIV/AIDS-INRs. In our study, to identify the typical HIV/AIDS-INRs syndrome, an epidemiological survey was first conducted in the Liangshan prefecture (China), a high HIV/AIDS prevalence region. The key TCM syndrome, Yang deficiency of spleen and kidney (YDSK), was evaluated by using a tandem mass tag combined with liquid chromatography-tandem mass spectrometry (TMT-LC-MS/MS). A total of 62 differentially expressed proteins (DEPs) of YDSK syndrome compared with healthy people were screened out. Comparative bioinformatics analyses showed that DEPs in YDSK syndrome were mainly associated with response to wounding and acute inflammatory response in the biological process. The pathway annotation is mainly enriched in complement and coagulation cascades. Finally, the YDSK syndrome-specific DEPs such as HP and S100A9 were verified by ELISA, and confirmed as potential biomarkers for YDSK syndrome. Our study may lay the biological and scientific basis for the specificity of TCM syndromes in HIV/AIDs-INRs, and may provide more opportunities for the deep understanding of TCM syndromes and the developing more effective and stable TCM treatment for HIV/AIDS-INRs.中文摘要艾滋病仍然是全世界最严重的公共卫生挑战, 尤其是对艾滋病免疫无应答者而言, 他们往往有更高的死亡率。由于中医药在促进患者免疫重建方面优势突出, 现已成为艾滋病免疫无应答者补充治疗的支柱之一。鉴于有效的中医药治疗基于精准的辨证, 探索艾滋病免疫重建不全中医证候分类的生物学依据备受青睐。在我们的研究中, 为了确定艾滋病免疫无应答者的中医证候分布规律, 首先在我国艾滋病高发区凉山州进行了流行病学调查。接着我们采用TMT-LC-MS/MS技术对典型中医证候脾肾阳虚证进行了蛋白组学研究, 筛选出62种差异表达蛋白。通过生物信息分析显示, 脾肾阳虚证中的差异表达蛋白主要与生物过程中的创伤反应和急性炎症反应等有关。通路富集主要集中在补体和凝血级联等方面。最后, 利用ELISA检测方法对脾肾阳虚证候特异性蛋白HP和S100A9进行验证, 最终将这两种证候特异性蛋白确认为脾肾阳虚证的生物标记物。这为艾滋病免疫无应答中医证候的特异性奠定了生物学和科学基础, 为深入了解中医证候, 开发更有效、更稳定的中医治疗提供了更多机会。.

Fuzheng Xiaozheng prescription (FZXZP), a traditional Chinese medicine, which was derived from the famous decoction, Sanjiasan, in the book of "Wenyilun" in Ming dynasty. Due to its function of invigorating the circulation of blood in Chinese medicine, it was usually used for treating the liver cirrhosis, hepatocellular carcinoma (HCC), etc. Clinical application found that FZXZP exhibited satisfactory therapeutic effects in HCC treatments. However, we still know little about the underlying mechanisms.In this study, we aim to gain a deeper insight into the inhibiting effects of FZXZP on HCC rats and preliminarily elucidate the underlying intervention effects.Two doses of FZXZP were adopted to evaluate the therapeutic effects on rat HCC, and then the intervention effects were evaluated from different aspects. High performance liquid chromatography (HPLC) was used for the active compounds prediction in FZXZP. Finally, the mRNA-Seq was conducted to reveal the intervention mechanisms and the mechanisms were further validated by quantitative Real-time PCR (qRT-PCR) and lipid contents analyses.The results showed that FZXZP significantly alleviated the serum biochemical indicators and improved the pathological characteristics of HCC rats. Mechanistically, FZXZP could regulate some lipid related metabolisms, including arachidonic acid, linoleic acid and retinol, as well as improving the steroid hormone biosynthesis, to improve the inflammatory statuses and restoring ability of HCC livers, and these were further confirmed by our following analyses on serum lipid contents and cytokine expressions. In addition, FZXZP could also negatively regulate four extracellular growth factors which could result in the blocking of two cancer-related signaling pathways, Ras/MAPK and Ras/PI3K-Akt.Our results suggested that FZXZP demonstrated significant inhibiting effects on rat HCC progresses, and these may be realized by improving the inflammatory statuses and blocking the Ras/MAPK and Ras/PI3K-Akt signaling pathways.

A series of highly active CF3-containing 3’-(nitroisoxazole)spiro[pyrrolidin-3,2′-oxindoles] were synthesized and found to be novel glutathione peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitors. Bioactive spirooxindole and isoxazole skeletons were combined, and the resulting compounds exhibited strong activities against both targets. In particular, compound 3d displayed excellent activity in the suppression of MDM2-mediated degradation of p53, as well as levels of GPX4, in MCF-7 breast cancer cells. Moreover, 3d also exhibited inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model to trigger ferroptotic and apoptotic cell death in in vivo experiments, which was consistent with the results of in vitro experiments.

Given the challenges in exploring lifelong therapy with little side effect for human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) cases, there is increasing interest in developing traditional Chinese medicine (TCM) treatments based on specific TCM syndrome. However, there are few objective and biological evidences for classification and diagnosis of HIV/AIDS TCM syndromes to date. In this study, iTRAQ-2DLC-MS/MS coupled with bioinformatics were firstly employed for comparative proteomic profiling of top popular TCM syndromes of HIV/AIDS: accumulation of heat-toxicity (AHT) and Yang deficiency of spleen and kidney (YDSK). It was found that for the two TCM syndromes, the identified differential expressed proteins (DEPs) as well as their biological function distributions and participation in signaling pathways were significantly different, providing biological evidence for the classification of HIV/AIDS TCM syndromes. Furthermore, the TCM syndrome-specific DEPs were confirmed as biomarkers based on western blot analyses, including FN1, GPX3, KRT10 for AHT and RBP4, ApoE, KNG1 for YDSK. These biomarkers also biologically linked with the specific TCM syndrome closely. Thus the clinical and biological basis for differentiation and diagnosis of HIV/AIDs TCM syndromes were provided for the first time, providing more opportunities for stable exertion and better application of TCM efficacy and superiority in HIV/AIDS treatment.

To explore different microRNA expression profiles between chronic hepatitis B (CHB) patients of Pi-Wei dampness-heat syndrome (PWDHS) and Gan depression Pi deficiency syndrome (GDPDS).By applying gene chip technology, blood samples from CHB patients of PWDHS (3 cases), GDPDS (3 cases), and healthy volunteers (3 cases) were withdrawn and microRNA detected. The microRNA was screened and functional analyses performed by using SAS system.Totally 77 microRNAs with differential expression were screened from CHB patients of PWDHS and healthy volunteers, including 60 up-regulated microRNAs and 17 down-regulated microRNAs. Functions of target genes were mainly associated with transcription factors, gas exchange, adverse stimulating, regulation of enzyme activities, developing of the immune system, and the process of actin filaments. Totally 41 microRNAs with differential expression were screened from CHB patients of GDPDS and healthy volunteers, including 32 up-regulated microRNAs and 9 down-regulated microRNAs. Functions of target genes were mainly associated with binding to nucleotide or chromatin, inhibition and activation of transcription, biosynthesis, regulation of metabolic process, regulation of enzyme activities, developing of the immune system, the process of actin filaments, and IL-12. Totally 6 microRNAs with differential expression were screened from CHB patients of PWDHS and CHB patients of GDPDS, including 1 up-regulated microRNA and 5 down-regulated microRNAs. Functions of target genes were mainly associated with transmembrane transport, regulation of transcription factors, metabolism of hormones, developing of the immune system, the process of actin filaments, regulation of metabolic process, response to exterior stimulation, and so on.There existed differentially expressed microRNAs (spectrum) between CHB patients of PWDHS and CHB patients of GDPDS.

To explore the characteristics of Chinese medicine (CM) syndromes of chronic hepatitis B (CHB) in Sichuan area, thus providing referential evidence for objective research of CHB.According to the CRF chart, 1 064 CHB patients' four diagnostic information from 8 clinical units were recorded in Sichuan region using cross-sectional method. The laws of CHB syndrome characteristics were explored using the K-means clustering analysis method.Based on the K-means cluster analysis, we found 8 categories that fulfill the clinical practice combined professional knowledge with experts' opinions. They were Pi-Wei dampness heat (326 cases, 30.6%), Gan and gallbladder dampness heat (193 cases, 18.1%), Gan and Pi dampness heat (158 cases, 14.8%), Gan depression and Pi deficiency (92 cases, 8.6%), Gan depression transforming into heat (89 cases, 8.4%), Pi deficiency with dampness encumbrance (74 cases, 7.0%), dampness-heat combined with yin deficiency of Gan and Shen (73 cases, 6.9%), yang deficiency mingled with blood stasis (59 cases, 5.5%).The results of cluster analysis showed Pi-Wei dampness heat, Gan and gallbladder dampness heat, Gan and Pi dampness heat, Gan depression and Pi deficiency, Gan depression transforming into heat, Pi deficiency with dampness encumbrance, dampness-heat combined with yin deficiency of Gan and Shen, yang deficiency mingled with blood stasis were mainly syndromes of CHB patients in Sichuan area.

To trace pressure-volume curves (P-V curves) with quasi-static technique in acute respiratory distress syndrome (ARDS) patients, and using it to explain the relationship between the end point of the expiratory limb and the change in the dead space of expiration.A prospective study was conducted. Fourteen ARDS patients receiving mechanical ventilation were included in the study. When P-V curves were traced with quasi-static technique, the spirometer was connected to the flow sensor. The start point of the expiratory limb was defined as tidal volume 1 (VT1) and the end point as VT2, and the difference between them (ΔVT=VT1-VT2) was calculated. The VT of spirometer (named VT3) and the predetermined VT (VT4) were recorded. Correlations of ΔVT and VT3, as well as VT4 and VT1, were analyzed with correlation analysis.ΔVTwas (417.40±119.68) ml, and VT3 was (399.29±121.36) ml, ΔVT and VT3 showed a good correlation (r=0.99, P=0.000), demonstrating that the ΔVT of the expiratory limb was correlated with the volume trapped in lung. VT4 was (908.21±106.52) ml, and VT1 was(892.26±106.32) ml, and they showed a good correlation (r=0.99, P=0.000).Because of part of the gas trapped at the end of expiration in ARDS patients, the dead space is increased, showing that the expiratory limb of the P-V curve cannot return to the base points, and the ΔVT of the expiratory limb is inversely proportional to the gas volume trapped in lung.

To observe the availability and security of optimal compliance strategy to titrate the optimal positive end-expiratory pressure (PEEP), compared with quasi-static pressure-volume curve (P-V curve) traced by low-flow method.Fourteen patients received mechanical ventilation with acute respiratory distress syndrome (ARDS) admitted in intensive care unit (ICU) of Tianjin Third Central Hospital from November 2009 to December 2010 were divided into two groups(n = 7). The quasi-static P-V curve method and the optimal compliance titration were used to set the optimal PEEP respectively, repeated 3 times in a row. The optimal PEEP and the consistency of repeated experiments were compared between groups. The hemodynamic parameters, oxygenation index (OI), lung compliance (C), cytokines and pulmonary surfactant-associated protein D (SP-D) concentration in plasma before and 2, 4, and 6 hours after the experiment were observed in each group.(1) There were no significant differences in gender, age and severity of disease between two groups. (2)The optimal PEEP [cm H(2)O, 1 cm H(2)O=0.098 kPa] had no significant difference between quasi-static P-V curve method group and the optimal compliance titration group (11.53 ± 2.07 vs. 10.57 ± 0.87, P0.05). The consistency of repeated experiments in quasi-static P-V curve method group was poor, the slope of the quasi-static P-V curve in repeated experiments showed downward tendency. The optimal PEEP was increasing in each measure. There was significant difference between the first and the third time (10.00 ± 1.58 vs. 12.80 ± 1.92, P0.05). And the optimal compliance titration method had good reproducibility as the optimal PEEP without significant difference in each measure. (3) After the quasi-static P-V curve traced, the heart rate (HR, bpm), temperature (centigrade), interleukin-6 (IL-6, ng/L), tumor necrosis factor-α (TNF-α, ng/L), SP-D (μg/L) showed a gradually increasing tendency, the mean artery pressure (MAP, mm Hg, 1 mm Hg = 0.133 kPa), continuous cardiac index [CCI, L×min(-1)×m(-2)], OI (mm Hg), and C [ml/cm H(2)O] showed a gradually decreased tendency, all of these parameters reached the peak or trough at 6 hours after the experiment, and there was significance compared with those before experiment (HR: 117.34 ± 8.53 vs. 93.71 ± 5.38, temperature: 38.05 ± 0.73 vs. 36.99 ± 1.02, IL-6: 144.84 ± 23.89 vs. 94.73 ± 5.91, TNF-α: 151.46 ± 46.00 vs. 89.86 ± 13.13, SP-D: 33.65 ± 8.66 vs. 16.63 ± 5.61, MAP: 85.47 ± 9.24 vs. 102.43 ± 8.38, CCI: 3.00 ± 0.48 vs. 3.81 ± 0.81, OI: 62.00 ± 21.45 vs. 103.40 ± 37.27, C: 32.10 ± 2.92 vs. 49.57 ± 7.18, all P0.05). The results suggested that the drawing of quasi-static P-V curve would aggravate the lung injury. And in optimal compliance titration method group, there were no significant differences in HR, MAP, temperature, CCI, OI, C, cytokines and SP-D before and after titration.Optimal compliance titration method has good reproducibility, safety and usability.