Background Strategies that specifically target the integrated stress response (ISR) as a therapeutic approach in sepsis remain largely unexplored. This study aimed to identify and validate ISR-related biomarkers in sepsis. Methods This study used 529 ISR-related genes (ISRRGs) alongside sepsis datasets. First, differentially expressed gene between sepsis and normal samples, key module genes associated with sepsis, and ISRRGs were intersected to identify candidate genes. Next, biomarkers were selected through three machine learning methods. Subsequently, enrichment analysis, immune infiltration analysis, regulatory network analysis, and drug prediction were conducted. Finally, the biomarkers were experimentally validated using RT-qPCR. Results Four biomarkers of sepsis (DYRK2, BCL2, NUP93, and NFATC2) were identified; collectively, these biomarkers are associated with the enrichment of translation initiation in sepsis. A total of 783 significantly upregulated pathways and 1203 significantly downregulated pathways were identified. These biomarkers were co-regulated by multiple microRNAs and transcription factors. Importantly, 726 drugs were predicted to interact with these biomarkers. Additionally, RT-qPCR results demonstrated that the expression levels of DYRK2, BCL2, NUP93, and NFATC2 differed significantly between sepsis and normal samples. Conclusion DYRK2, BCL2, NUP93, and NFATC2 were identified as biomarkers of sepsis, offering new diagnostic and therapeutic targets for its treatment.

Activating transcription factor 3 (ATF3) plays a dual role in hepatic pathophysiology, particularly in its well-established involvement in activating hepatic stellate cells and promoting liver fibrosis in chronic liver disease. However, the role of ATF3 and its molecular mechanisms in acute liver injury remain unclear, despite the urgent need for effective therapeutic strategies for this condition. This study aimed to elucidate the protective role of ATF3 and its underlying mechanisms in acute liver injury. We utilized a carbon tetrachloride (CCL4)-induced acute liver injury mouse model and hepatic stellate cells (HSCs) as an in-vitro model. Our findings demonstrate that ATF3 overexpression significantly alleviates early symptoms of acute liver injury, including reduced inflammation and improved liver function, leading to a better prognosis. Mechanistically, we discover that ATF3 exerts its protective effects by inhibiting the aberrant activation of endogenous retroelements (EREs). This inhibition prevents ERE-induced genomic instability and the subsequent activation of the cGAS/STING innate immune pathway, thereby suppressing the production of pro-inflammatory cytokines such as interferon-beta (IFNβ). Further analysis reveals that ATF3 directly binds to the promoter regions of EREs, transcriptionally repressing their expression. In summary, this study identifies ATF3 as a critical negative regulator of ERE activation in acute liver injury, elucidating a novel mechanism by which ATF3 mitigates inflammation and promotes hepatic repair through ERE regulation. These findings suggest that targeting the ATF3-ERE axis represents a promising therapeutic strategy for acute liver injury and enhances our understanding of how transcription factors modulate innate immune responses through interaction with EREs.

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder characterized by abnormalities in the inflammation-like ovulatory process. Elevated thrombospondin-1 (THBS1) is associated with these disruptions, but the impact of Leu-Ser-Lys-Leu-NH2 (LSKL), a THBS1 inhibitor, on PCOS-related abnormalities remains unclear. This study aims to explore the roles of THBS1 and LSKL in PCOS pathogenesis. PCOS were induced by administration of dehydroepiandrosterone (DHEA) to rats and granulosa cells (GCs) for 21 days. Thereafter, LSKL was administered to rats. Molecular docking was employed to assess the binding affinity between LSKL and THBS1. Cell viability, apoptosis, and reactive oxygen species (ROS) levels in GCs were evaluated using the Cell Counting Kit-8 (CCK8) assay and flow cytometry. In rats, parameters including body weight, estrous cycle, ovarian histopathology, serum hormone levels (luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol), ovarian oxidative stress, and the expression of PI3K/AKT signaling and apoptosis-related proteins were analyzed. In vitro, molecular docking confirmed a strong binding affinity between LSKL and THBS1. LSKL alleviated DHEA-induced damage, reduced ROS accumulation, and inhibited apoptosis in dysfunctional GCs, while enhancing PI3K/AKT pathway activation. In vivo, LSKL mitigated ovarian injury and oxidative stress, restored estrous cycle regularity, normalized serum hormone levels, improved ovarian morphology (including reduced cystic dilation and follicular dysplasia), and suppressed ovarian apoptosis, all while boosting PI3K/AKT activity. These results position THBS1 as a potential therapeutic target for PCOS and demonstrate that LSKL mitigates ovarian damage, oxidative stress, and apoptosis in PCOS by inhibiting THBS1 and activating the PI3K/AKT pathway.

Nebivolol (Neb) relaxes coronary arteries and increases coronary artery blood flow, but the underlying mechanisms need further elucidation. The vascular tension of rat coronary artery (RCA) was recorded with a wire myograph. Transmembrane K+ currents through voltage-dependent K+ (Kv) channels were measured with a patch clamp. Kv1.2 expressions were evaluated with immunofluorescent staining and Western blot. Neb (0.1-30 μM) evoked marked relaxation in RCAs pre-contracted with KCl or U46619. Denudation and L-NAME pretreatment weakened the relaxation by less than 20 %. Neb pretreatment depressed contractile responses of RCAs to various vasoconstrictors including 60 mM KCl, 0.3 μM U46619 and 0.1 μM Bay K8644. In the arterial smooth muscle cell (ASMC) of RCA, Neb reduced 60 mM KCl-induced elevation of intracellular Ca2+ ([Ca2+]in)-sensitive fluorescent intensity and increased Kv currents. Incubation of RCAs with Neb increased Kv1.2 expressions in RCA ASMCs. Inhibitor study showed that Kv channel inhibitor 4-aminopyridine (4-AP, 1 mM) and protein kinase A (PKA) inhibitor H-89 (1 μM) attenuated Neb-induced RCA relaxation and Kv current increment in RCA ASMCs, while p38 MAPK inhibitor SB239063 (1 μM) had no effect. In summary, the present study demonstrated that Neb relaxed RCAs through PKA-mediated upregulation of Kv channels in RCA ASMCs.

Ethnopharmacological relevance Lichong decoction (LD) is extensively employed in the treatment of uterine leiomyoma (ULM), demonstrating remarkable clinical effectiveness with an absence of notable adverse reactions. Its composition aligns with the traditional Chinese medicine (TCM) etiology of ULM, making it a highly suitable therapy. Nonetheless, the precise mechanisms underlying its therapeutic actions remain to be fully elucidated. Aim of the study The objective of this study was to clarify the therapeutic mechanism of LD improving ULM. Materials and methods The effects of LD on ULM cell viability, proliferation, and apoptosis were assessed using CCK-8, crystal violet staining, EdU incorporation, TUNEL, and Annexin V-FITC/PI assays. Gene microarray was used to profile differential gene expression after LD treatment. A rat ULM model was created to evaluate LD's anti-tumor efficacy, measuring body weight, uterine weight index, and sex hormone levels. Histopathological changes were analyzed with hematoxylin and eosin staining, Masson's trichrome staining, and transmission electron microscopy. Protein and RNA expression changes were analyzed via immunohistochemistry, western blotting, and qPCR. UHPLC-QE-MS enabled a detailed non-targeted LD analysis. Key components were identified through their correlation with serum sex hormones and inflammatory cytokines, and then examined by molecular docking studies. Results Experiments showed that LD reduced ULM cell viability and induced apoptosis. Gene expression profiling identified 313 differentially expressed genes. Enrichment analysis combined with experimental validation demonstrated that LD can reduce ULM fibrosis and inflammation by inhibiting the CXCL8/PI3K/AKT pathway. The analysis identified 494 primary compounds and 87 serum components in LD. Key compounds such as formononetin, palmatine, curcumenol, and hecogenin, which exhibit high affinity for CXCL8, may contribute to the anti-inflammatory and anti-tumor properties of LD. Conclusion This study demonstrates that LD effectively inhibits ULM proliferation and fibrosis by improving the inflammatory microenvironment, primarily through the inhibition of CXCL8. These findings highlight the therapeutic potential of LD for ULM and provide new insights into its mechanisms.

BackgroundRecurrent pregnancy loss (RPL) represents a critical reproductive health concern, with nearly half of RPL cases lacking clinically identifiable etiologies, termed unexplained RPL (uRPL). Neutrophil extracellular traps (NETs), released by activated neutrophils, have been implicated in the pathogenesis and progression of various reproductive disorders. However, the relationship between NETs and uRPL remains poorly characterized.MethodsThis study enrolled 34 patients with uRPL and 30 healthy controls. Serum NETs biomarkers (MPO-DNA, citH3) were quantified via ELISA. Decidual tissues underwent histopathology (H&E), immunohistochemistry, and transcriptomics (6uRPL vs. 5 controls). Machine learning identified key NETs-related differentially expressed genes, validated by Western blotting. Immune cell infiltration and gene-immune correlations were assessed bioinformatically.ResultsuRPL patients exhibited elevated serum NETs biomarkers (MPO-DNA, citH3; p<0.01) and increased decidual neutrophil infiltration. Immunohistochemistry confirmed upregulated MPO and citH3 in uRPL (p<0.01). Transcriptomics identified four key DE-NRGs (C3AR1, ITGAM, ITGB2, LYZ), validated at the protein level (p<0.05). Immune profiling revealed increased CD8+ T cells, M2 macrophages, and neutrophils, alongside reduced CD4+ memory T cells, follicular helper T cells, and monocytes in uRPL. All DE-NRGs correlated positively with M2 macrophages (r>0.6) and negatively with follicular helper T cells and monocytes (r<-0.5). LYZ also correlated with neutrophils (r>0.5). A nomogram incorporating DE-NRGs demonstrated robust diagnostic accuracy (AUC>0.85).ConclusionThis study establishes a novel link between NETs and the pathogenesis of uRPL. It highlights the abnormal activation of C3AR1, ITGAM, ITGB2, and LYZ, along with M2 macrophage polarization, as crucial factors in decidual immune dysregulation. These findings suggest that NETs could serve as therapeutic targets, while DE-NRGs may act as potential biomarkers for uRPL.

Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection, leading to systemic inflammation and organ dysfunction. Macrophage polarization plays a critical role in pathogenesis of sepsis, and the influence of B lymphocyte-induced maturation protein-1 (Blimp-1) on this polarization is an underexplored yet pivotal aspect. This study aimed to elucidate the role of Blimp-1 in macrophage polarization and metabolism during sepsis. Using a murine cecal ligation and puncture model, we observed elevated Blimp-1 expression in M2 macrophages. Knockdown of Blimp-1 by macrophage-targeted adeno-associated virus in this model resulted in decreased survival rates, exacerbated tissue damage, and impaired M2 polarization, underscoring its protective role in sepsis. In vitro studies with bone marrow-derived macrophage (BMDM), RAW264.7, and THP-1 cells further demonstrated Blimp-1 promotes M2 polarization and modulates key metabolic pathways. Metabolomics and dual-luciferase assays revealed Blimp-1 significantly influences purine biosynthesis and the downstream Ornithine cycle, which are essential for M2 macrophage polarization. In vitro studies with BMDM further suggested that the purine biosynthesis and Ornithine cycle metabolic regulation is involved in Blimp-1’s effects on M2 macrophage polarization, and mediates Blimp-1’s impact on septic mice. Our findings unveil a novel mechanism by which Blimp-1 modulates macrophage polarization through metabolic regulation, presenting potential therapeutic targets for sepsis. This study highlights the significance of Blimp-1 in orchestrating macrophage responses and metabolic adaptations in sepsis, offering valuable insights into its role as a critical regulator of immune and metabolic homeostasis.

Background: Compound Danshen dripping pills (CDDP), a traditional Chinese medicine, has had an extensive application in the treatment of angina pectoris (AP) in China. However, research on the bioactive ingredients and underlying mechanisms of CDDP in AP remains unclear. Objective: In the present study, we explored the major chemical components and potential molecular mechanisms linked to the anti-angina effects of CDDP through the application of network pharmacology and molecular docking. Methods: The potential targets of active ingredients in CDDP were sourced from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and the Swiss Target Prediction Database (STPD). Additionally, targets related to angina pectoris (AP) were retrieved from various databases, including Gene Cards, DisGeNET, Dis Genet, the Drug Bank database (DBD), and the Therapeutic Target Database (TDD). Protein- protein interaction networks were also established, and core targets were identified based on their topological significance. GO enrichment analysis and KEGG pathway analysis were conducted using the R software. Interactions between active ingredients and potential targets selected through the above process were investigated through molecular docking. Results: Seventy-six active ingredients were selected with the following criteria: OB ≥ 30%, DL ≥ 0.18. 383 targets of CDDP and 1488 targets on AP were gathered, respectively. Afterwards, 194 common targets of CDDP and anti-AP targets were defined, of which 12 were core targets. GO enrichment analysis indicated that CDDP acted on AP by response to lipopolysaccharide, regulating the reactive oxygen species and metal ion metabolism, and epithelial cell proliferation. In addition, KEGG enrichment analysis indicated that the signaling pathways were notably enriched in lipid and atherosclerosis, fluid shear stress and atherosclerosis, IL-17 signaling pathway, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt signaling pathway, and TNF signaling pathway. Moreover, the molecular docking manifested excellent binding capacity between the active ingredients and targets on AP. Conclusion: This study comprehensively illustrated the bioactive, potential targets, and molecular mechanisms of CDDP against AP, offering fresh perspectives into the molecular mechanisms of CDDP in preventing and treating AP.

Background and Aims:Portal vein thrombosis (PVT) is a challenging complication in liver cirrhosis, with no currently available sensitive diagnostic markers. This study aimed to investigate the potential of neutrophil extracellular traps (NETs) and Deoxyribonuclease (DNase) as diagnostic indicators for PVT in chronic hepatitis B (CHB)-related decompensated cirrhosis. Methods:We analyzed 145 CHB-related decompensated cirrhosis patients from the Ditan study and 33 from the Changgung validation study, categorizing them based on PVT occurrence. Plasma samples were assessed for NET markers, including cell-free DNA (cfDNA) and histone-DNA complexes, along with DNase activity. Results:PVT patients exhibited elevated levels of cfDNA and histone-DNA complexes, and reduced DNase activity. This pattern persisted regardless of hepatocellular carcinoma (HCC) status. Histone-DNA levels, DNase activity, and hemoglobin were identified as independent risk factors for PVT. Receiver operating characteristic curve analysis revealed that high histone-DNA levels may serve as a potential diagnostic marker for PVT, with an area under the curve of 0.8628 in the Ditan study and 0.7521 in the Changgung study. When combined with cfDNA and DNase activity, the area under the curve improved to 0.8774 in the Ditan study and 0.7975 in the Changgung study. Conclusions:Imbalances in NET homeostasis are associated with PVT in CHB-related decompensated cirrhosis, including cases involving HCC. Histone-DNA complexes, a significant risk factor for PVT, show potential as a diagnostic marker for PVT in decompensated cirrhosis, particularly in HBV-related HCC.

Pneumocystis pneumonia (PCP) is a fungal pulmonary disease with high mortality in immunocompromised patients. Neutrophils are essential in defending against fungal infections; however, their role in PCP is controversial. Here we aim to investigate the effects of neutrophil extracellular traps (NETs) on Pneumocystis clearance and lung injury using a mouse model of PCP. Intriguingly, although neutrophils play a fundamental role in defending against fungal infections, NETs failed to eliminate Pneumocystis, but instead impaired the killing of Pneumocystis. Mechanically, Pneumocystis triggered Leukotriene B4 (LTB4)-dependent neutrophil swarming, leading to agglutinative NET formation. Blocking Leukotriene B4 with its receptor antagonist Etalocib significantly reduced the accumulation and NET release of neutrophils in vitro and in vivo, enhanced the killing ability of neutrophils against Pneumocystis, and alleviated lung injury in PCP mice. This study identifies the deleterious role of agglutinative NETs in Pneumocystis infection and reveals a new way to prevent NET formation, which provides new insights into the pathogenesis of PCP.

Sortilin C-terminal fragments (sorfra) can co-deposit in β-amyloid (Aβ) plaques in human brain. However, sorfra plaques develop in the cerebrum with a spatiotemporal trajectory as of tauopathy. Here we examined sorfra pathogenesis relative to neuritic plaque evolution in the human brains with amyloid and tau pathologies converged in the neocortex and hippocampus. Sorfra plaques occurred in correlation with pTau/tangle, but not Aβ, pathologies across cerebral regions, neighboring cortical/hippocampal areas, and along the sulcal valley to gyral hilltop transition. Sorfra plaques and neuritic plaques were matchable in location, shape and size between consecutive sections, and were colocalized in double-labeling preparations. Microscopical study and tissue clearance three-dimensional imaging revealed sorfra/Aβ colocalized as well as independent plaques. Among the former, sorfra labeling correlated negatively to Aβ /amyloid labeling and β-secretase-1 labeling in dystrophic neurites. Sorfra plaques were depleted of microtubule-associated protein 2 (MAP2) labeled neuronal somata and dendrites, whereas normal looking MAP2/sortilin co-labeled profiles occurred nearby. Sorfra deposits were seen in astrocytes but not microglia around the plaques. Taken together, sorfra plaques are anatomically matchable to silver stained neuritic plaques. They develop with tangle-related somatodendritic degeneration, presenting as nonamyloid growth of the Aβ plaques and formation of Aβ-independent neuritic plaques during Alzheimer's disease pathogenesis. ### Competing Interest Statement The authors have declared no competing interest.

Introduction Traditional Chinese medicine (TCM) and Western medicine (WM) stem from distinct cultural and regional contexts, with the primary difference in their approaches to clinical reasoning.This study aims to investigate the cognitive preferences of TCM and WM physicians in clinical diagnosis and treatment, providing valuable insights for the advancement of TCM. Methods We implemented a two-phase mixed methods approach comprising questionnaires and semi-structured interviews. The Thinking Style Inventory (TSI) was used to evaluate the thinking styles of physicians through convenience sampling. Additionally, a total of six physicians (three practicing TCM and three WM) were selected by purposive sampling and open-ended responses regarding self-cognition and influencing factors were analyzed using thematic analysis. Results A total of 150 surveys and six interviews consistently indicated a preference among both TCM and WM physicians for Legislative, Executive, Hierarchical, Liberal, and External styles. In contrast, TCM physicians exhibited a tendency towards Legislative and Liberal styles, whereas WM physicians leaned towards Executive and Judicial styles. Thematic analysis of the interviews revealed four themes: self-understanding, thinking characteristics, influencing factors, and style changes. Conclusion Our study identified that within TCM and WM, a blend of shared characteristics and distinct individuality in thinking styles existed, exhibiting variations in the growth processes of physicians. Both TCM and WM physicians attributed the formation of their thinking styles to factors such as education, internship experience, Chinese social culture and personal disposition. Furthermore, empirical research methods emerged as effective tools for studying clinical reasoning in healthcare contexts.

Background: At present, acupuncture-related practices have been widely used to treat psoriasis. In our study, we investigated the effect and explored the mechanism of electroacupuncture (EA) on acupoints Baihui (DU20) and Xuehai (SP10) for the treatment of psoriasis. Methods: Imiquimod-induced psoriasis-like mouse model was used in this study. Mice were treated with electroacupuncture at DU20 and SP10 (depth of 2-3 mm, frequency of 2/15 Hz, intensity of 0.5-1.0 mA, 10 min/day). The severity of psoriasis-like lesions for each group was assessed. In addition, histological analysis of the lesions were performed. The levels of inflammatory cytokines were determined using Elisa. The expression levels of Substance P (SP) and NK1R were measured using Western blotting. In addition, NK1R inhibitor was administrated to evaluate the target of electroacupuncture in our mouse model. Results: Electroacupuncture significantly alleviated IMQ-induced skin lesions and epidermal thickness, accompanied with reduced keratinocyte proliferation, CD3+, CD4+, and CD8+ T cells infiltration. The reduced levels of inflammatory cytokines was observed after electroacupuncture treatment. In addition, electroacupuncture inhibited the expression levels of SP and NK1R. NK1R inhibitor could ameliorate lesional symptoms and suppress epidermal thickening and CD3+, CD4+, and CD8 + T cell infiltration. Conclusions: Electroacupuncture relieved psoriasis-like inflammation and T cell infiltration. This therapeutic action was likely mediated by the modulation of Substance P and its receptor NK1R. (c) 2023 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Autoimmune encephalitis, a class of encephalitis, is clinically characterized by multifocal or diffuse brain injury, including aberrant mental behavior, convulsions, and near-event memory impairment. In this article, we describe a female patient with autoimmune encephalitis who tested positive for leucine-rich glioma inactivated 1 (LGI1) antibodies and had hippocampal inflammatory edema in the lesion area. During the first 3 months of her illness, the patient primarily experienced memory loss, the onset of rigid twitching in her extremities that lasted for 1 min while in remission, and incontinence. After gamma globulin administration, methylprednisolone shock, and other symptomatic therapies during hospitalization, the patient’s psychiatric symptoms and seizures improved considerably; however, she did not fully recover her memory. After receiving fire acupuncture for 6 months, the patient’s understanding, orientation, and calculation skills improved considerably. Her memory and mental state were also improved at the follow-up visit. In this case, the use of fire acupuncture for the treatment of autoimmune encephalitis resulted in favorable outcomes with important benefits for conditions affecting the central nervous system; however, more convincing data are required to support the effectiveness of this treatment method.

Background: Psoriasis is a psychosomatic immune skin disease with psychological factors contributing to the disease. Substance P (SP) is highly expressed in the psoriatic lesions of patients and is involved in pathological disease progression. Tribulus terrestris L. has been used as a Chinese herbal medicine for disease prevention for thousands of years. Terrestrosin D (TED) has been identified as the effective monomeric component of Tribulus terrestris L..Purpose: We investigated whether TED could reverse imiquimod-induced psoriatic lesions, and then, investigated its potential mechanism of action both in vivo and in vitro.Methods: 5% imiquimod cream was applied onto the backs of mice for 6 days to induce psoriasis-like skin lesions. The psoriatic area and severity index (PASI) was then used for scoring disease severity. Pathological changes and Ki-67 expression levels in skin lesions were measured using hematoxylin and eosin (H & E) and immunofluorescence staining after TED administration. The in vivo and in vitro expression levels of inflammatory cytokines, the ratio of DCs, and SP were measured using ProcartaPlex Mouse Cytokine panels, flow cytometry, and western blotting. Behavioral assessments were determined using the open field and elevated plus-maze (EPM) test.Results: TED decreased PASI scores, epidermal thickness, Ki-67 expression levels, the ratio of DCs in the spleen, and secretion of IL-12p70, IL-18, and TNF-alpha in imiquimod-induced psoriasis-like murine models. Furthermore, TED increased IL-10 secretion levels, improved behavior, and down-regulated the expression levels of SP. Additionally, TED inhibited the in vitro maturation and activation of SP-induced CD11c(+) DCs and the release of IL-12p70 and IL-23.Conclusion: TED reduced DCs maturation, down-regulated the expression levels of inflammatory factors, and improved skin lesions and behavior of psoriasis-like murine models by inhibiting the interaction between Substance P and Dendritic cells.

目的 探讨靛玉红及丹参酮Ⅱa联用促进雄黄降解突变型PMLA216T-RARα的作用机制.方法 用不同浓度雄黄作用于野生型及突变型PMLA216T-RARα,观察2组细胞PML-RARα降解作用,验证PMLA216T-RARα存在砷剂耐药.根据CCK8测出的IC50值确定各组分浓度,使用不同浓度、不同组合的雄黄、靛玉红、丹参酮Ⅱa作用于转染PMLA216T-RAR1α 细胞,应用蛋白质印迹法检测单用、两两联合及三者联合对PML-RARα的降解及自噬相关因子(p-mTOR、LC3B)的作用.分别联用蛋白酶体抑制剂卡非佐米及自噬抑制剂巴佛洛霉素A1,应用蛋白质印迹法检测各组细胞中PML-RARα的降解情况.结果 与对照组(不用药物干预)比较,雄黄浓度为0.5 μmol/L,作用于PML-RARα野生型及突变型PMLA216T-RARα 时,均使PML-RARα发生了明显降解(均P＜0.01),突变型PMLA216T-RARα表达的PML-RARα均比野生型高(均P＜0.01).与对照组比较,雄黄4μmol/L、靛玉红8umol/L、丹参酮Ⅱa 8 μmol/L作用于PMLA216T-RARα时,均使PML-RARα发生降解(均P＜0.01),可降低p-mTOR水平(均P＜0.01),升高LC3B水平(P＜0.05,P＜0.01),雄黄+丹参酮Ⅱa+靛玉红三者联合时上述作用最强(P＜0.01).与对照组比较,雄黄+丹参酮Ⅱa+靛玉红、雄黄+丹参酮Ⅱa+靛玉红+卡非佐米联用作用于PMLA216T-RARα时,均使PML-RARα发生明显降解(均P＜0.01);与对照组比较,单用卡非佐米、单用巴佛洛霉素A1、雄黄+丹参酮Ⅱa+靛玉红+巴佛洛霉素A1,作用于PMLA216T-RARα时,均使PML-RARα发生了明显蓄积,且雄黄+丹参酮 Ⅱa+靛玉红+巴佛洛霉素A1组PML-RARα表达高于单用卡非佐米及单用巴佛洛霉素A1组(均P＜0.01).结论 靛玉红及丹参酮Ⅱa联用可通过自噬增强雄黄对突变型PMLA216T-RARα的降解作用,三者联用自噬作用最强,可能为复方黄黛片治疗急性早幼粒细胞白血病的作用机制之一.

To the Editor:Peliosis hepatis （PH） is an uncommon benign vascular disorder characterized by widespread blood-filled cysts in the liver.This disease was first described by Wagner in 1861,and because the liver lesions were generally red or blue-purple,it was first named PH by Schoenlack in 1916 [1].The etiology of PH is not completely clear now,which is mainly related to drug factors,immune factors,and infections.The diagnosis of PH is difficult because of the lack of specific clinical manifestations and imaging features.Pathological biopsy represents the gold standard in diagnosis of PH [2].

Backgroud: Uterine fibroids (ULs) are the most common benign tumors of the reproductive tract in gynecology and their clinical presentations include menorrhagia, pelvic pressure, dysmenorrhea, and anemia. Surgical resection and the hormonal drug administration are the primary treatment. The plant Astragalus membranaceus (astragalus) has a long history of use in traditional Chinese medicine and studies have shown that it has antitumor effects. However, the role and mechanism of astragalus in ULs are not completely clear. The present study aimed to investigate the astragalus mechanism of action against ULs based on network pharmacology approach, in order to provid insights for the development of a safe and effective drug for the ULs treatment.Methods: The astragalus active ingredients and the potential drug targets were screened by the Traditional Chinese Medicine System Pharmacology Database and Analytical Platform (TCMSP). The gene expression profiles of ULs were obtained from Gene Expression Omnibus (GEO). The intersection of astragalus components target genes and differentially expressed genes between UL and normal patients were obtained using Perl software to provide the astragalus-ULs drug regulatory network. The protein–protein interaction (PPI) network was established using the STRING online database and Cytoscape software, followed by the topological properties analysis of the PPI networks. GO (Gene ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses were conducted by R software. The KEGG relational network was constructed using Cytoscape software. Results: A total of 21 astragalus active ingredients and 406 drug targets were obtained from the TCMSP. Seventeen of these targets overlap with ULs disease targets and were considered potential targets for the ULs treatment by astragalus. The analysis of the regulatory network showed that the astragalus active components with the most targets are quercetin, kaempferol, mangiferin, tetrodotoxin and isorhamnetin. Target genes with the highest Dgree values obtained from the PPI network analysis are estrogen receptor 1 (ESR1), tumor suppressor factor p53 (TP53), neurotrophic tyrosine kinase receptor 1 (NTRK1) and E3 ubiquitin ligase protein (CUL3). GO and KEGG enrichment analyses indicate that these targets are mainly involved in biological processes related to cellular response to reactive oxygen species, oxidative stress and response to lipopolysaccharides. The main signal transduction pathways involved include the IL-17 and TNF signaling pathways, the AGE-RAGE signaling pathway in diabetic complications and proteoglycans in cancer.Conclusions: The present study demonstrates that the astragalus therapeutic use against ULs have multicomponent and multi-target properties, providing a novel approach to further investigate the astragalus mechanism of action in the treatment of ULs.

目的:通过建立脾虚-银屑病样复合小鼠模型探讨脾虚对银屑病皮损及分子机制的影响.方法:苦寒泻下结合营养限制法建立脾虚证模型后,咪喹莫特乳膏局部涂抹诱导银屑病样模型.观察小鼠皮损面积和疾病严重程度(PASI)及其组织形态学变化;免疫组织化学法检测皮损中增殖细胞核抗原(PCNA)和CD3的表达;RT-PCR技术检测皮损中FOXP3、ROR-γt、白细胞介素2(IL-2)基因表达水平.结果:与对照-IMQ组比较,脾虚-IMQ组小鼠皮损鳞屑和表皮厚度明显升高(P＜0.05),炎性细胞浸润显著,皮损中ROR-γtmRNA表达的升高趋势有所减缓,但Foxp3 mRNA显著降低(P＜0.05).结论:脾虚可加重银屑病皮损的严重程度,尤其鳞屑增多、皮损肥厚,与脾虚血燥的临床表现较一致,探索其机制可能与Treg/Th 17平衡偏移有关.

OBJECTIVE:To investigate the efficacy of Lichong decoction (LD) from Traditional Chinese Medicine, on micro-angiogenesis in a mouse model of hysteromyoma.METHODS:A mouse model of hysteromyoma was developed by orthotopic intrauterine injection of primary human myoma cells isolated from patients from the Beijing Obstetrics and Gynecology Hospital into CB-17 Scid mice. Mice were administered high-dose LD, low-dose LD, mifepristone or water (control) daily by gavage for 4 weeks. Uterine diameter and coefficient (uterine weight/body weight) were measured. Uterine morphology was assessed by light microscopy (hematoxylin and eosin) and transmission electron microscopy. Serum levels of estradiol, progesterone, follicle-stimulating hormone and luteinizing hormone (LH) were measured by enzyme-linked immunosorbent assay. Uterine protein expression of hypoxia inducible factor (HIF)-1α, CD31 and proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry. VEGF and HIF-1α mRNAs were quantified by RT-PCR.RESULTS:High-dose LD, low-dose LD and mifepristone reduced uterine diameter and coefficient, and attenuated the morphologic abnormalities associated with hysteromyoma. High-dose LD, low-dose LD and mifepristone inhibited hysteromyoma-induced micro-angiogenesis, as evidenced by a decrease in the number of new microvessels co-immunostaining for CD31 and PCNA (P < 0.01). High-dose LD and mifepristone lowered serum levels of estradiol, progesterone and LH (P < 0.05). High-dose LD, low-dose LD and mifepristone down-regulated HIF-1α mRNA and protein expressions and VEGF mRNA expression (P < 0.01).CONCLUSION:The inhibition of hysteromyoma by LD may involve reductions in HIF-1α and VEGF expression and suppression of micro-angiogenesis.