Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases

The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease

Abstract As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis

Molecular target anticancer drugs are commonly used in various forms of cancers. It is a concern that the risk of serious adverse events (SAEs) and fatal adverse events (FAEs) of molecular target drugs are increasing. An up-to-date meta-analysis of all Phase II/III/IV randomized trials of molecular target anticancer drugs was conducted to calculate the increased risk of SAEs and FAEs. A systematic search of PubMed, Web of Science, and Cochrane Library up to April 6, 2017, was conducted. The study enrolled Phase II/III/IV randomized trials of cancer that compared molecular target drugs alone versus placebo or performed single-arm analysis of molecular target drugs. Data on SAEs and FAEs were extracted from the included studies and pooled to compute risk ratio (RR), the overall incidence, and 95% confidence interval (CI). In this meta-analysis, a total of 19,965 and 26,642 patients in randomized 53 and 65 Phase II/II/IV trials were included in the analysis of SAEs and FAEs associated with molecular target anticancer drug, respectively. There were significant differences in the relationship of molecular target anticancer drugs with SAEs (RR = 1.57, 95% CI = 1.35–1.82, P < 0.01, I2 = 81%) and FAEs (RR = 1.51, 95% CI = 1.19–1.91, P < 0.01, I2 = 0%) compared to placebo. The overall incidence of SAEs and FAEs was 0.269 (95% CI = 0.262–0.276, P < 0.01) and 0.023 (95% CI = 0.020–0.025, P < 0.01), respectively. Molecular target anticancer drugs significantly increased the risk of SAEs and FAEs. For patients taking molecular target drugs, efforts are needed to prevent the occurrence of SAEs and FAEs

New Advances in the Treatment for Small Cell Lung Cancer / 中国肺癌杂志

Small cell lung cancer (SCLC) is a refractory cancer with high degree of malignancy, rapid disease progression, poor prognosis and easy recurrence. In the past 30 years, the traditional treatment of SCLC, mainly chemotherapy and radiotherapy, has not changed significantly, and the effective treatment method for clinical needs is extremely urgent. The rapid development of precision medicine has revealed the molecular biological characteristics of SCLC, so its diagnosis and treatment will into a new era. At present, some studies have shown that anti-angiogenic drugs, immunotherapy and so on have improved the efficacy of SCLC treatment to some extent, and there are more studies on the diagnosis and treatment of SCLC, so a new field of SCLC treatment are coming and bringing more survival benefits to patients. New studies on targeted therapy, anti-angiogenesis drugs and immunotherapy of molecular pathology of SCLC are emerging. This paper reviews the new diagnosis and treatment methods of SCLC to provide new guidance for its clinical treatment.
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HtrA1 suppresses the growth of pancreatic cancer cells by modulating Notch-1 expression

Pancreatic cancer is well known to be the most deadly malignancy with the worst survival rate of all cancers. High temperature requirement factor A1 (HtrA1) plays an important role in cancer cell proliferation, migration, apoptosis, and differentiation. This study aimed to explore the function of HtrA1 in pancreatic cancer cell growth and its underlying mechanism. We found that the expression of HtrA1 was lower in pancreatic cancer tissue compared to the adjacent normal tissue. Consistently, HtrA1 levels were also decreased in two human pancreatic cancer cell lines, PANC-1 and BXPC-3. Moreover, enforced expression of HtrA1 inhibited cell viability and colony formation of PANC-1 and BXPC-3 cells. Overexpression of HtrA1 promoted apoptosis and suppressed migratory ability of tumor cells. On the contrary, siRNA-mediated knockdown of HtrA1 promoted the growth potential of pancreatic cancer cells. In addition, we found that up-regulation of HtrA1 reduced the expression of Notch-1 in pancreatic cancer cells. On the contrary, knockdown of HtrA1 increased the expression levels of Notch-1. Furthermore, overexpression of Notch-1 abolished the anti-proliferative effect of HtrA1 on pancreatic cancer cells. Taken together, our findings demonstrated that HtrA1 could inhibit pancreatic cancer cell growth via regulating Notch-1 expression, which implied that HtrA1 might be developed as a novel molecular target for pancreatic cancer therapy.

Medication regularity and potential targets of Professor XU Jing-fan's prescription for treating ulcerative colitis / 中国中药杂志

Ulcerative colitis (UC) is a chronic nonspecific inflammation mainly involving rectum and colon mucosa, which seriously affects the health and quality of life of patients, and is listed as one of modern refractory diseases by WHO. Professor XU Jing-fan, a great master of traditional Chinese medicine, has accumulated rich experiences in the treatment of UC. The study collected Professor XU's 77 prescriptions of treating UC, analyzed the frequency of traditional Chinese medicines and there categories, and investigated the medication regularity by the system clustering method. The findings showed that the most frequently used drugs were clearing-heat herbs, which were followed by hemostatic herbs, excreting-dampness herbs, improving-digestion herbs and tonifying-Qi herbs. At the same time, the commonly combined drugs were excavated. Finally, in order to analyze potential molecular targets of the frequently used herbs, GO enrichment analysis and KEGG signal pathway enrichment analysis were performed with bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine (BATMAN-TCM). The results indicated that Chinese herbal compounds may treat UC by activating PPAR-γ pathway and regulating intestinal inflammation. The exact mechanisms shall be verified through subsequent molecular biological experiments.

Clinical application of high mobility group box nuclear protein 1 subcomponent in the progression of liver cancer / 中华肝脏病杂志

The biological functions of high-mobility group (HMG) proteins include regulation of DNA replication, transcription, recombination and repair. According to molecular weight, sequence alignment and DNA structural characteristics, HMG proteins are subdivided into three superfamilies (HMGA, HMGB and HMGN). Recently, HMGB family members (HMGB1, HMGB2, HMGB3, and HMGB4) found to interact with hepatitis B or C virus. Therefore, activation of relevant signaling molecules to regulate transcription of genes related to hepatocellular carcinoma as a mediator of inflammation promoting HCC progression has attracted considerable attentions. This article focuses on the clinical application of the expression of HMGB family members in the process of HCC progression.

Key signal molecules of wingless-related integration pathway and targeted therapy for liver cancer / 中华肝脏病杂志

Hepatocellular carcinoma is one of the most common digestive system tumors. Its occurrence and development are considered as multi-factorial and multi-step process. Recent studies have shown that wingless-related integration (Wnt) pathway plays an important role in the HCC progression and is associated with malignant transformation of hepatocytes, HCC metastasis, drug resistance and liver cancer stem cells. This article analyzes the expression of key signaling molecules in Wnt pathway and its value in diagnosis, prognosis and targeted therapy, and outlines the research progress of Wnt pathway targeted drugs for the treatment of HCC, with a view to providing targeted therapy research for HCC reference.

Progress of signaling pathways regulating the sensitivity of irradiation in cancer therapy / 肿瘤研究与临床

Radiotherapy characterized by invasive, localization and low toxicity has been recognized as one of the standard cancer therapy regimes, especially for non-surgically resectable advanced cancers. However, inherent and acquired resistance of cancer cells has significantly impeded the efficacy of radiotherapy. Of all the resistance determinants, varieties of anti-apoptotic signaling pathways or anti-survival proteins aberrant activation in malignant tumor cells play crucial roles in radiation insensitivity. This paper mainly focuses on clarifying the roles of the interesting key molecular signals including Ras, insulin-like growth factor type 1 receptor, transforming growth factor-beta, histone deacetylase and heat shock protein 90 in regulating radiotherapy sensitivity, in order to find the potential targets to improve the efficacy of radiotherapy.

RHO GTPasas como blancos moleculares en cáncer: Estrategias y oportunidades terapéuticas / Rho GTPases as molecular targets in cancer. Strategies and therapeutic opportunities

Las Rho GTPasas son una familia de proteínas que actúan como interruptores moleculares en diversas vías de señalización coordinando la regulación de distintos procesos celulares. La desregulación de dichas proteínas se vincula con transformación maligna y progresión tumoral en distintos tipos de cáncer. Por estos motivos, en los últimos años las Rho GTPasas fueron postuladas como blancos moleculares interesantes. En este trabajo describimos las distintas estrategias estudiadas utilizando a las Rho GTPasas como blanco y su grado de avance, mostrando una estrategia novedosa para el tratamiento del cáncer.

Rho GTPases are molecular switches that control the different cellular processes. Deregulation of these proteins is associated to transformation and malignant progression in several cancer types. Given the evidence available of the role of Rho GTPases in cancer it is suggested that these proteins can serve as potential therapeutic targets. This review focuses on the strategies used to develop Rho GTPases modulators and their potential use in therapeutic settings.

Advances in personalized treatment of small cell lung cancer / 中国肿瘤临床

Small cell lung cancer (SCLC) is a lethal malignancy characterized by rapid growth, early metastatic spread, and unfavorable survival outcomes. Optimizing treatment for patients with SCLC has been the focus for investigators. The emergence of precision medi-cine and personalized treatment brought significant breakthroughs into SCLC treatment and changed the therapeutic model. The de-velopment of molecular bioinformatics increased our understanding of complex molecular mechanisms of SCLC, and novel targets for personalized treatment have been developed. Clinical trials testing these targets are ongoing, which show the potential of personal-ized treatment for SCLC.

Correlation between p-MNK1 expression and postoperative survival rate in patients with non small cell lung cancer / 实用医学杂志

Objective To investigate the expression of p-MNK1 in non-small cell lung cancer and its relationship with clinic pathological features and prognosis.Methods The level of p-MNK1 in 115 cases of nonsmall cell lung cancer was detected by tissue microarray technique and immunohistochemistry technique.Results The level of p-MNK 1 in non-small cell lung cancer was correlated with cancer tissue type (P ＜ 0.05),clinical stage (P ＜ 0.05),lymph node metastasis (P ＜ 0.01) and prognosis (P ＜ 0.05).Cox multiple regression analysis showed that p-MNK1 expression was an independent prognostic factor for non-small cell lung cancer (P ＜ 0.01).Conclusion The level of p-MNK1 in non-small cell lung cancer is associated with poor prognosis.It can be used as an independent prognostic marker and a new therapeutic target.

Distribution and clinical significance of EML4-ALK fusion gene in phase Ⅰ lung cancer / 中华胸心血管外科杂志

Objective To detect the mutation frequency of EML4-ALK fusion gene in lung cancer patients, and to inves-tigate the distribution of mutation character for EML4-ALK fusion gene in Ⅰ stage lung cancer patients and clinical features as well as provide a reference for the individual treatment of lung cancer .Methods 256 fresh tumor tissue specimens of lung cancer patients were screened from the specimen bank of our hospital and all the patients had accepted the surgical treatment from February 2013 to December 2014.Total RNA was extracted and then be transcribed into cDNA, the amplification-refrac-tory mutation system(ARMS) was used to detect mutation of EML4-ALK fusion gene.The results according to the positive con-trol, negative control and RNA quality control for EML4-ALK fusion type were analyzed.Results During the 256 patients ofⅠ stage lung cancer, there were 17 patients(6.64%) had mutations in EML4-ALK fusion gene.In lung adenocarcinoma mu-tation rate(16/207, 7.73%) was higher than that of lung squamous cell mutation rate(1/39, 2.56%), lung adeno-squamous mutation rate(0/4, 0) and large cell carcinoma(0/5, 0) of the mutation rate;young lung cancer patients( <63 years) of the mutation rate(14/139, 10.07%) was significantly higher than the high age of lung cancer patients(≥63 years old) mutation rate(3/117, 2.56%), P =0.009.EML4-ALK fusion with tumor invasion and visceral pleura group incidence (9/80, 11. 25%) was significantly higher than that of non-invasive and visceral pleura group incidence rate(8/176, 4.55%), P =0.045.Conclusion The occurence of EML4-ALK fusion correlates with patients’ age as well as whether visceral pleura is in-vaded, type 1 EML4-ALK fusion was detected more in phase I lung cancer patients.

Research progress of epithelial mesenchymal transition mediated by FOX family in tumor metastasis / 中国药理学通报

Epithelial mesenchymal transition ( EMT) is one of the important biological processes in tumor invasion and metastasis . However , due to the complexity of EMT signaling pathway and its unclear molecular mechanism , the treatment of EMT is still a worldwide problem .But many studies have proved that EMT is not an irreversible process .In recent years , the research of FOX gene family in EMT shows its important role in tumor metastasis . This review focuses on the FOX-mediated EMT process in many kinds of tumor , aiming to have a better understanding of EMT signaling network , and provide a new target for the effective pre-vention of EMT .

The research progression of the voltage-gated sodium channels in tumor / 中国基层医药

Voltage-gated sodium channels are highly expressed in exciting cells,and play an important role in the depolarization of the membrane potential and the secretion and release of neurotransmitters.The recent research showed that the voltage gated sodium channels are highly expressed in colon cancer,breast cancer,prostate cancer and non-small cell lung cancer,and are closely associated with tumor proliferation,invasion,metastasis and other malignant biological behaviors.However,the mechanisms by which the ion channels regulate the biological behaviors and how the ion channels are mediated are still not clear.

Evaluation of Dermatological Disorders Caused by Anti-neoplastic Agents with an Adverse Event Spontaneous Reporting Database / 医薬品情報学

<b>Introduction</b>: Dermatological disorders are one of the adverse events caused by cancer chemotherapy and are a dose-limiting factor for some anti-neoplastic agents.  The severe symptoms associated with these disorders affect the patients’ quality of life (QOL).  Early countermeasures for the onset of dermatological disorders associated with anti-neoplastic agent administration might be important.<br><b>Materials and Methods: </b>We analyzed the occurrences of dermatological disorders after administration of an anti-neoplastic agent in the Food and Drug Administration Adverse Event Reporting System (FAERS), and compared the adverse event (AE) reporting ratio of the total reports.  In addition, we studied the association between anti-neoplastic agents and dermatological disorders using cluster analysis.  Reports for 15 anti-neoplastic agents (4 anti-neoplastic agents and 11 molecular target drugs) were analyzed.<br><b>Results: </b>After excluding duplicate data in FAERS, 6,157,897 reports were analyzed.  The number of reports that showed a dermatological disorder was 534,934.  The reporting ratio of hand-foot syndrome with sorafenib and capecitabine was 11.20% and 7.05%, respectively.<br><b>Conclusions: </b>We set the cluster number at six; cluster features obtained were as follows: (1) the reporting ratio of hand-foot syndrome was especially high, followed by the reporting ratio of rash, (2) the reporting ratio of rash and erythema was high.  Similar anti-neoplastic agents may demonstrate similar occurrence tendencies of AEs and cluster features.  Further studies are required to draw conclusions over these findings.  Information services based on the feature of each cluster might be useful to improve patient QOL at the clinical site.

Effect of nucleophosmin on breast cancer resistance in MCF-7/MTX cells / 中国药学杂志

OBJECTIVE: To investigate the mechanism of nucleophosmin (NPM) in the formation of breast cancer drug resistance. METHODS: The methotrexate-resistant breast cancer cells (MCF-7 /MTX) was established by escalating the concentrations of methotrexate to drug-sensitive MCF-7 cells (MCF-7/S). The cells viability of MCF-7/MTX was detected by MTT test, cell growth curve was drawn and doubling time was calculated. The cell morphology and ultrastructure were observed using optical and transmission electron microscopy. The expression of NPM and factors related to drug resistance were tested by Real-time PCR and Western blot assay. Then the NPM level was attenuated by RNA interfering technology, and the resistance mechanism was explored in MCF-7/MTX cells. RESULTS The MCF-7/MTX cell line was successfully established and resistance factor was 64. The resistant cells has spindle shaped morphology and tended to grow slowly, and the variations appeared in the internal structure of cells. MCF-7/MTX cells possessed cross-resistance to various chemotherapeutic drugs. The expressions of NPM and multidrug-resistant factors P-gp, MRP1, BCRP were up-regulated in the resistant cells. Further, the overexpression of NPM activated PI3K/Akt signaling pathway and inhibited downstream apoptotic factors. Then knockdown of NPM by siRNA significantly decreased the drug resistance of MCF-7/MTX cells, suppressed PI3K/Akt pathway and promoted the downstream cells apoptosis. CONCLUSION The high expression of NPM has an important role in the formation of breast cancer drug resistance, and it is expected to be a novel molecular target for breast cancer treatment in clinical.

Network pharmacology-based prediction and verification of the molecular targets and pathways for schisandrin against cerebrovascular disease / 中国天然药物

AIM@#To illuminate the molecular targets for schisandrin against cerebrovascular disease based on the combined methods of network pharmacology prediction and experimental verification.@*METHOD@#A protein database was established through constructing the drug-protein network from literature mining data. The protein-protein network was built through an in-depth exploration of the relationships between the proteins. The computational platform was implemented to predict and extract the sensitive sub-network with significant P-values from the protein-protein network. Then the key targets and pathways were identified from the sensitive sub-network. The most related targets and pathways were also confirmed in hydrogen peroxide (H2O2)-induced PC12 cells by Western blotting.@*RESULTS@#Twelve differentially expressed proteins (gene names: NFKB1, RELA, TNFSF10, MAPK1, CHUK, CASP8, PIGS2, MAPK14, CREB1, IFNG, APP, and BCL2) were confirmed as the central nodes of the interaction network (45 nodes, 93 edges). The NF-κB signaling pathway was suggested as the most related pathway of schisandrin for cerebrovascular disease. Furthermore, schisandrin was found to suppress the expression and phosphorylation of IKKα, as well as p50 and p65 induced by H2O2 in PC12 cells by Western blotting.@*CONCLUSION@#The computational platform that integrates literature mining data, protein-protein interactions, sensitive sub-network, and pathway results in identification of the NF-κB signaling pathway as the key targets and pathways for schisandrin.

Research progress on novel pathways and molecular targets for the treatment of sarcoma / 国际外科学杂志

Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors.They are not sensitive to chemotherapy,which requires the development of tissue-specific or pathway-specific therapies.As our understanding of the molecular mechanisms driving sarcomas is rapidly advancing,the number of targeted therapies is also increasing.Recently identified novel druggable targets including the MDM2 amplifications in welldifferentiated and dedifferentiated liposarcomas,the fusion NAB2:STAT6 of solitary fibrous tumor,the SDH mutations in gastrointestinal stro mal tumors,the suppression of Mcl1 in synovial sarcomas,CDK4 in alveolar rhabdomyosarcoma.They will play an important role in the treatment of sarcoma.Here,the author do an overview of these factors.

A case of no small cell lung carcinoma with leptomeningeal metastasis by elrotinib succeeded

<b>Introduction</b>: It is said that molecular target agents are more durable than cytotoxicic ones, although they have their own specific side effects. We experienced a case of non-small cell lung cancer with leptomeningeal metastasis and she had molecular target agents, she had palliation of symptom and prolongation of survival time. <b>Case</b>: Patient is 76 years old Japanese woman without smoking history. In April 2010 speech and gate disturbance was appeared on her, she was examined by CT and MRI, these revealed lung cancer, intrapulmonary metastasis, lymph nodal involvement, leptomeningeal metastasis, brain metastasis, and spinal bone metastasis in vertebras (T1bN1M1b, Stage IV). Symptoms such as gate disturbance, decrease of oral intake, drowsiness was regression rapidly, so patient and family decided discharge to go to home. She started to take elrotinib 100 mg on yth May. at home. She took elrotinib 150 mg since 6th June 2010 until July 2011 on her death. 2 weeks after administration of elrotinib she came to be able to eat and get up. On 6th August 2010 after administration of elrotinib primary lesion of lung cancer showed PR by CT, leptomeningeal and brain metastases showed SD by MRI. Grade 2 of skin rashu was manageable with topical corticosteroids. The remaining days from a diagnosis of the metastasis to lung cancer with leptomeningeal metastasis are reported with around three months. A symptom was relieved by the dosage of erlotinib,and there was not a serious side effect, and the patient could survive for one year and 5 months.