SUMO-Activating Enzyme Subunit 1 Is Associated with Poor Prognosis, Tumor Progression, and Radio-Resistance in Colorectal Cancer.

Concurrent chemoradiotherapy is an effective treatment option for patients with low-grade colorectal cancer (CRC) in the local disease stage. At present, the principle of the Taiwan Medical Center is to treat CRC patients with combination radiotherapy and chemotherapy (high-dose 5-FU) for a period of about five weeks prior to surgery. Radical resection of the tumor is performed at least six to eight weeks after concurrent chemoradiotherapy (CCRT). However, this approach fails to produce the desired therapeutic effect in approximately 20% to 30% of patients, and such patients are unnecessarily exposed to the risks of radiation and drug toxicity posed by this therapy. Therefore, it is crucial to explore new biomarkers to predict the prognosis of CRC. SUMO-activating enzyme subunit 1 (SAE1) plays an important role in SUMOylation, a post-translational modification involved in cellular functions, such as cell proliferation, cell cycle, and apoptosis. In our study, to explore the clinical-pathological role of SAE1 protein in CRC, we evaluated the clinical data and paraffin sections from CRC patients. The expression of SAE1 was evaluated using immunohistochemical analysis, and clinical parameters were analyzed using chi-square and Kaplan-Meier survival tests. The results of in vitro proliferation and radiosensitive assays were compared between control groups and SAE1 siRNA groups. Western blotting was also used to detect the expressions of the SAE1, PARP, cyclin D1, p-NF-κB, and NF-κB proteins. Flow cytometry and colony formation assays were used to detect the effect of SAE-1 on radiosensitivity. In vivo, we detected the growth curve in a mouse xenograft model. The results showed that SAE-1 was revealed to be an independent prognostic biomarker of CRC. SAE1 knockdown inhibited CRC proliferation in vitro and in vivo, and led to the cleavage of PARP, downregulation of cyclin D1 protein expression, and downregulation of p-NF-κB/NF-κB. Additionally, SAE1 knockdown promoted radiosensitivity in CRC cells. Therefore, it was inferred that SAE1 may be used as a potential therapeutic target in CRC treatment.

Suppression of TGFß-Induced Interleukin-6 Secretion by Sinulariolide from Soft Corals through Attenuation of the p38-NF-kB Pathway in Carcinoma Cells.

Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGFß, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGFß-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGFß and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGFß-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGFß activities. In addition, SC-1 inhibits TGFß-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-κB and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis.

Combined Detection of CA19-9 and MUC1 Using a Colorimetric Immunosensor Based on Magnetic Gold Nanorods for Ultrasensitive Risk Assessment of Pancreatic Cancer.

We herein report a facile approach for developing an enzyme-free colorimetric immunosensor based on a magnetic iron oxide (IO)-coated gold nanorod (MGNR) nanocomposite with high electron transfer ability to accelerate the color bleaching reaction of methyl orange (MO) in the presence of NaBH4 for ultrasensitive detection of cancer antigens. In the case of MO, the reaction rate of MGNRs showed approximately 45.6-fold and 1520.8-fold higher than that of Cys-GNRs and NaBH4, respectively. The proposed colorimetric immunosensor was demonstrated to enable simple, cost-effective, sensitive, and specific carbohydrate antigen 19-9 (CA19-9) and mucin 1 (MUC1) detection for risk evaluation of pancreatic cancer (PC) with a small volume of serum sample without the use of any enhancing solutions or enzymes. By increasing the concentration of CA19-9 and MUC1, more MGNRs remained in the plate well to enhance the color bleaching of MO. As a proof-of-concept, the limit of detection (LOD) of 3.5 × 10-5 U/mL for CA19-9 and 5.2 × 10-6 U/mL for MUC1 was obtained with a wide linear quantification range from 8.6 × 10-5 U/mL to 1.4 × 10-2 U/mL for CA19-9 and 1.3 × 10-5 U/mL to 2.1 × 10-3 U/mL for MUC1, suggesting potential clinical applications for the early risk evaluation of PC.

Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions / 中国天然药物

Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil (MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases (UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s (CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate (GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid (GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord / 华中科技大学学报（医学）（英德文版）

Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic constituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β (IL-1β), which plays a critical role in the development and maintenance of neuropathic pain. In the present study, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were significantly decreased after spinal nerve ligation (SNL), and the changes were accompanied by inhibited autophagy in the spinal microglia and increased mRNA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.

Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord / 华中科技大学学报（医学）（英德文版）

Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic constituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β (IL-1β), which plays a critical role in the development and maintenance of neuropathic pain. In the present study, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were significantly decreased after spinal nerve ligation (SNL), and the changes were accompanied by inhibited autophagy in the spinal microglia and increased mRNA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.

Clinical Observation and Analysis of Severe Chemotherapy-induced Bone Marrow Suppression Effect / 中国药房

OBJECTIVE:To observe the occurrence of severe myelosuppression after chemotherapy and to improve its therapeutic effects. METHODS:A total of 288 cases of 268 patients with grade Ⅳ bone marrow suppression induced by chemotherapy treatment were analyzed. RESULTS:Of the 288 cases,The median day when absolute neutrophil coun(tANC)

Development of clinical researches on prevention aromatase inhibitorassociated bone loss by zoledronic acid / 中国临床药理学与治疗学

Aromatase inhibitors(AIs) are standard therpy for postmenopausal women with estrogen responsive breast cancers.By inhibiting the aromatase enzyme,causing decreases in endogenous estrogens,the treatment of Als is responsible for lower bone mineral density(BMD) and increased fractures.Therefore,early recognition, prevention,and/or treatment of AI-induced bone loss is needed.Zoledronic acid is specific inhibitors of osteoclasts and extensively used in bone metastasis patients.Recently, there are several trials evaluating the use of in- travenous zoledronic acid as prevention and treatment of AI-induced bone loss in postmenopausal women with breast cancer.In this article, we aim to review the use of zoledronic acid in this population including the response and safety.