树枝状大分子的抗菌作用研究进展

目的 对各种树枝状大分子抗菌效能及其毒性的研究进展进行总结,为该类物质的进一步开发及应用提供参考。方法 查阅国内外相关文献,进行分析、归纳和综述。结果 具有抗菌活性的树枝状大分子主要包括糖、阳离子、肽、阴离子类及聚酰胺-胺类等树枝状大分子,上述大分子抗菌谱广,活性高,不容易诱导细菌耐药且生物相容性较好。 结论 树枝状大分子是一类潜在的抗菌候选分子及抗菌涂层材料,有良好的应用前景。     

Topical immunotherapy with diphencyprone (DPCP) for in-transit and unresectable cutaneous melanoma lesions: an inaugural Canadian series

Background: Diphencycprone (DPCP) is an immune contact sensitizer applied to melanoma lesions. Early studies show favorable efficacy. We present the first North-American series of patients treated with DPCP.

Methods: A single center retrospective study of patients with in-transit or unresectable melanoma lesions treated with DPCP from December 1,2014 to December 31,2015 was completed. Primary objectives were response rate and toxicity. Secondary objective was health-related quality of life assessment with the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire.

Results: Fifteen consecutive patients were identified with median age of 78 (range 43–92). 73% of patients had prior treatment. Two patients (13%) had a complete response after 25 and 32 weeks, respectively. Four patients (27%) had a partial response with a mean treatment time of 30 weeks (range 6–51 weeks). Six (40%) had stable disease. Six patients stopped DPCP – three from systemic progression and three from toxicity. The most common toxicity was blisters; one patient had significant skin ulceration that resolved on stopping DPCP. Median FACT-M score was 142.95 (possible total 172). Mean overall follow-up time was 22.7 weeks.

Conclusion: DPCP is a feasible option for in-transit and other melanoma cutaneous lesions ineligible/refractory to surgery and may delay need for systemic therapy.     

Drug-induced pathology of the upper gastrointestinal tract

Drugs can produce a wide range of pathology in the upper gastrointestinal tract. Often, the injury pattern is non-specific. Pill-induced oesophagitis usually affects the mid oesophagus. In the stomach, many drugs, particularly non-steroid anti-inflammatory drugs (NSAIDs), can cause ulcers, erosions or reactive gastropathy. Some drugs produce specific injury patterns that can be recognized by pathologists. Proton pump inhibitors cause parietal cell hyperplasia and fundic gland polyps. Kayexalate may cause erosions or ulcers, with ‘mosaic’ crystals within the exudate, but other resins may show crystals that can be confused for Kayexalate. Iron therapy, mucosal calcinosis, and mucosal lanthanum deposition share the presence of crystals in the mucosa of affected patients. Various agents can cause non-specific mucosal changes that mimic celiac disease, GVHD, or inflammatory bowel disease, such as olmesartan, idelalisib, and checkpoint inhibitors. Colchicine causes variable injury, and interference with microtubule assembly results in mitotic arrest. Hepatic arterial infusion chemotherapy may cause gastroduodenal ulcers associated with marked epithelial atypia that can be mistaken for carcinoma. Recognition of these histological patterns enables pathologists to make a diagnosis of drug-induced upper gastrointestinal injury and potentially to identify the specific agent responsible.     

白细胞介素17A及其受体拮抗剂治疗银屑病的不良反应

【摘要】 白细胞介素17A在银屑病的发生发展中具有关键作用。目前,有多种白细胞介素17A及其受体拮抗剂在多个国家上市并应用于银屑病的治疗,取得了明确疗效。然而,该类生物制剂在临床试验阶段及上市后,仍然有多项不良反应报道,包括上呼吸道感染、念珠菌感染、中性粒细胞减少和炎症性肠病等,严重者甚至可危及生命。本文综述3种白细胞介素17A及其受体拮抗剂司库奇尤单抗、ixekizumab和brodalumab的临床安全性。     

Molecular mechanism of reproductive toxicity induced by Tripterygium Wilfordii based on network pharmacology

To explore the possible molecular mechanism of reproductive toxicity of Tripterygium wilfordii from the perspective of network pharmacology and bioinformatics.The compounds of T wilfordii were obtained by querying the relevant Chinese medicine database, the effective compounds were screened and the corresponding targets were obtained, and then compared with the reproductive toxicities related to disease targets obtained from the disease gene database to infer the potential toxic targets of reproductive toxicity of T wilfordii. Then, the key targets of reproductive toxicity of T wilfordii were screened using Search Tool for the Retrieval of Interacting Genes/Protein and Cytoscape. The gene ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as module analysis, were performed on the key targets using Database for Annotation, Visualization, and Integrated Discovery and Cytoscape, respectively. Finally, the network between effective compounds-toxic targets was conducted to see how the compounds interacted.A total of 48 effective compounds and 482 potential toxic targets related to the reproductive toxicity of T wilfordii were screened. The enrichment analysis results showed that the key targets were mainly enriched in biological processes such as response to drug, ionotropic glutamate receptor signaling pathway, and KEGG pathways such as neuroactive ligand-receptor interaction, cAMP signaling pathway. In the protein-protein interaction network of potential toxic targets, there were 78 key targets such as TP53, INS, IL6, AGT, ADCY3, and so on. Enrichment analysis of the top module with 19 genes from module analysis indicated that T wilfordii might cause reproductive toxicity by gene ontology terms and KEGG pathways such as regulation of vasoconstriction, G-protein coupled receptor signaling pathway, inflammatory response, cAMP signaling pathway, and so on. In the network between effective compounds of T wilfordii and key targets, there were 5 compounds with high degree including Tingenone, Wilfordic Acid, Abruslactone A, Nobilin, and Wilforlide B.The complex molecular mechanism of reproductive toxicity of T wilfordii can be preliminarily elucidated with the help of the network pharmacology method, and the analysis results can provide some reference for the further mechanism research of reproductive toxicity of T wilfordii.     

From the Cover: Tonoplast CBL–CIPK calcium signaling network regulates magnesium homeostasis in Arabidopsis

Although Mg²⁺ is essential for a myriad of cellular processes, high levels of Mg²⁺ in the environment, such as those found in serpentine soils, become toxic to plants. In this study, we identified two calcineurin B-like (CBL) proteins, CBL2 and CBL3, as key regulators for plant growth under high-Mg conditions. The Arabidopsis mutant lacking both CBL2 and CBL3 displayed severe growth retardation in the presence of excess Mg²⁺, implying elevated Mg²⁺ toxicity in these plants. Unexpectedly, the cbl2 cbl3 mutant plants retained lower Mg content than wild-type plants under either normal or high-Mg conditions, suggesting that CBL2 and CBL3 may be required for vacuolar Mg²⁺ sequestration. Indeed, patch-clamp analysis showed that the cbl2 cbl3 mutant exhibited reduced Mg²⁺ influx into the vacuole. We further identified four CBL-interacting protein kinases (CIPKs), CIPK3, -9, -23, and -26, as functionally overlapping components downstream of CBL2/3 in the signaling pathway that facilitates Mg²⁺ homeostasis. The cipk3 cipk9 cipk23 cipk26 quadruple mutant, like the cbl2 cbl3 double mutant, was hypersensitive to high-Mg conditions; furthermore, CIPK3/9/23/26 physically interacted with CBL2/3 at the vacuolar membrane. Our results thus provide evidence that CBL2/3 and CIPK3/9/23/26 constitute a multivalent interacting network that regulates the vacuolar sequestration of Mg²⁺, thereby protecting plants from Mg²⁺ toxicity.Plants absorb essential mineral nutrients from the soil and translocate them to different organs for specific physiological processes. Most of these minerals are in the ionic forms and require a wide array of transporters to move them across the cell membranes and sort them into subcellular compartments (1). Although plants rely on a sufficient supply of mineral nutrients for proper growth and development, an excess of minerals often causes toxicity to plant cells. To adapt to the constantly changing availability of minerals in the environment, plants have evolved mechanisms that enhance ion uptake under low-nutrient conditions and sequester excessive ions in the vacuole when external levels are high. Such mechanisms enable plant cells to maintain a steady level of each nutrient ion, namely, ionic homeostasis. At the molecular level, this homeostasis entails the coordinated functions of a large number of regulatory molecules that constitute elaborate signaling networks to control the affinities and activities of numerous ion transporters. In these signaling networks, Ca²⁺ serves as a central messenger (2). A number of external ionic stresses can evoke stimulus-specific cellular Ca signals that are represented by the distinct spatiotemporal patterns of Ca²⁺ fluxes between cytosol and Ca²⁺ stores (3, 4). These “Ca²⁺ signatures” can be detected and relayed into diverse downstream signaling events by plant Ca²⁺-sensor proteins that manifest conformational changes upon binding Ca²⁺ and subsequently regulate the function of target proteins (5–7).Calcineurin B-like (CBL) proteins are a group of Ca²⁺ sensors that physically and functionally interact with a family of plant-specific protein kinases designated as “CBL-interacting protein kinases” (CIPKs) (8). Interaction between CBLs and CIPKs is mediated by the regulatory C-terminal region of CIPKs and is required for full activation of the kinase activity (9–11). Although CIPKs appear to be soluble in the cytosol, CBL proteins are largely associated with the cellular membranes through their N-terminal motifs that are subject to lipid modifications (12). Some CBLs, such as CBL1, -4, -5, and -9, are anchored to the plasma membrane through myristoylation and acylation at their N-terminal region (13). Other CBLs including, CBL2, -3, and -6, are localized to the vacuolar membrane via the N-terminal tonoplast targeting sequence that contains multiple cysteine residues subject to S-acylation (14, 15). It has been suggested that the dynamic localization of CIPKs is determined by their specific CBL partners, resulting in alternative CBL–CIPK complexes at either the plasma membrane or the tonoplast (16–18).Growing evidence has highlighted the CBL–CIPK regulatory pathways in plant responses to environmental stresses in general and ionic stresses in particular (19). In the Ca²⁺-dependent salt overly sensitive (SOS) pathway, the Ca sensor CBL4/SOS3 (20) and the protein kinase CIPK24/SOS2 (21) form a functional module to regulate the Na⁺/H⁺ exchanger SOS1 at the plasma membrane, thus facilitating Na⁺ extrusion under salt stress (22). Another CBL protein, CBL10/SCaBP8, was identified as a shoot-specific partner of CIPK24 in salt stress adaptation (16, 23, 24). In response to limited K⁺ supply, the Ca sensors CBL1 and CBL9 positively regulate CIPK23 and recruit the kinase to the plasma membrane, which in turn activates the K⁺ channel AKT1 for optimal K⁺ nutrition (25–27). Interestingly, the CBL1/9–CIPK23 module also regulates nitrate (NO₃⁻) uptake and sensing processes by phosphorylating the dual-affinity NO₃⁻ transporter CHL1 (28). A recent study shows that CIPK23, in complex with CBL1 or CBL9, could trigger the opening of the S-type anion channel SLAC1 or SLAH3 through its phosphorylation in a Ca-dependent manner (29).Ionic homeostasis is regulated mainly by ion transport across the plasma membrane and vacuolar membrane (tonoplast). Although CBL–CIPK signaling modules are well recognized as playing a critical role in the transport of several minerals across the plasma membrane, very little is known about the possible function of vacuolar CBL–CIPK complexes. Our recent work revealed a highly redundant role for tonoplasts CBL2 and CBL3 in plant development and ion homeostasis that is correlated with the regulation of vacuolar H⁺-ATPase (V-ATPase) activity (14). In this study, we describe a novel function of CBL2 and CBL3 in the regulation of Mg²⁺ homeostasis through a V-ATPase–independent pathway in Arabidopsis. Downstream of CBL2 and CBL3 are four functionally redundant CIPKs that are recruited to the tonoplast by interacting with CBL2 and CBL3. Our results thus build a CBL–CIPK network at the tonoplast that regulates vacuolar sequestration to detoxify excessive Mg²⁺ in plant cells.     

Development of reduced-intensity hematopoietic stem cell transplantation in the National Cancer Center Hospital,Japan

Reduced-intensity hematopoietic stem cell transplantation (RIST) is a new approach of stem cell transplantation, which has shown promising features as reported in multiple phase I and II studies. Elderly patients, who are not eligible for conventional myeloablative hematopoietic stem cell transplantation (HSCT), are now treatable with RIST. It has also reduced regimen-related toxicity and provided better prognosis in short-term follow-up than that of conventional HSCT. Favorable results have been reported particularly in hematological malignancies, such as chronic myelocytic leukemia and malignant lymphoma. Among solid tumors, metastatic renal cell carcinoma was found to respond well to RIST. Clinical studies are currently being conducted to evaluate the efficacy of RIST in other types of solid tumors. However, the mechanism of graft-versus-host disease and graft-versus-tumor remains unclear. More knowledge on the mechanism is crucial to enhance antitumor effect and to further improve the prognosis.     

The use of methotrexate in rheumatoid arthritis

OBJECTIVE: To address the long-term efficacy and toxicity issues related to methotrexate (MTX) and compare it with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Review of the international literature on the clinical use of MTX in rheumatoid arthritis (RA) disease. RESULTS: MTX has emerged as a relatively safe and effective treatment for RA that compares favorably with other therapies, particularly because of its considerably longer median drug survival. The toxicity profile of MTX is well established and includes serious and sometimes fatal liver disease, pneumonitis, and cytopenias. Hence, regular and careful monitoring of patients taking MTX is essential, particularly when MTX is combined with other DMARDs. Folate supplementation can reduce some of the most common side effects of MTX, but it has not yet been established whether this translates into a reduced risk of serious disease. Another potential approach to reducing the toxicity of MTX is therapeutic drug monitoring and dose individualization. However, correlations between pharmacokinetics and clinical response have been addressed in only a few studies and with conflicting results. CONCLUSIONS: MTX is an effective DMARD with a relatively safe profile compared with other therapies. Folate supplementation can significantly reduce the risk of MTX toxicity. Finally, it is essential that patients be monitored carefully to reduce the potential serious toxicities of MTX.     

复方苯佐卡因凝胶的局部毒性研究

目的评价复方苯佐卡因凝胶的局部刺激性和致敏性。方法依照国家食品药品监督管理局《化学药物刺激性、过敏性和溶血性研究技术指导原则》(以下简称指导原则),采用大鼠口腔黏膜刺激性实验法、兔眼刺激性实验法以及豚鼠皮肤致敏实验法。结果复方苯佐卡因凝胶给大鼠口腔正常黏膜连续涂药3次,相当于3 g.kg-1,均无刺激和毒性反应;一次性按每只0.1 g给兔眼结膜涂药,亦未出现刺激性反应;给每只豚鼠皮肤0.2 g致敏接触和激发接触,均无过敏反应发生。结论复方苯佐卡因凝胶对口腔黏膜无刺激性,对皮肤也没有致敏性。