MALAT1生物学功能及其与炎症-肿瘤的关系

非编码RNA(noncoding RNA,ncRNA)是人类基因组学研究的重要领域,其中长度超过200 bp的长链非编码RNA(long non-coding RNA,LncRNA),占80%以上。肺腺癌转移相关转录子1(metastasis-associated lung adenocarcinoma transcript 1,MALAT1)属LncRNA家族重要成员,伴随着MALAT1亚细胞结构定位特点、招募SR蛋白家族作用及其在多种人类恶性肿瘤中异常表达等现象逐步揭示,其与炎症-肿瘤间可能存在的关系也将成为进一步研究的焦点,结合MALAT1的分子生物学特点作一综述。

肿瘤坏死因子-α在炎症与肿瘤中的作用

肿瘤坏死因子-α（TNF-α）主要是由脂多糖刺激巨噬细胞而分泌的一种蛋白质，具有多种生物活性的炎性细胞因子，与其他细胞因子共同作用参与激活免疫反应，介导全身炎症，诱发肿瘤的发生，并可致肿瘤坏死。TNF-α被认为与调节致病性休克、组织损伤和内毒素血症等相关；是所发现的抗肿瘤活性较强的炎性细胞因子，在炎症与肿瘤的发生发展中具有重要作用。

The IκB kinase- a bridge between inflammation and cancer

A potential link between inflammation and cancer has been suspected for over a century, but the exact molecular mechanisms connecting the two remained nebulous. We proposed that NF-κB transcription factors regulated via the IκB kinase （IKK） complex play a critical role in coupling inflammation and cancer and have set out to test this hypothesis in mouse models of cancer. Using mice bearing mutations in the genes coding for the IKKβ and IKKα catalytic subunits we obtained evidence supporting a critical role for IKKβ in tumor promotion and more recently identified the involvement of IKKα in metastatogenesis. Whereas the major pro-tumorigenic function of IKKβ is mediated via NF- κB, the proetastatic function of IKKα is NF-κB-independent. In addition to illustrating the critical roles of the two IKK molecules in linking inflammation and cancer and providing an explanation for increased cancer risk in response to persistent infections and inflammation, these results also identify new targets for development of novel anti-cancer therapies and preventive strategies. Instead of targeting the cancer cell itself, as done by conventional anti-cancer drugs, the new therapeutics will target processes that occur within inflammatory cells that are essential for cancer development and progression. Unlike cancer cells, inflammatory cells retain a normal and stable genome and therefore are unlikely to become genetically resistant to therapeutic intervention.

Network pharmacology-based approach to investigate the mechanisms of Yiyi Fuzi Baijiang Powder in the treatment of malignant tumors

Objective:To systematically investigate the main active components,targets,target-related diseases and action mechanism of Yiyi Fuzi Baijiang powder(YFBP)of Zhang Zhongjing,a Chinese physician of Eastern Han Dynasty of China(3 century A.D.)using the method of network pharmacology.Methods:The active components of YFBP were identified from several databases(TCMSP,TCM Database@Taiwan and TCMID).The potential active compounds were screened based on oral bioavailability and drug-like index in the TCMSP database.DrugBank,TCMSP,and TCMID database searches were performed to predict target-related diseases.Biological functions and KEGG pathway outcomes of all potential targets were analyzed using the DAVID database.Results:A total of 24 active compounds of YFBP,133 related targets,and 305 potential related diseases were obtained.These results showed that YFBP may treat inflammation,pain,and cancer.The functional enrichment analysis indicated that YFBP probably exerts its therapeutic effects by regulating neuroactive ligand-receptor interactions,the TNF signaling pathway,and the PI3K-Akt signaling pathway.Conclusion:This study provides preliminary confirmation that YFBP has the great potentials to treat inflammation,pain,and tumors,which supports Zhang Zhongjing’s original intention to treat intestinal carbuncle with ancient prescription YFBP,but also provides a scientific basis for its treatment in the malignant tumors.

Gastric sarcoidosis mimicking irritable bowel syndrome-Cause not association?

Sarcoidosis is a systemic disease of unknown aetiology that may affect any organ in the body. The gastrointestinal tract however is only rarely affected outside the liver. Symptoms may be non-specific. Irritable bowel syndrome （IBS） is a common diagnosis. The recognition of IBS is aided by the use of the Rome Ⅱ criteria-in the absence of organic disease. We describe the first case of a patient with gastric sarcoidosis who presented with IBS symptoms but subsequently responded to immunosuppressive therapy.

Lipopolysaccharide preconditioning induces protection against lipopolysac-charide -induced neurotoxicity in organotypic midbrain slice culture

Objective To identify the protective effect of lipopolysaccharide （LPS） preconditioning against LPS-induced inflammatory damage in dopaminergic neurons of midbrain slice culture and the possible mechanisms. Methods After cultured in vitro for 14 d, the rat organotypic midbrain slices were pretreated with different concentrations （0, 1, 3, 6 or 10 ng/mL） of LPS for 24 h followed by treatment with 100 ng/mL LPS for 72 h. The whole slice viability was detelmined by measurement of the activity of lactic acid dehydrogenase （LDH）. Tyrosine hydroxylase-immunoreactive （TH-IR） neurons and CD 1 1 b/c equivalent-immunoreactive （OX-42-IR） microglia in the slices were observed by immunohistochemical method, and tumor necrosis factor-α （TNF-α levels in the culture media were detected by enzymelinked immunosorbent assays （ELISA）. Results In the slices treated with 100 ng/mL LPS for 72 h, the number of TH-IR neurons reduced from 191± 12 in the control slices to 46±4, and the LDH activity elevated obviously （P 〈 0.01）, along with remarkably increased number of OX-42-IR cells and production of TNF-α （P 〈 0.01）. Preconditioning with 3 or 6 ng/mL LPS attenuated neuron loss （the number of TH-IR neurons increased to 126± 12 and 180± 13, respectively） and markedly reduced LDH levels （P 〈 0.05）, accompanied by significant decreases of OX-42-IR microglia activation and TNF-α production （P 〈 0.05）. Conclusion Low-dose LPS preconditioning could protect dopaminergic neurons against inflammatory damage in rat midbrain slice culture, and inhibition of microglial activation and reduction of the proinflammatory factor TNF-α production may contribute to this protective effect. Further understanding the underlying mechanism of LPS preconditioning may open a new window for treatment of Parkinson＇s disease.

Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease

The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and myelotoxicity.Due to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse reactions.Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects.In this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.

Exploring the phytoconstituents targeting TNF-αas potential lead compounds to treat inflammatory diseases:an in-silico approach

Objective To explore the anti-inflammatory phytoconstituents from various plant sources as tumour necrosis factor-α(TNF-α)-inhibitor,a mediator involved in the inflammatory disorder,by in silico molecular docking.Methods Based on previous findings,we performed the in silico assessment of anti-inflammatory phytoconstituents from different medicinal plants to understand their binding patterns against TNF-α(PDB ID:6OP0)using AutoDock Vina.Molecular docking was performed by setting a grid box(25×25×25)Åcentered at[-12.817×(-1.618)×19.009]A with 0.375A of grid spacing.Furthermore,Discovery Studio Client 2020 program was utilized to assess two-and three-dimensional(2D and 3D)hydrogen-bond interactions concerning an amino acid of target and ligand.Physicochemical properties were reported using the Lipinski’s rule and SwissADME database to support the in silico findings.Results From the selected medicinal plants,more than 200 phytocompounds were screened against TNF-α protein with binding scores in the range of -12.3 to -2.5 kcal/mol.Amongst them,emodin,aloe-emodin,pongamol,purpuritenin,semiglabrin,ellagic acid,imperatorin,α-tocopherol,and octanorcucurbitacin A showed good binding affinity as -10.6,-10.0,-10.5,-10.1,-11.2,-10.3,-10.1,-10.1,and -10.0 kcal/mol,respectively.Also,the absorption,distribution,metabolism,excretion,and toxicology(ADMET)profiles were well within acceptable limits.Conclusion Based on our preliminary findings,we conclude that the selected phytoconstituents have the potential to be good anti-inflammatory candidates by inhibiting the TNF-α target.These compounds can be further optimized and validated as new therapeutic components to develop more effective and safe anti-inflammatory drugs.

Invasive front of colorectal cancer:Dynamic interface of pro-/anti-tumor factors

Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carci-noma cells known as epithelial mesenchymal transition (EMT). EMT can be identified histologically by the presence of "tumor budding" ,a feature which can be highly specific for tumors showing an inf iltrating tumor growth pattern. Importantly,tumor budding and tumor border configuration have generated considerable interest as additional prognostic factors and are also recognized as such by the International Union Against Cancer. Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front. In fact,several tumor-associated antigens such as CD3,CD4,CD8,CD20,Granzyme B,FOXP3 and other immunological or inflammatory cell types have been identified as poten-tially prognostic in patients with this disease. Evidence seems to suggest that the balance between protumor (including budding and inf iltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer. On one hand,the inf iltrating tumor border configuration and tumor budding promote progression and dissemination of tumor cells by penetrating the vascular and lymphatic vessels. On the other,the host attempts to fend off this attack by mounting an immune response to protect vascular and lymphatic channels from invasion by tumor buds. Whereas standard pathology reporting of breast and prostate cancer involves additional prognostic features,such as the BRE and Gleason scores,the ratio of pro-and anti-tumor factors could be a promising approach for the future development of a prognostic score for patients with colorectal cancer which could complement tumor node metastasis staging to improve the clinical management of patients with this disease.

针刺对实验性脑出血大鼠炎性反应的时效研究

目的:观察针刺对脑血肿早期周围组织病理形态结构、炎症反应的影响,探讨不同时机介入针刺对脑出血病理状态下的脑保护作用。方法:采用自体血注入尾状核模型大鼠,随机分为正常组、模型组和四个针刺组。针刺组分别于造模成功后3 h、9 h、24 h、48 h开始针刺,每日针刺2次,连续针刺3 d,针刺组与模型组均在造模成功后5 d处死,断头取脑,观察相关指标。结果:针刺能改善脑血肿周围组织病理改变,减轻脑水肿,改善神经功能缺损情况,降低炎症反应相关因子肿瘤坏死因子-α(TNF-α)、细胞间黏附分子-1(ICAM-1)的表达,这些作用均与介入时机正性相关。结论:针刺能减轻脑出血大鼠脑组织炎症反应,提示超早期介入能获得更好疗效。

Gastric carcinogenesis

Gastric cancer is the second most common cancer worldwide and the second most common cause of cancer-related deaths. Despite complete resection of gastric cancer and lymph node dissection, as well as improvements in chemotherapy and radiotherapy, there are still 700 000 gastric cancer-related deaths per year worldwide and more than 80% of patients with advanced gastric cancer die of the disease or recurrent disease within 1 year after diagnosis. None of the treatment modalities we have been applying today can influence the overall survival rates:at present, the overall 5-year relative survival rate for gastric cancer is about 28%. Cellular metaplasia due to chronic inflammation, injury and repair are the most documented processes for neoplasia. It appears that chronic inflammation stimulates tumor development and plays a critical role in initiating, sustaining and advancing tumor growth. It is also evident that not all inflammation is tumorigenic. Additional mutations can be acquired, and this leads to the cancer cell gaining a further growth advantage and acquiring a more malignant phenotype. Intestinalization of gastric units, which is called "intestinal metaplasia"; phenotypic antralization of fundic units, which is called "spasmolytic polypeptide-expressing metaplasia"; and the development directly from the stem/progenitor cellzone are three pathways that have been described for gastric carcinogenesis. Also, an important factor for the development of gastrointestinal cancers is peritumoral stroma. However, the initiating cellular event in gastric metaplasia is still controversial. Understanding gastric carcinogenesis and its precursor lesions has been under intense investigation, and our paper attempts to highlight recent progress in this field of cancer research.

Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues

AIM: To investigate the relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma (HCC) tissues and their clinicopathological features.METHODS: The paraffin-embedded specimens from 70 cases with HCC were stained using EliVision immunohistochemistry with mAbs against CD68, tryptase,and CD34. The counts of tumor-associated macrophage (TAM), mast cell (MC) and tumor microvessel (MV) were performed in the tissue sections.RESULTS: The mean counts of TAM, MC, and MV in HCC tissues were significantly higher than those in pericarcinomatous liver tissues (TAM: 69.31± 11.58 vs 40.23±10.36; MC: 16.74±5.67 vs 7.59±4.18; MV:70.11±12.45 vs 38.52± 11.16, P＜0.01). The MV count in the patients with metastasis was markedly higher than that with non-metastasis (P＜0.01). In addition, the MC count in the patients with poorly differentiated HCC was obviously higher than that with well differentiated HCC (P＜ 0.01). The correlation analysis showed that the TAM count was significantly correlated with the count of MV(r=0.712, P＜0.01), and the MC count was obviously correlated with the MV count (r= 0.336, P＜ 0.05).CONCLUSION: TAM and MC might be closely related to the enhancement of tumor angiogenesis. The MV count might be associated with tumor invasion and metastasis.Moreover, the MC count might be associated with tumor differentiation and prognosis of HCC.

Genetic and epigenetic changes associated with cholangiocarcinoma:From DNA methylation to microRNAs

Cholangiocarcinomas are malignant epithelial liver tumors arising from the intra- and extra-hepatic bile ducts. Little is known about the molecular development of this disease, and very few effective treatment options are available. Thus, prognosis is poor. Genetic and epigenetic changes play an integral role in the neoplastic transformation of human cells to their malignant counterparts. This review summarizes some of the more prevalent genetic alterations （by microRNA expression） and epigenetic changes （hypermethylation of specific gene promoters） that are thought to contribute to the carcinogenic process in cholancliocarcinoma.

Activation and signaling of the p38 MAP kinase pathway

The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

Advances in the relationship between Hashimoto’s thyroiditis and thyroid cancer

In recent years,the incidence of Hashimoto’s thyroiditis and thyroid cancer has shown a rapid growth trend.These two diseases have severely affected the public health.Many epidemiological studies have shown that thyroid cancer is often associated with Hashimoto’s thyroiditis.Hashimoto’s thyroiditis may promote the occurrence of thyroid cancer,as well as affecting the progression of the tumor,lymph node metastasis,and even the prognosis of patients.In this paper,the relationship between Hashimoto’s thyroiditis and thyroid cancer and the pathogenesis of thyroid cancer are reviewed regarding molecular mechanism,clinical pathology,and serology.

Adalimumab and pharmacokinetics:Impact on the clinical prescription for inflammatory bowel disease

Anti-tumor necrosis factor(TNF) drugs are widely prescribed for inflammatory disease. A loss of response to adalimumab is frequent and the pharmacokinetics of anti-TNF therapy have important implications for patient management. Individual factors such as albumin, body weight, and disease severity based on the C-reactive protein level influence drug metabolism. Adalimumab trough levels are associated with clinical remission. On the other hand, the detection of antibodies is associated with clinical relapse. Immunosuppressive therapy could reduce antibody formation although the clinical impact is not proven. New algorithms are available to provide personalized treatment and adapt the dosage. More data are needed on dose de-escalation.

Impact of medical therapies on inflammatory bowel disease complication rate

Crohn's disease and ulcerative colitis are progressive diseases associated with a high risk of complications over time including strictures,fistulae,perianal complications,surgery,and colorectal cancer.Changing the natural history and avoiding evolution to a disabling disease should be the main goal of treatment.In recent studies,mucosal healing has been associated with longer-term remission and fewer complications.Conventional therapies with immunosuppressive drugs are able to induce mucosal healing in a minority of cases but their impact on disease progression appears modest.Higher rates of mucosal healing can be achieved with anti-tumor necrosis factor therapies that reduce the risk of relapse,surgery and hospitalization,and are associated with perianal fistulae closure.These drugs might be able to change the natural history of the disease mainly when introduced early in the course of the disease.Treatment strategy in inflammatory bowel diseases should thus be tailored according to the risk that each patient could develop disabling disease.

严重烧伤患者外周血高迁移率族蛋白B-1水平的检测及其临床意义

目的检测严重烧伤后患者血浆高迁移率族蛋白B-1(HMGB1)水平的变化并探讨其临床意义。方法用酶联免疫吸附试验法检测77例严重烧伤患者血浆HMGB1水平,同步检测肿瘤坏死因子-α(TNF-α)含量,并与30名健康对照组进行比较。结果 77例严重烧伤患者按烧伤面积分为3组,A组31例,烧伤总面积30%～49%,B组25例,烧伤总面积50%～69%,C组21例,烧伤总面积70%～95%;烧伤患者血浆HMGB1及TNF-α水平在A组为(22.15±6.34)ng/ml、(89.26±21.41)pg/ml,B组为(26.24±9.71)ng/ml、(132.45±76.32)pg/ml,C组为(36.45±11.63)ng/ml、(213.61±87.45)pg/ml,对照组为(2.17±1.13)ng/ml、(45.32±13.84)pg/ml,烧伤各组HMGB1及TNF-α水平明显高于对照组(P<0.01);24例特大面积烧伤患者根据预后情况分为生存组和死亡组进行动态观察,两组患者血浆HMGB1水平在伤后第1天即显著升高(P<0.01),在伤后3～21d,死亡组明显高于生存组(P<0.05),而TNF-α含量在伤后第3～7d达高峰,以后逐渐下降,到21d时生存组与死亡组相比已差异无统计学意义。结论严重烧伤后HMGB1的表达异常升高,HMGB1作为重要的晚期炎症介质和TNF-α相互诱生相互作用,参与严重烧伤后全身炎症反应综合征的病理生理过程,动态观察其水平变化有助于烧伤患者病程监测及预后判断。

Brazilein inhibits neuronal inflammation induced by cerebral ischemia and oxygen-glucose deprivation through targeting NOD2 expression

Brazilein is reported to have immunosuppressive effect on cardiovascular and cerebral-vascular diseases. The essential roles of innate immunity in cerebral ischemia are increasingly identified, but no studies concerning the influence of brazilein on the innate immunity receptors have been reported. The present study was designed to investigate the regulation of NOD2 （Nucleotide-binding oligomerization domain-containing protein 2） by brazilein for its protection of neuron in cerebral ischemia in vivo and oxygen-glucose deprivation in vitro. The results showed that brazilein could reverse the elevated expression of NOD2 and TNFa （tumor necrosis factor alpha） elicited by cerebral ischemia and reperfusion. This reduction could also be detected in normal mice and C 17.2 cells, indicating that this suppressive effect of brazilein was correlated with NOD2. The results from GFP reporter plasmid assay suggested brazilein inhibited NOD2 gene transcription. In conclusion, brazilein could attenuate NOD2 and TNFα expression in cerebral ischemia and NOD2 may be one possible target of brazilein for its immune suppressive effect in neuro-inflammation.

Harnessing the immune system for the treatment of breast cancer

Standard treatment options for breast cancer include surgery, chemotherapy, radiation, and targeted therapies, such as adjuvant hormonal therapy and monoclonal antibodies. Recently, the recognition that chronic inflammation in the tumor microenvironment promotes tumor growth and survival during different stages of breast cancer development has led to the development of novel immunotherapies. Several immunotherapeutic strategies have been studied both preclinically and clinically and already have been shown to enhance the efficacy of conven- tional treatment modalities. Therefore, therapies targeting the immune system may represent a promising next-generation approach for the treatment of breast cancers. This review will discuss recent findings that elucidate the roles of suppressive immune cells and proinflammatory cytokines and chemokines in the tumor-promoting microen- vironment, and the most current immunotherapeutic strategies in breast cancer.