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Atopic dermatitis (AD) is a chronic, relapsing, inflammatory dermatosis with a variety of clinical manifestations and difficult to cure. Currently, many AD drug candidates have entered the research and development pipeline. In order to provide technical specifications for the clinical development of AD drugs, the Center for Drug Evaluation of National Medical Products Administration released the "Technical Guidelines for Clinical Trials of Drugs for AD Treatment" (Draft for Comments) in November 2022. Non-clinical pharmacodynamics evaluation is an important research before the drug enters clinical trials. Oxazolone (OXA)- and 2,4-dinitro-fluorobenzene (DNFB)-induced models are the most popular classical hapten-induced AD murine models, but variations of modeling are existing in the methods from different studies, including sensitization sites, haptens' dosages, the period of challenges, and the skin lesions severity evaluation as well. In this study, the investigation of OXA- and DNFB-induced AD murine models with various conditions of modeling was performed to compare the characteristics of hapten-induced AD murine models in the pathological process and severity according to the appearance of AD patients, and the guidance of pharmacodynamics evaluation of AD-therapeutic drugs in clinical trials as well, which may provide a proposal for AD treatment drug candidates in the non-clinical pharmacodynamics evaluation. All animal experiments were approved by the Animal Care & Welfare Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (approval No.: 00007782 and 00007784).
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Objective:To understand the current situation of the demand for Internet plus nursing service among nurses at different levels, and analyze the influencing factors, so as to provide reference for the improvement of relevant national policies.Methods:A total of 19 762 in-service nurses from 32 provinces in China were investigated by cross sectional survey in April to May 2019. The demand for Internet plus nursing services was investigated, including 5 dimensions, including institutional demand, safety demand, demand for fees, quality demand and training needs.Results:Among the 19 762 nurses surveyed, there were 135, 4 736, 8 847, 4 827 and 1 217 nurses at N0-N4 levels respectively. The safety needs of nurses ranked first(4.68±0.52). The institutional needs of N3 and N4 nurses were the most significant, and the safety needs of N0-N2 nurses were the most significant; Training demand was the third demand of nursing staff at all levels. Multiple linear regression analysis showed that education and professional title were the factors that affected nurses′ demand for Internet plus nursing service( P<0.01). Conclusions:Nurses at different levels have a high and diversified demand for Internet+ nursing services.
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Objective:To investigate the nutritional risk and prevalence of malnutrition in patients with terminal stage gastrointestinal malignant tumors in a tertiary hospital in Changsha.Methods:Cluster sampling was used to conduct a cross-sectional survey of inpatients from Departments of Gastroenterology, Gastrointestinal Surgery, Hepatobiliary Surgery and Oncology in Hunan Provincial People's Hospital from January 2019 to July 2020. Nutritional Risk Screening 2002 (NRS 2002) was used to assess the prevalence of nutritional risk with malnutrition defined as concurrent presence of BMI < 18.5 kg/m 2, poor general condition and NRS 2002 nutritional impairment score of 3. Step 2 of Global Leadership Initiative on Malnutrition (GLIM) diagnostic criteria (without whole body muscle mass) was adopted to diagnose malnutrition. Step 3 of GLIM criteria was used to evaluate the prevalence of severe malnutrition. Results:A total of 802 patients registered in the 4 departments were selected for screening via cluster sampling and 514 were enrolled according to the inclusion/exclusion criteria. The prevalence of nutritional risk in patients with terminal stage gastrointestinal cancer was 49.8% (256/514). The prevalence of malnutrition and severe malnutrition per GLIM criteria were 41.6% (214/514) and 18.3% (94/514), respectively.Conclusions:Although nutritional support therapy is not recommended for patients with end-stage cancer. This paper suggests that the prevalence of nutritional risk and malnutrition in patients with end-stage gastrointestinal cancer is not as high as described in some articles.
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The limited treatment options for the increasing occurrence of Lassa hemorrhagic fever in West Africa poses an urgent need for the discovery and development of novel therapeutics. Dietary supplements, especially natural products that are edible and safe for human use, are a good source of drug discovery with potential for uncovering novel applications. In this study, we tested 40 natural products of dietary supplements and identified capsaicin, a common dietary supplement abundant in chili peppers, as an inhibitor of Lassa virus (LASV) entry with EC of 6.9-10.0 μmol/L using an HIV based pseudovirus platform. Capsaicin inhibits the entry of five LASV strains but not against the Old World arenavirus lymphocytic choriomeningitis virus (LCMV), showing a preferential activity against LASV. Capsaicin inhibits LASV entry by blocking the pH dependent viral fusion through affecting the stable signal peptide (SSP)-GP2 transmembrane (GP2) region of the LASV surface glycoprotein. Mutational study revealed the key residues Ala25, Val431, Phe434 and Val435 in SSP-GP2 region in capsaicin's antiviral effect. This study for the first time reveals a direct acting antiviral effect of capsaicin against the hemorrhagic fever causing LASV, providing detailed interaction hot spots in the unique SSP-GP2 interface of LASV glycoprotein that is crucial in fusion inhibition, and offering a new strategy in discovering and developing antivirals from natural products that are safe for human use.
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[This corrects the article DOI: 10.1016/j.apsb.2017.08.003.].
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Mengla virus (MLAV), isolated from the bats in China, was identified as a new genus of filovirus in 2019, i.e. Dianlovirus genus of Filoviridae family. Among filoviruses, Ebola virus (EBOV) and Marburg virus (MARV) are the most contagious viruses with mortality rates of 24%-90%. Phylogenetic analysis showed that MLAV was closely related to MARV among the members of filovirus family. MLAV enters into host cells via viral glycoprotein (GP). The recombinant virus study indicated that MLAV has a potential for bat-to-human cross-species transmission. In this study, a GP-mediated MLAV entry evaluating model was established, and by using this model, we investigated the susceptibility of MLAV to the human cell lines sourced from different tissues and the African green monkey kidney cell lines. Four compounds, chloroquine, tetrandrine, clomiphene, and toremifene, which were known as EBOV and MARV entry blockers, were tested for HIV/MLAV-GP infection. It was found that chloroquine effectively blocked the entry of MLAV with the half maximal effective concentration (EC50) of 1.56 μmol·L-1, resembling its anti-EBOV and -MARV activities. To the best of our acknowledge, there is no anti-MLAV drug reported by far, and the identification of chloroquine as an MLAV entry inhibitor may provide an insight for developing anti-filovirus agents.
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Arenaviruses are enveloped RNA viruses, and eight members in this family are known to cause human hemorrhagic fever. Treatments for the viral hemorrhagic fever (VHF) by arenaviruses are very limited. We have identified the first flavone, tangeretin, with broad-spectrum inhibitory activities on VHF-arenaviruses infection by blocking viral entry. In this study, we evaluated thirty-four tangeretin analogues and found 3,5,6,7,4'-pentamethoxyflavone as a Lassa virus entry inhibitor, with EC50 of 5.2 µmol·L-1, by blocking the viral fusion process. The compound 3,5,6,7,4'-pentamethoxyflavone is effective on all known VHF-arenaviruses, with EC50 range of 0.84-10.2 µmol·L-1. These results suggest that 3,5,6,7,4'-pentamethoxyflavone is able to serve as a start point for discovery of arenavirus entry inhibitors from flavone natural products.
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Purpose To clarify the effect of adenosine on brain metastasis of lung cancer and the possible mechanism of adenosine promoting brain metastasis of lung cancer. Methods Western blot was used to dynamically detect the expression level of hypoxia inducible factor-1 (HIF-1) in lung cancer cells and tight junction protein ZO-1 in brain microvascular endothelial cells on blood-brain barrier. The content of adenosine in lung cancer cell culture was determined by ELISA. Fluorescence analysis was used to detect the changes of permeability of the blood-brain barrier model in vitro. Hemocytometer counts the number of A549 lung cancer cells in Transwell's lower chamber. Results The expression level of HIF-1 in lung cancer cells and the content of adenosine in lung cancer cell culture reached the highest level when lung cancer cells were deprived of oxygen for 12 hours. At the same time, the expression level of ZO-1 protein in the blood-brain barrier was the lowest, the blood-brain barrier permeability was the highest (7.11), and the number of lung cancer cells passing through the blood-brain barrier model was the highest (84.6). The permeability of the blood-brain barrier model increased after the action of adenosine, and its change trend was consistent with the effect of hypoxic lung cancer cell culture solution. Conclusion Hypoxia can induce the lung cancer cell to release adenosine, the increased adenosine can reduce the expression of tight junction protein ZO-1 in blood brain barrier, which leads to the increase of permeability of blood-brain barrier and eventually lead to brain metastasis of lung cancer.
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With the development of the era of big data,Internet plus,a rapidly aging population has put forward higher requirements for health needs,improve the medical service system,medical institutions to promote functional integration and service mode innovation is an important step in the construction of health Chinese, and construction of "hospital community family" chronic disease health information management has increasingly become a focus on the construction of social medical service system concerned. In this paper, through the SWOT model analysis of China's construction of "hospital community family" chronic disease information model of health management advantages and disadvantages, opportunities, challenges and threats, summarizes the current problems, to improve and promote the health management model of chronic disease information provided the strategy for reference.
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Arenaviruses are enveloped RNA viruses. The genus mammarenavirus contains nine members that are known to be human pathogens, and eight of them cause human hemorrhagic fever. Lassa hemorrhagic fever, caused by Lassa virus (LASV) infection, is the most prevalent arenavirus hemorrhagic fever with potential to cause major epidemics. LASV belongs to category A agents, and biosafety level-4 (BSL-4) facility is required for live virus experiments. Currently there are few specific treatments available for arenavirus diseases. Here, we established efficient cell-based pseudovirus infection models using an HIV-1 core (pNL4-3.Luc.R-E-) packed with arenavirus glycoproteins. Nine recombinant arenaviruses (arenavirus-GP/HIV-luc) were generated, and 17 cell lines were tested for susceptibilities to these viruses. These pseudovirus infection models were further validated by known arenavirus entry inhibitors. The models are safe and specific to pseudovirus infection, which are readily used for pharmacodynamic evaluation of arenavirus entry inhibitors in BSL-2 laboratory. The models will facilitate screening of the anti-arenavirus drugs and vaccines.
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<p><b>OBJECTIVE</b>To assess the effect of long-term high-fat diet on the expressions of insulin receptor substrates in the hippocampus and spatial learning and memory ability of obese rats.</p><p><b>METHODS</b>A total of 100 4-week-old male SD rats were randomly divided into two groups and fed with common diet (CD group, n=40) or high-fat diet (HFD group, n=60) for 16 weeks. At 4, 8, 12, 16 and 20 weeks, 8 rats were randomly selected from each group for testing their spatial learning and memory function using Morris water maze. After the tests, the rats were sacrificed for measurement of the metabolic parameters and detection of the expressions of insulin receptor substrate-1 (IRS-1) and IRS-2 mRNAs in the CA1 region of the hippocampus.</p><p><b>RESULTS</b>Compared with those in CD group, the rats in HFD group showed a prolonged escape latency, longer swimming distance, faster average swimming speed, and shorter stay in the platformat 12 weeks. In HFD group, the serum levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and fasting insulin were all significantly increased (P<0.05) and the level of high-density lipoprotein cholesterol decreased (P<0.01) in comparison with those in CD group at each of the time points. No significant difference was found in fast glucose levels between the two groups (P>0.05), but the expressions of IRS-1 and IRS-2 mRNAs were significantly decreased in HFD group at 12 weeks (P<0.05).</p><p><b>CONCLUSION</b>In obese rats, long-term feeding with high-fat diet leads to insulin resistance, which interferes with hippocampal expression of insulin receptor substrates and insulin metabolism to cause impairment of the cognitive function and accelerate cognitive deterioration.</p>
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Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4 (BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and drugs. An HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here, we successfully constructed nine pseudo-filovirus models covering all filovirus genera and three pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses. The pseudo-filovirus-infected mice showed visualizing bioluminescence in a dose-dependent manner. A bioluminescence peak in mice was reached on day 5 post-infection for Ebola virus and Marburg virus and on day 4 post-infection for Lloviu virus. Two known filovirus entry inhibitors, clomiphene and toremiphene, were used to validate the model. Collectively, our study shows that all genera of filoviruses can be well-pseudotyped and are infectious . The pseudo-filovirus-infection mouse models can be used for activity evaluation of anti-filovirus drugs. This sequential and evaluation system of filovirus entry inhibitors provides a secure and efficient platform for screening and assessing anti-filovirus agents in BSL-2 facilities.
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Abstarct:Objective To evaluate mid-term efficacy and complications of Prestige LP cervical disc arthroplasty ( CDA) for treatment of single-level cervical spondylotic myelopathy .Methods Retrospectively analyzed the clinical data of 29 patients who underwent Prestige LP cervical disc arthroplasty from June 2009 to December 2013 and were followed up for 2 to 6 years.Among them, there were 19 males and 10 females, and the average age was (45.4 ±7.6)years old (ranged from 28 to 58 years old).Cardinal symptom of spinal compression occured in 20 cases of them,and nerve root compression occured in the other 9 cases.Clinical symptoms and functional outcomes were evaluated with Japanese Orthopaedic Association(JOA) scores,neck and arm visual analog scale(VAS) scores,and Neck Disability Index(NDI).Oerpation segmental range of motion(ROM) were evaluated with follow-up dynamic X-ray.Displacement,subsidence of the prosthesis,heterotopic ossifi-cation(HO) and other complications were also investigated .Results The 29 patients were followed up for 24 to 66 months,(35.5 ±10.4) months averagely .At the final follow-up,the JOA score,NDI,Neck-VAS and Arm-VAS were (15.62 ±1.12) points,(14.65 ±5.68)%,(1.93 ± 1.10) points,and (0.76 ±0.99) points respectively,which were significant improved compared with (12.03 ±2.23) points,(42.52 ± 16.31)%,(5.00 ±2.22) points,and (4.59 ±3.18) points preoperatively,and the differences were of statistical significance (P<0.05). The opreation segmental ROM was (7.37 ±3.11)°,which was better remained compared with (8.50 ±3.35)°before operation.After the surgery,there were 1 case of forward displacement ,3 cases of backward displacement ,1 case of subsidence of the prosthesis ,3 cases of adja-cent segment degenerations ,and 14 cases of heterotopic ossification .Conclusion The mid-term efficacy and safety of Prestige LP cervical disc arthroplasty is fine .But there is a high incidence of the prosthesis-related complications which may counteract the function of protecting the adjacent segment .Therefore,the indication,operation skills and perioperative period management of cervical disc arthroplasty are impor -tant aspects to avoid the adverse effect .
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Objective To compare the effect of radionuclide bone imaging and MRI in locating responsible vertebrae after osteoporotic vertebral compressive fractures (OVCF).Methods A retrospective analysis was made on 25 patients with OVCF treated by percutaneous kyphoplasty (PKP)from May 2015 to December 2015.There were 4 males and 21 females,at age range of 63-87 years [(73.3 ±6.16)years].The fractured vertebrae included 2 T4,3 T5,2 T6,2 T7,5 T8,3 T9,3 T10,7 T11,9 T12,11 L1,10 L2,2 L3,5 L4 and 1 L5.Cervical imaging examinations (X-ray,bone mineral density,MRI,radionuclide bone imaging) were performed on admission.Oswestry disability index (ODI) and visual analogue scale (VAS) were estimated before operation and 1 d after operation.Results of MRI and radionuclide bone imaging were compared.Results A total of 64 vertebrae were included in our study.Thirty-six vertebrae were recognized as fresh OVCFs by MRI,and 40 by radionuclide bone imaging.Kappa-test indicated the results of the examination methods were statistically significant (P ＜0.05).Specificity (96.6％) and accuracy (98.4％) of MRI were higher than radionuclide bone imaging bone scan (82.8％,92.2％).Conclusions Radionuclide bone imaging has a high consistency with MRI in locating responsible vertebrae after OVCF,but MRI is associated with higher specificity and accuracy.In exceptional cases,radionuclide bone imaging can partly replace MRI as a way to locate OVCF.
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Objective To investigate the curative effect of transpedicular screw fixation plus percutaneous vertebroplasty (PVP) for treatment of severe thoracolumbar osteoporotic vertebral compression fractures (OVCF).Methods Twenty-one patients with severe OVCF presenting to our hospital from July 2012 to May 2015 were analyzed retrospectively.There were nine male and twelve female patients,aged 50-78 years (mean,68.8 years).The level of injury was T1 1 in four patients,T12 in six,L1 in five,L2 in three,L3 in two and L4 in one.Time between injury and surgery was 2-16 d (mean,7.5 d).All patients underwent pedicle screw fixation at the injured level combined with PVP.Visual analogue scale (VAS) was used for evaluation of lower back pain after operation,Oswestry disability index(ODI) for lower back function,lateral thoracolumbar film for Cobb angle and anterior vertebral height compression ratio,and American Spinal Injury Association (ASIA) score for spinal cord nerve function.Postoperative complications were recorded.Results All patients were followed up for 12-21 months [(15.7 ± 2.9) months].Postoperative studies showed significant differences in VAS [(2.9 ± 1.1) scores],ODI [(30.8 ± 7.5) ％],Cobb angle [(21.5 ± 7.3) °] and anterior vertebral height compression ratio [(44.3 ± 13.9) ％] compared to the preoperative measures (P ＜ 0.05).Cobb angle and anterior vertebral height compression ratio at the final follow-up were (23.4 ± 7.7)° and (49.1 ± 13.7)％ respectively,and had no significant differences from the postoperative measures (P ＞ 0.05).According to the ASIA score,eight patients with neural function injury had one to two level recovery at the final follow-up.Asymptomatic cement leakage occurred in seven patients after operation.There was no internal fixation breakage at the final follow-up.Conclusions Transpedicular screw fixation plus PVP can not only restore the height and strength of the injured vertebrae and correct kyphotic deformity,but also relieve low back pain and improve function of the spine.Therefore,the technique is a safe,reliable and effective surgical treatment for severe thoracolumbar OVCF.
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The purpose of this study is to investigate the activity and mechanism of a new anti-tumor agent T03. MTT and colony formation assay were performed to determine anti-proliferation activity of T03 in vitro. Antitumor activity was observed by Renca xenograft model in vivo. The effect of T03 on cell cycle and apoptosis were measured by FCM analysis. Western blotting was performed to investigate the expression level of proteins in HepG2 cell lines treated with T03. T03 had anti-tumor activity by inhibiting tumor cell growth and colony formation in vitro, especially on hepatocellular carcinoma cells (HCC). At the concentration of 10 micromol x L(-1), T03 induced cell apoptosis and cell cycle arrest in HCC. Moreover, it proved that T03 reduced the tumor weight with the rate of 42.30% without any obviously side effect in Renca xenograft model. At the concentration of 2.0 micromol x L(-1), T03 was able to reduce the level of p-c-Raf (Ser259), and thus blocked Raf/MEK/ERK and AKT signaling in HepG2 cell lines. The result suggested that T03 has the potential to inhibit cell proliferation and induce cell apoptosis both in vitro and in vivo, particularly active against HCC, indicating T03 and its analogues may serve as a new anti-cancer drug against hepatocellular carcinoma.
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Animals , Humans , Antineoplastic Agents , Pharmacology , Apoptosis , Carcinoma, Hepatocellular , Pathology , Cell Cycle Checkpoints , Cell Proliferation , Hep G2 Cells , Liver Neoplasms , Pathology , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
A series of 2-(3-butynoicamidophenyl)benzothiazole derivatives were synthesized starting from 4-fluoro-3-nitrobenzoic acid. Structures of all the synthesized compounds were confirmed by 1H NMR and HR-MS. Their antitumor activities against human tumor cells lines (HCT116, Mia-PaCa2, U87-MG, A549, NCI-H1975) were evaluated by MTT assay. The results revealed that most of the synthesized compounds showed potent activities against HCT116, Mia-PaCa2, U87-MG tumor cells lines. Particularly, compounds 14c and 14h exhibited better activity with IC50 values of 1 x 10(-8) mol x L(-1) against U87-MG and HCT116 respectively. The structure-activity relationship of compounds was also discussed preliminarily.
Subject(s)
Humans , Antineoplastic Agents , Pharmacology , Benzothiazoles , Pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Nitrobenzoates , Structure-Activity RelationshipABSTRACT
A series of 2-(3-butynoicamidophenyl)benzothiazole derivatives were synthesized starting from 4-fluoro-3-nitrobenzoic acid. Structures of all the synthesized compounds were confirmed by 1H NMR and HR-MS. Their antitumor activities against human tumor cells lines (HCT116, Mia-PaCa2, U87-MG, A549, NCI-H1975) were evaluated by MTT assay. The results revealed that most of the synthesized compounds showed potent activities against HCT116, Mia-PaCa2, U87-MG tumor cells lines. Particularly, compounds 14c and 14h exhibited better activity with IC50 values of 1 x 10(-8) mol x L(-1) against U87-MG and HCT116 respectively. The structure-activity relationship of compounds was also discussed preliminarily.
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The purpose of this study is to investigate the activity and mechanism of a new anti-tumor agent T03. MTT and colony formation assay were performed to determine anti-proliferation activity of T03 in vitro. Antitumor activity was observed by Renca xenograft model in vivo. The effect of T03 on cell cycle and apoptosis were measured by FCM analysis. Western blotting was performed to investigate the expression level of proteins in HepG2 cell lines treated with T03. T03 had anti-tumor activity by inhibiting tumor cell growth and colony formation in vitro, especially on hepatocellular carcinoma cells (HCC). At the concentration of 10 micromol x L(-1), T03 induced cell apoptosis and cell cycle arrest in HCC. Moreover, it proved that T03 reduced the tumor weight with the rate of 42.30% without any obviously side effect in Renca xenograft model. At the concentration of 2.0 micromol x L(-1), T03 was able to reduce the level of p-c-Raf (Ser259), and thus blocked Raf/MEK/ERK and AKT signaling in HepG2 cell lines. The result suggested that T03 has the potential to inhibit cell proliferation and induce cell apoptosis both in vitro and in vivo, particularly active against HCC, indicating T03 and its analogues may serve as a new anti-cancer drug against hepatocellular carcinoma.
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The link between nonresolving inflammation and cancer is well documented. On the one hand, epidemiologic evidence supports that approximately 25% of all human cancer worldwide is caused by nonresolving inflammation. On the other hand, inflammatory cells are found in the microenvironment of most, if not all, tumors. In the tumor micro-environment, inflammatory cells and molecules influence almost every aspect of cancer. MicroRNAs (miRNAs) participate in the initiation and progression of nonresolving inflammation-related cancer by regulating the key genes and related signaling pathways. Further investigation into the molecular mechanisms by which miRNAs carry out their functions will be of great value in the prevention, early diagnosis, and treatment of tumors.