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Xu-Dong Zhao Run-He Qin Jing-Jing Yang Sheng-Song Xu Hui Tao Xuan-Sheng Ding Kai-Hu Shi 《Inflammation research》2018,67(8):681-690
Aim and objective
Regulation of microRNA gene expression by DNA methylation may represent a key mechanism to drive cardiac fibrosis progression. Cardiac fibroblast autophagy is the primary source of cardiac fibrosis, but the mechanisms underlying this process are incompletely understood. Here we found that DNMT3A suppression of the microRNA-200b (miR-200b) through pathway leads to cardiac fibroblast autophagy in cardiac fibrosis.Methods
To understand the impact of DNMT3A on miR-200b at cardiac fibrosis, the rat cardiac fibrosis model was established via the abdominal aortic coarctation. Cardiac fibroblasts (CFs) were harvested from SD neonate rats and cultured. The expression of DNMT3A, miR-200b, collagen I was measured by western blotting, immunohistochemistry and qRT-PCR. Gain- or loss-of-function approaches were used to manipulate DNMT3A and miR-200b.Results
DNMT3A level was upregulated and negatively correlated with miR-200b expression in fibrosis tissues and cardiac fibroblast. We found that autophagy was activated by miR-200b inhibitor and inactivated by miR-200b mimic in the rat cardiac fibroblast. Knockdown of DNMT3A notably increased the expression of miR-200b.Conclusions
Taken together, these findings indicate that DNMT3A regulation of miR-200b controls cardiac fibroblast autophagy during cardiac fibrosis and provide a basis for the development of therapies for cardiac fibrosis.3.
Sari?Matsui Liming?Zhou Yohei?Nakayama Masaru?Mezawa Ayako?Kato Naoto?Suzuki Natsuko?Tanabe Tomohiro?Nakayama Yuki?Suzuki Noriaki?Kamio Hideki?Takai Yorimasa?Ogata
Objective
MicroRNAs (miRNAs) play important roles in biological processes such as cell differentiation, development, infection, immune response, inflammation and tumorigenesis. We previously reported that the expression of miR-200b was significantly increased in inflamed gingiva compared with non-inflamed gingiva. To elucidate the roles of miR-200b in the inflamed gingiva, we have analyzed the effects of miR-200b on the expression of IL-6 in human gingival fibroblasts (HGF).Materials and methods
Total RNA and protein were extracted from HGF after stimulation by interleukin-1β (IL-1β; 1 ng/ml) or tumor necrosis factor-α (TNF-α; 10 ng/ml) and transfected with miR-200b expression plasmid or miR-200b inhibitor. IL-6, IL-1β, inhibitor of nuclear factor kappa-B kinaseβ (IKKβ), Zinc-finger E-box-binding homeobox 1 (ZEB1) and E-cadherin mRNA and protein levels were analyzed by real-time PCR and Western blot.Results
IL-1β and TNF-α increased IL-6 mRNA and protein levels, and they were significantly suppressed by miR-200b overexpression, whereas they were further increased by miR-200b inhibitor in HGF. IKKβ and ZEB1 which are target genes of miR-200b negatively regulate E-cadherin. MiR-200b suppressed the expression of IKKβ and ZEB1 and increased E-cadherin mRNA and protein levels in HGF.Conclusions
These results suggest that miR-200b attenuates inflammatory response via IKKβ and ZEB1 in periodontal tissue.4.
Julia?Alcaide Rafael?Funez Antonio?Rueda Elisabeth?Perez-Ruiz Teresa?Pereda Isabel?Rodrigo Rafael?Cove?as Miguel?Mu?oz Maximino?Redondo
Background
Alterations to apoptosis are a common occurrence in human tumours. The aim of our study was to determine the influence of apoptotic variations on the carcinogenesis and prognosis of colorectal carcinomas (CRCs).Methods
A TUNEL assay was performed on archival material from 103 colorectal carcinomas, 26 adenomas and 20 samples of normal epithelia.Results
The number of apoptotic cells was higher in CRCs (1.09?±?0.13) than in adenomas (0.38?±?0.23, p?=?0.059) and normal epithelium (0.06?±?0.04, p?=?0.001). In addition, the apoptotic index (AI) was greater in metastatic disease (stage IV) than in other stages (p?=?0.017). No relationship was found between apoptotic rates and age, gender or tumour grade. However, patients with tumours that showed higher AI values had a significantly lower disease-free survival (DFS) and overall survival (OS) than those with tumours that had lower AIs (p?=?0.020 and p?=?0.027). In a multivariate Cox proportional hazards model, AI remained a significant independent predictor of survival.Conclusions
We conclude that disregulated apoptosis is an important event during CRC development and progression. Higher AIs are associated with more aggressive tumours and a poorer prognosis for patients with CRC.5.
Background
Hyperglycemia is a significant risk factor for diabetic retinopathy and induces increased inflammatory responses and retinal leukostasis, as well as vascular damage. Although there is an increasing amount of evidence that miRNA may be involved in the regulation in the pathology of diabetic retinopathy, the mechanisms by which miRNA mediate cellular responses to control onset and progression of diabetic retinopathy are still unclear. The purpose of our study was to investigate the hypothesis that miR-15a/16 inhibit pro-inflammatory signaling to reduce retinal leukostasis.Methods
We generated conditional knockout mice in which miR-15a/16 are eliminated in vascular endothelial cells. For the in vitro work, human retinal endothelial cells (REC) were cultured in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. Transfection was performed on REC in high glucose with miRNA mimic (hsa-miR-15a-5p, hsa-miR-16-5p). Statistical analyses were done using unpaired Student t test with two-tailed p value. p?<?0.05 was considered significant. Data are presented as mean?±?SEM.Results
We demonstrated that high glucose conditions decreased expression of miR-15a/16 in cultured REC. Overexpression of miR-15a/16 with the mimic significantly decreased pro-inflammatory signaling of IL-1β, TNFα, and NF-κB in REC. In vivo data demonstrated that the loss of miR-15a/16 in vascular cells led to increased retinal leukostasis and CD45 levels, together with upregulated levels of IL-1β, TNFα, and NF-κB.Conclusions
The data indicate that miR-15a/16 play significant roles in reducing retinal leukostasis, potentially through inhibition of inflammatory cellular signaling. Therefore, we suggest that miR-15a/16 offer a novel potential target for the inhibition of inflammatory mediators in diabetic retinopathy.6.
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Logan M. Lawrence Michelle R. Stone Daniel G. Rainham Melanie R. Keats 《International journal of behavioral medicine》2017,24(1):120-126
Purpose
Physical activity (PA) is an effective intervention for improving the quality of life of colorectal cancer survivors (CRC) and may reduce the risk of cancer recurrence and cancer specific and all-cause mortality. However, most CRC survivors are not sufficiently active to receive these benefits. Sedentary behavior (SB) has also been linked to morbidity and mortality risk independent of activity level, thereby presenting an additional opportunity to improve health outcomes of CRC survivors. The built environment is known to influence PA and SB; however, little is known about where CRC survivors engage in PA and SB. The objective of this exploratory study was to objectively identify locations where CRC survivors engage in PA and SB in order to inform health promoting interventions.Method
Activity and location of CRC survivors (n = 31) was monitored for 1 week between January 2014 and April 2015 in Nova Scotia, Canada. Bouts of PA and SB were time-matched with GPS data to attribute bouts to specific geographic locations.Results
Participants’ home environment was the main location for both time spent in PA bouts (73.7 %) and time spent in SB bouts (90.5 %).Conclusion
This study is the first to objectively identify environments where CRC survivors are active and sedentary. These findings highlight the importance of considering the home environment when developing intervention strategies to increase PA and reduce SB in CRC survivors.8.
Background
Matrix metalloproteinases (MMPs) play a role in cancer progression by degrading extracellular matrix and basement membranes, assisting in tumour neovascularization and in supporting immune response in cancer.Methods
We studied the prognostic value of immunohistochemical expression of MMP-2, MMP-8, and MMP-9 in a series of 619 colorectal cancer patients using tissue microarray specimens.Results
Of the samples, 56% were positive for MMP-2, 78% for MMP-8, and 60% for MMP-9. MMP-9 associated with low WHO grade (p?<?0.001). In univariate analysis of Dukes’ B tumours, MMP-9 negativity associated with poor survival (p?=?0.018), and MMP-9 positivity was an independent prognostic marker in multivariate analysis of these tumours (p?=?0.034).Conclusion
Negative MMP-9 expression can predict poor prognosis in Dukes’ B colorectal tumours and may prove useful for identifying patients, who should be offered adjuvant treatment.9.
Fabio Grizzi Gianluca Basso Elena Monica Borroni Tommaso Cavalleri Paolo Bianchi Sanja Stifter Maurizio Chiriva-Internati Alberto Malesci Luigi Laghi 《Inflammation research》2018,67(5):375-389
Introduction
Colorectal cancer (CRC) still represents the third most commonly diagnosed type of cancer in men and women worldwide. CRC is acknowledged as a heterogeneous disease that develops through a multi-step sequence of events driven by clonal selections; this observation is sustained by the fact that histologically similar tumors may have completely different outcomes, including a varied response to therapy.Methods
In “early” and “intermediate” stage of CRC (stages II and III, respectively) there is a compelling need for new biomarkers fit to assess the metastatic potential of their disease, selecting patients with aggressive disease that might benefit from adjuvant and targeted therapies. Therefore, we review the actual notions on immune response in colorectal cancer and their implications for biomarker development.Results
The recognition of the key role of immune cells in human cancer progression has recently drawn attention on the tumor immune microenvironment, as a source of new indicators of tumor outcome and response to therapy. Thus, beside consolidated histopathological biomarkers, immune endpoints are now emerging as potential biomarkers.Conclusions
The introduction of immune signatures and cellular and molecular components of the immune system as biomarkers is particularly important considering the increasing use of immune-based cancer therapies as therapeutic strategies for cancer patients.10.
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Yusuke Kanda Tokuichi Kawaguchi Mitsuhiko Osaki Kunishige Onuma Takahiro Ochiya Tomoyuki Kitagawa Futoshi Okada 《Inflammation research》2018,67(10):839-846
Objective
In sporadic colon tumors, multistep process of well-known genetic alterations accelerates carcinogenesis; however, this does not appear to be the case in inflammation-related ones. We previously established a model of inflammation-related colon carcinogenesis using human colonic adenoma cells, and identified fascin as a driver gene of this process. We analyzed the microRNAs involved in the stable fascin expression in colon adenocarcinoma cells.Materials and methods
miRNA microarray analysis was performed using FPCK-1-1 adenoma cells and its-derived FPCKpP1-4 adenocarcinoma cells through chronic inflammation. To assess the involvement of miRNA in the inflammation-related carcinogenesis, sphere-forming ability, expression of colon cancer stemness markers, and stability of fascin protein via the proteasome using tough decoy RNA technique.Results
We found that 17 miRNAs including miR-146a were upregulated and 16 miRNAs were downregulated in FPCKpP1-4 adenocarcinoma cells. We revealed that miR-146a in the adenocarcinoma cells brought about acquisition of sphere formation, cancer stemness, and inhibition of proteasomal degradation of the fascin protein.Conclusions
We found that stable fascin expression is brought about via the inhibition of proteasome degradation by miR-146a in the process of a chronic inflammation-related colon carcinogenesis.13.
Carina G. Uasuf Caterina Di Sano Sebastiano Gangemi Giuseppe Albeggiani Diego Cigna Paola Dino Ignazio Brusca Mark Gjomarkaj Elisabetta Pace 《Inflammation research》2018,67(8):671-679
Background
Although IL-33/ST2 axis is involved in the development of allergic diseases, its contribution in food allergy is still unknown.Methods
In this study, we assessed the serum levels of IL-33 and its s-ST2 receptor in 53 control patients (without allergic diseases), 47 peach (Pru p 3)-sensitized allergic patients (SAP), and in 68 non-Pru p 3-SAP. Basophil activation test (BAT) was used to assess the basophil activation due to allergen exposure before and after the addition of s-ST2 to the blood samples from 5 Pru p 3-SAP.Results
IL-33 levels in Pru p 3-SAP were higher than in non-Pru p 3-SAP and in normal controls. Lower s-ST2 levels were found in Pru p 3-SAP than in non-Pru p 3-SAP. IL-33/s-ST2 ratio was higher in Pru p 3-SAP than in both non-Pru p 3-SAP and controls. Higher IL-33/s-ST2 ratio was observed in Pru p 3-SAP with severe than in those with mild systemic symptoms. BAT analysis in Pru p 3-SAP showed a decrease in basophil activation due to Pru p 3 exposure after the addition of s-ST2 to the blood samples.Conclusions
An imbalance in the baseline levels of IL-33/ST2 pathway is present in Pru p 3-SAP. The measurement of this pathway might be helpful to detect patients at a higher risk of developing severe systemic symptoms.14.
Background
Various plant extracts have been suggested to be used as auxiliary agents in chemotherapy considering their anti-proliferative effect on cancer cells. However, recent reports reveal that plant extracts may function as inducers of autophagy of cancer cells. In general, autophagy confers survival advantage for cells responding to stress conditions, thus representing an important mechanism for chemo-resistance. This study was aimed to investigate the effectiveness of combined use of Salidroside (Sal, a phenylpropanoid glycosides from Rhodiola rosea L) with anti-tumor agents against colorectal cancer (CRC) cells, and moreover to evaluate the potential role of autophagy in the combined therapy.Methods
CRC cells, HCT-116, were incubated with Sal alone or in combination with conventional chemotherapy agents including oxaliplatin (OXA), 5-fluorouracil (5-FU) and Doxorubicin (ADM). Cell proliferative characteristics were evaluated by cell viability and apoptosis rate. The protein expression was assessed by Immunofluorescent and Western blot assays.Results
Sal, alone or in combination with anti-tumor agents, increased expression of autophagic biomarkers, including LC3B and Becline-1, suggesting an autophagy induction. Except for the up-regulation of p-AMPK, p-mTOR, p-NF-κB (p65), TGF-β, p-JAK2 and p-STAT3 were down-regulated by Sal. Because autophagy is positively correlated with the activation of AMPK/mTOR, NF-κB, TGFβ1 and JAK2/STAT3 cascades, the autophagy induced by Sal may associate with AMPK activation. Indeed, blockage of AMPK signaling via Compound C or AMPK knockdown inhibited the autophagy. The blockage of AMPK signaling or a direct inhibition of autophagy via 3-MA increased effectiveness of combined use of Sal with anti-tumor agents against CRC.Conclusions
Inhibition of autophagy enhances synergistic effects of Sal and anti-tumor agents against colorectal cancer. This study provides experimental evidence and theoretical reference for improvement of a novel chemotherapy treatment protocol.15.
Raju?SR?Adduri Viswakalyan?Kotapalli Neha?A?Gupta Swarnalata?Gowrishankar Mukta?Srinivasulu Mohammed?Mujtaba?Ali Subramanyeshwar?Rao Shantveer?G?Uppin Umanath?K?Nayak Snehalatha?Dhagam Mohana?Vamsy?Chigurupati Murali?Dharan?Bashyam
Background
Squamous cell carcinoma of tongue (SCCT) is expected to harbor unique clinico-pathological and molecular genetic features since a significant proportion of patients are young and exhibit no association with tobacco or alcohol.Methods
We determined P53, epidermal growth factor receptor, microsatellite instability, human papilloma virus infection and loss of heterozygosity status at several tumor suppressor loci in one hundred and twenty one oral SCCT (SSCOT) samples and analyzed their association with clinico-pathological features and patient survival.Results
Our results revealed a significantly higher incidence of p53 nuclear stabilization in early (as against late) onset SCCOT. FHIT loss was significantly associated with p53 nuclear stabilization and the association was stronger in patients with no history of tobacco use. Samples harboring mutation in p53 DNA binding domain or exhibiting p53 nuclear stabilization, were significantly associated with poor survival.Conclusion
Our study has therefore identified distinct features in SCCOT tumorigenesis with respect to age and tobacco exposure and revealed possible prognostic utility of p53.16.
Alessandra Bitto Daniela Giuliani Giovanni Pallio Natasha Irrera Eleonora Vandini Fabrizio Canalini Davide Zaffe Alessandra Ottani Letteria Minutoli Mariagrazia Rinaldi Salvatore Guarini Francesco Squadrito Domenica Altavilla 《Inflammation research》2017,66(5):389-398
Objective and design
Alzheimer’s disease (AD) is associated with amyloid plaques (Aβ) and hyperphosphorylated tau protein tangles in the brain. We investigated the possible neuroprotective role of flavocoxid, a dual inhibitor of cyclooxygenases-1/2 (COX-1/2) and 5-Lipoxygenase (5-LOX), in triple-transgenic (3xTg-AD) mice.Subjects
Mice were 3 months at the beginning of the study.Treatment
Animals received once daily for 3-month saline solution or flavocoxid (20 mg/kg/ip).Methods
Morris water maze was used to assess learning and memory. Histology was performed to evidence Aβ plaques and neuronal loss, while inflammatory proteins were determined by western blot analysis.Results
Saline-treated 3xTg-AD mice showed an impairment in spatial learning and memory (assessed at 6 months of age), and increased expression of inflammatory and apoptotic molecules. Treatment of 3xTg-AD mice with flavocoxid reduced: (1) learning and memory loss; (2) the increased eicosanoid production and the phosphorylation level of amyloid precursor protein (APP-pThr668), Aβ 1–42, p-tau (pThr181), pERK, and the activation of the NLRP3 inflammasome; (3) Aβ plaques; and (4) neuronal loss, compared to saline-treated animals.Conclusions
Pharmacological blockade of both COX-1/2 and 5-LOX was able to counteract the progression of AD by targeting pathophysiological mechanisms up- and downstream of Aβ and tau.17.
Objective and design
The objective of this study is to uncover the signal transduction pathways of N-formyl methionyl-leucyl-phenylalanine (fMLP) in monocyte.Materials or subjects
Freshly isolated human peripheral blood monocytes (PBMC) were used for in vitro assessment of signal transduction pathways activated by fMLP.Treatment
Time-course and dose–response experiments were used to evaluate the effect of fMLP along with the specific inhibitors/stimulators on the activation of downstream signaling kinases.Methods
Freshly isolated human PBMC were stimulated with fMLP for the desired time. Western blot and siRNA analysis were used to evaluate the activated intracellular signaling kinases, and flow analysis was performed to assess the levels of CD11b. Furthermore, luminescence spectrometry was performed to measure the levels of released hydrogen peroxide in the media.Results
fMLP strongly stimulated the activation of AKT and ERK1/2 through a RhoA-GTPase-dependent manner and also induced H2O2 release by monocytes. Furthermore, fMLP mediated its effects through restricted activation of formylpeptide receptor-like 1 (FPRL1/FPR2), but independently of either EGFR transactivation or intracellular calcium release. In addition, NAC reversed fMLP- and H2O2-induced activation of Akt and RhoA-GTPase.Conclusion
Collectively, these data suggested that fMLP-activated ERK1/2 and Akt pathways through specific activation of the FPRL1/ROS/RoA-GTPase pathway.18.
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Background
Response rates to surveys are declining and this threatens the validity and generalisability of their findings. We wanted to determine whether paper quality influences the response rate to postal surveysMethods
A postal questionnaire was sent to all members of the British Society of Gynaecological Endoscopy (BSGE). Recipients were randomised to receiving the questionnaire printed on standard quality paper or high quality paper.Results
The response rate for the recipients of high quality paper was 43/195 (22%) and 57/194 (29%) for standard quality paper (relative rate of response 0.75, 95% CI 0.33–1.05, p = 0.1Conclusion
The use of high quality paper did not increase response rates to a questionnaire survey of gynaecologists affiliated to an endoscopic society.20.
Funda Erol Cipe Cigdem Aydogmus Nina K. Serwas Gonca Keskindemirci Kaan Boztuğ 《Journal of clinical immunology》2018,38(3):273-277