The functions and prognostic values of m6A RNA methylation regulators in thyroid carcinoma.

BACKGROUND: N6-Methyladenosine (m6A) is the most common RNA modification and regulates RNA splicing, translation, translocation, and stability. Aberrant expression of m6A has been reported in various types of human cancers. m6A RNA modification is dynamically and reversibly mediated by different regulators, including methyltransferase, demethylases, and m6A binding proteins. However, the role of m6A RNA methylation regulators in thyroid cancer remains unknown. The aim of this study is to investigate the effect of the 13 main m6A RNA modification regulators in thyroid carcinoma. METHODS: We obtained clinical data and RNA sequencing data of 13 m6A RNA methylation regulators from The Cancer Genome Atlas (TCGA) THCA database. We performed consensus clustering to identify the clinical relevance of m6A RNA methylation regulators in thyroid carcinoma. Then we used LASSO Cox regression analysis to generate a prognostic signature based on m6A RNA modification regulator expression. Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Gene Set Enrichment Analyses were performed to explore differential cellular processes and signaling pathways between the two groups based on risk signature. RESULTS: We found that most of the m6A RNA modification regulators are down-regulated in 450 patients with thyroid carcinoma. We derived a three m6A RNA modification regulator genes-based risk signature (FTO, RBM15 and KIAA1429), that is an independent prognostic biomarker in patients with thyroid carcinoma. Moreover, we found that this risk signature could better predict outcome in male than female. Functional research in vitro demonstrated that the m6A RNA methylation regulators involved in the model acted significant role in the proliferation and migration of thyroid cancer cells. CONCLUSIONS: Our study revealed the influence of m6A RNA methylation regulators on thyroid carcinoma through biological experiments and three-gene prognostic model.

A Supramolecular-Based Dual-Wavelength Phototherapeutic Agent with Broad-Spectrum Antimicrobial Activity Against Drug-Resistant Bacteria.

With the ever-increasing threat posed by the multi-drug resistance of bacteria, the development of non-antibiotic agents for the broad-spectrum eradication of clinically prevalent superbugs remains a global challenge. Here, we demonstrate the simple supramolecular self-assembly of structurally defined graphene nanoribbons (GNRs) with a cationic porphyrin (Pp4N) to afford unique one-dimensional wire-like GNR superstructures coated with Pp4N nanoparticles. This Pp4N/GNR nanocomposite displays excellent dual-modal properties with significant reactive-oxygen-species (ROS) production (in photodynamic therapy) and temperature elevation (in photothermal therapy) upon light irradiation at 660 and 808 nm, respectively. This combined approach proved synergistic, providing an impressive antimicrobial effect that led to the complete annihilation of a wide spectrum of Gram-positive, Gram-negative, and drug-resistant bacteria both in vitro and in vivo. The study also unveils the promise of GNRs as a new platform to develop dual-modal antimicrobial agents that are able to overcome antibiotic resistance.

miR-92a-3p promotes breast cancer proliferation by regulating the KLF2/BIRC5 axis.

BACKGROUND: Breast cancer remains the most common malignancy in females around the world. Recently, a growing number of studies have focused on gene dysregulation. In our previous study, Krüppel-like factors (KLFs) were found to play essential roles in breast cancer development, among which KLF2 could function as a tumor suppressor. Nevertheless, the underlying molecular mechanism remains unclear. METHODS: miR-92a-3p was identified as the upstream regulator of KLF2 by starBase v.3.0. The regulation of KLF2 by miR-92a-3p was verified by a series of in vitro and in vivo assays. Further exploration revealed that Baculoviral IAP Repeat Containing 5 (BIRC5) was the target of KLF2. ChIP assay, dual-luciferase reporter analysis, quantitative real-time PCR, and western blot were performed for verification. RESULTS: miR-92a-3p functioned as a tumor promoter by inhibiting KLF2 by binding to its 3'-untranslated region (3'-UTR). In addition, KLF2 could transcriptionally suppress the expression of BIRC5. CONCLUSION: Collectively, our results uncovered the miR-92a-3p/KLF2/BIRC5 axis in breast cancer and provided a potential mechanism for breast cancer development, which may serve as promising strategies for breast cancer therapy.

Urolithin A Attenuates Helicobacter pylori-Induced Damage In Vivo.

Urolithin A (UA) is a metabolite produced in the gut following the consumption of ellagic acid (EA) rich foods. EA has shown anti-inflammatory, antioxidant, and anticancer properties. Because EA is poorly absorbed in the gastrointestinal tract, urolithins are considered to play a major role in bioactivity. Helicobacter pylori (H. pylori) infection is the most common chronic bacterial infection all over the world. It is potentially hazardous to humans because of its relationship to various gastrointestinal diseases. In this study, we investigated the effect of UA on inflammation by H. pylori. The results indicated that UA attenuated H. pylori-induced inflammation in vitro and in vivo. UA also reduced the secretion of H. pylori virulence factors and tissue injuries in mice. Furthermore, UA decreased the relative abundance of Helicobacteraceae in feces of H. pylori-infected mice. In summary, taking UA effectively inhibited the injury caused by H. pylori.

MicroRNA miR-19b-3p mediated G protein γ subunit 7 (GNG7) loss contributes lung adenocarcinoma progression through activating Hedgehog signaling.

G protein γ subunit 7 (GNG7) is a subunit of heterotrimeric G protein. It has been demonstrated low expressed GNG7 in various cancers. Nevertheless, the role of GNG7 in lung adenocarcinoma (LUAD) remains unclear. In the present study, GNG7 expression in LUAD tissues and cell lines was analyzed by RT-qPCR, western blot and immunohistochemical. Kaplan-Meier analysis was performed for determining the prognostic value of GNG7 expression. Then, the function of GNG7 in LUAD progression was examined by cell proliferation, invasion and mouse xenograft assays. In addition, the underlying biological mechanisms of GNG7 in LUAD progression were explored via the bioinformatics analysis and experimental validation. We found GNG7 was markedly down-regulated in LUAD tissues and cell lines. Clinically, low expression of GNG7 was associated with the dismal prognosis of LUAD patients. Gain-of-function analysis showed that GNG7 overexpression inhibited proliferation and invasion of LUAD cell in vitro, and compromised tumor formation ability in vivo. Besides, mechanistic study revealed that overexpression of GNG7 affected the progression of LUAD via inhibiting activation of Hedgehog signaling. Moreover, bioinformatics prediction and experimental verification confirmed that GNG7 was targeted by miR-19b-3p, which was elevated expression in LUAD and promoting the progression of LUAD. Furthermore, rescue experiments demonstrated that GNG7 reintroduction weakened miR-19b-3p-mediated aggressive tumor phenotypes of LUAD cells. These findings suggested miR-19b-3p/GNG7 axis contributed to the progression of LUAD through Hedgehog signaling, which might be a potential therapeutic target for LUAD treatment.

Tibial cortex transverse distraction in treating diabetic foot ulcers: what are we concerned about?

OBJECTIVE: To assess the effect and complications of tibial cortex transverse distraction (TCTD) in treating diabetic foot ulcers and draw attention to the concerning issues of this procedure. METHODS: This case series included 30 patients with diabetic foot ulcers from four centers. The ulcers had not healed after >6 months. The patients then underwent TCTD combined with other procedures (debridement, vacuum sealing drainage, and others). All patients were followed up for >12 months postoperatively. RESULTS: Three patients underwent amputation because of aggravated infections. Tibial fractures occurred in two patients after surgery, and the fractures healed after 3 months of plaster fixation. Pin-site infections occurred in five patients, and the infected pin site healed after the patients underwent pin removal and dressing changes for 3.3 ± 2.1 weeks. The ulcers of the other 27 patients healed by 13.5 ± 8.2 weeks postoperatively, and the postoperative visual analog scale score was significantly lower than the preoperative score. CONCLUSIONS: Although TCTD can be performed as an adjuvant treatment for diabetic foot ulcers, the effect should not be exaggerated and the complications should not be ignored. Further research is needed to propose a standard operative procedure and avoid postoperative complications such as tibial fractures.

NID2 can serve as a potential prognosis prediction biomarker and promotes the invasion and migration of gastric cancer.

BACKGROUND: Nidogen-2 (NID2) is a ubiquitous component in the basement membrane and plays an important role in the development of malignant tumors. However, the specific function and mechanism of the NID2 gene in gastric cancer remains unclear. In this study, we aimed to investigate the role of NID2 in gastric cancer(GC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of NID2 in 67 GC tissues and adjacent normal tissues. The relationship between NID2 expression and clinicopathological features was further analyzed. In addition, we evaluated the expression of NID2 in GC based on data from the GEPIA and Kaplan-Meier Plotter database and compared the database results with our own experimental results. Invasion and wound healing assays were used to detect the function of NID2 in MKN45 and SGC7901 cells. Finally, the NID2 network and its possible related genes are constructed by the bioinformatics framework. RESULTS: The expression level of NID2 was found to be significantly over-expressed in gastric cancer cells and tissues compared with normal controls and positively associated with TNM stage, showing a poor prognosis of GC patients. In vitro experiments indicated that NID2 was able to promote the ability of invasion and migration in GC cells. Bioinformatics prediction showed NID2 might regulate the progression of GC via protein digestion and absorption, amoebiasis, PI3K-AKt-signaling pathway, focal adhesion and ECM-receptor interaction pathways. CONCLUSION: Our study demonstrates that up-regulated NID2 plays an important role in promoting the invasion and migration of GC cells and has a potential of being a novel biomarker for diagnosis, treatment and prognosis of GC in the future.

Estrogen receptor-α-miR-1271-SNAI2 feedback loop regulates transforming growth factor-ß-induced breast cancer progression.

BACKGROUND: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-ß (TGF-ß) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited. METHODS: The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ERα-miR-1271-SNAI2 feedback loop. RESULTS: miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-ß-induced EMT in a miR-1271 dependent manner. Furthermore, ERα transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2. CONCLUSIONS: Our data uncover the ERα-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-ß network in breast cancer progression.

miR-190 enhances endocrine therapy sensitivity by regulating SOX9 expression in breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. Therapies targeting ERα have been successfully used in patients with ERα+ breast cancer. However, intrinsic or acquired resistance to anti-estrogen therapy presents a major challenge. The Wnt/ß-catenin signaling pathway regulates various processes that are important for cancer progression, and emerging evidences have shown a close interaction between Wnt/ß-catenin and ERα signaling. miR-190 is also involved in ER signaling and our previous study indicated that miR-190 suppresses breast cancer metastasis. METHODS: The effect of miR-190 on breast cancer anti-estrogen sensitivity was investigated both in vitro and in vivo. The protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of the zinc-finger E-box binding homeobox 1/ ERα-miR-190-SRY-related high mobility group box 9 (ZEB1/ERα-miR-190-SOX9) axis. RESULTS: miR-190 increased the anti-estrogen sensitivity of breast cancer cells both in vitro and in vivo. miR-190 inhibited Wnt/ß-catenin signaling by targeting SOX9, and its expression inversely correlated with that of SOX9 in breast cancer samples. Furthermore, ERα and ZEB1 competitively regulated miR-190 expression. CONCLUSIONS: Our data uncover the ZEB1/ERα-miR-190-SOX9 axis and suggest a mechanism by which the Wnt/ß-catenin signaling pathway is involved in breast cancer anti-estrogen therapy.

Identification of core genes and clinical roles in pregnancy-associated breast cancer based on integrated analysis of different microarray profile datasets.

More women are delaying child-birth. Thus, the diagnosis of pregnancy-associated breast cancer (PABC) will continue to increase. The aim of this study was to identify core candidate genes of PABC, and the relevance of the genes on the prognosis of PABC. GSE31192 and GSE53031 microarray profile datasets were downloaded from the Gene Expression Omnibus database and differentially expressed genes were analyzed using the R package and GEO2R tool. Then, Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery. Moreover, the Search Tool for the Retrieval of Interacting Genes and the Molecular Complex Detection Cytoscape software plug-in were utilized to visualize protein-protein interactions and to screen candidate genes. A total of 239 DEGs were identified in PABC, including 101 up-regulated genes mainly enriched in fatty acid activation and the fibroblast growth factor signaling pathway, while 138 down-regulated genes particularly involved in activation of DNA fragmentation factor and apoptosis-induced DNA fragmentation. Fourteen hub genes with a high degree of connectivity were selected, including CREB1, ARF3, UBA5, SIAH1, KLHL3, HECTD1, MMP9, TRIM69, MEX3C, ASB6, UBE2Q2, FBXO22, EIF4A3, and PXN. Overall survival (OS) analysis of core candidate genes was performed using the Gene Expression Profiling Interactive Analysis and UALCAN websites. High ASB6 expression was associated with worse OS of PABC patients. Molecular subtypes and menopause status were also associated with worse OS for PABC patients. In conclusion, ASB6 could be a potential predictor and therapeutic target in patient with PABC.

SNHG5 Promotes Breast Cancer Proliferation by Sponging the miR-154-5p/PCNA Axis.

Breast cancer is the most common malignant tumor and the main cause of cancer-associated mortality in females worldwide. Long non-coding RNAs (lncRNAs) have been reported to play vital roles in breast cancer development and progression; however, our understanding of most lncRNAs in breast cancer is still limited. In this study, we demonstrated that small nucleolar RNA host gene 5 (SNHG5) promotes breast cancer cell proliferation both in vitro and in vivo, and depletion of SNHG5 significantly led to cell-cycle arrest at G1 phase. Accumulating evidence has shown that many lncRNA transcripts could function as competing endogenous RNAs (ceRNAs) by competitively binding common microRNAs (miRNAs). We found that SNHG5 acts as a sponge for miR-154-5p, reducing its ability to repress proliferating cell nuclear antigen (PCNA). SNHG5 promoted breast cancer proliferation and cell-cycle progression by upregulation of PCNA expression. Clinically, we observed an increased SNHG5 expression in breast cancer, whereas miR-154-5p was decreased in breast cancer tissues compared with the adjacent normal breast tissues. Furthermore, the SNHG5 expression was significantly negatively correlated with miR-154-5p expression. Taken together, our data uncover the SNHG5-miR-154-5p-PCNA axis and provide a novel mechanism to explain breast cancer proliferation.

N-Oxyamide-linked glycoglycerolipid coated AuNPs for receptor-targeting imaging and drug delivery.

The synthesis of a series of new N-oxyamide-linked glycoglycerolipids and their assembly with gold nanoparticles for receptor-targeting imaging and drug delivery are reported.

Protective effects of pinacidil hyperpolarizing cardioplegia on myocardial ischemia reperfusion injury by mitochondrial KATP channels.

BACKGROUND: Many studies have indicated that hyperpolarizing cardioplegia is responsible for myocardial preservation and researchers have suggested that the adenosine triphosphate-sensitive potassium channels (K(ATP)) were the end effectors of cardio-protection. But whether mitochondrial K(ATP) plays an important role in hyperpolarizing cardioplegia is not apparent. The present study investigated the effect of hyperpolarizing cardioplegia containing pinacidil (a nonselective K(ATP) opener) on ischemia/reperfusion injury in rat hearts, especially the role of mitochondrial K(ATP) in pinacidil hyperpolarizing cardioplegia. METHODS: Sprague-Dawley rat hearts were Langendorff-perfused for 20 minutes with Krebs-Henseleit buffer at 37°C before equilibration. Cardiac arrest was then induced in different treatments: there was no arrest and ischemia in the normal group, the control group were arrested by clamping the aorta, depolarizing caidioplegia (St. Thomas solution containing 16 mmol/L KCl) and hyperpolarizing cardioplegia groups used St. Thomas solution containing 0.05 mmol/L pinacidil and 5 mmol/L KCl to induce cardiac arrest in group hyperkalemic and group pinacidil, in group hyperkalemic + 5-hydroxydecanote (5HD) and Pinacidil + 5HD, 5HD (0.1 mmol/L) was added to the above two solutions to block mitochondria K(ATP) channels. Global ischemia was then administrated for 40 minutes at 37°C, followed by 30 minutes of reperfusion. At the end of equilibration and reperfusion, hemodynamics, ultrastructure, and mitochondrial function were measured. RESULTS: In the control group, ischemia/reperfusion decreased the left ventricular developed pressure, heart rate, coronary flow, mitochondrial membrane potential, impaired mitochondrial respiratory function, increased reactive oxygen species and left ventricular end diastolic pressure. Damage to myocardial ultrastructure was also evident. Both depolarized arrest and especially hyperpolarized cardioplegia significantly reduced these lesions. 5HD partially blocked the beneficial effects of pinacidil cardioplegia but showing no effects on hyperkalemic arrest. CONCLUSIONS: Pinacidil cardioplegia provides better cardioprotection with preservation of hemodynamics, ultrastructure, and mitochondrial function than traditional cardioplegia. The mitochondria K(ATP) channels may play an important role in the protection mechanism.