The emerging roles of N6-methyladenosine RNA modifications in thyroid cancer.

Thyroid cancer (TC) is the most predominant malignancy of the endocrine system, with steadily growing occurrence and morbidity worldwide. Although diagnostic and therapeutic methods have been rapidly developed in recent years, the underlying molecular mechanisms in the pathogenesis of TC remain enigmatic. The N6-methyladenosine(m6A) RNA modification is designed to impact RNA metabolism and further gene regulation. This process is intricately regulated by a variety of regulators, such as methylases and demethylases. Aberrant m6A regulators expression is related to the occurrence and development of TC and play an important role in drug resistance. This review comprehensively analyzes the effect of m6A methylation on TC progression and the potential clinical value of m6A regulators as prognostic markers and therapeutic targets in this disease.

A Potential Autophagy-Related-Gene Based Signature in Patients with Preeclampsia.

OBJECTIVE: Preeclampsia (PE) is a significant cause of maternal and offspring mortality and morbidity. The purpose of this study is to identify the potential diagnostic signatures of autophagy-related genes (ATGs) in pregnancies with preeclampsia. METHODS: The expression profile of mRNA was obtained from GSE75010 (placenta samples) and GSE48424 dataset (blood samples). The potential differentially expressed ATGs of PE were screened by R software. The gene-ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, correlation analysis, and protein-protein interactions (PPI) were applied for the differentially expressed ATGs. The diagnostic markers of PE were then screened based on least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE). Receiver operating characteristic (ROC) analysis was used to investigate the predictive value of these diagnostic markers. Target miRNAs were predicted based on the miRDB, DIANA-micro T, Targetscan, and miRWalk databases, and were further validated in GSE84260. RESULTS: A total of 20 differentially expressed ATGs were identified between PE and healthy pregnancies. Functional analysis of differentially expressed ATGs indicated several enriched terms related to autophagy, apoptosis, angiogenesis, inflammation, immune response, hypoxia-inducible factor 1 (HIF-1), forkhead box O (FoxO) and AMP-activated protein kinase (AMPK) signaling pathway. A total of 12 ATGs were recognized based on LASSO and SVM-RFE, which made an excellent distinction in both the placenta tissues (area under the curve [AUC] = 0.903) and the blood samples (AUC = 0.972). Furthermore, four feature ATGs (leptin [LEP], ERO1-like [ERO1L], phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [PIK3CB], and mitogen-activated protein kinase 8 [MAPK8]) were screened and also shown an excellent diagnostic efficacy (AUC = 0.869 in placenta samples, and AUC = 0.914 in blood samples). Additionally, 81 target miRNAs were predicted according to the 4 feature ATGs. After evaluating the miRNA expression pattern of GSE84260, 11 miRNAs were selected. Finally, a miRNA-mRNA regulatory network was constructed, which may participate in the development of PE. CONCLUSIONS: We established an autophagy-related-gene based signature that may predict pregnancies with PE. And we also constructed a miRNA-mRNA regulatory network, which may deepen our understanding of the molecular mechanism underlying the development of PE.

Autophagy in sepsis-induced acute lung injury: Friend or foe?

Sepsis-induced acute lung injury (ALI) is a life-threatening syndrome with high mortality and morbidity, resulting in a heavy burden on family and society. As a key factor that maintains cellular homeostasis, autophagy is regarded as a self-digesting process by which damaged organelles and useless proteins are recycled for cell metabolism, and it thus plays a crucial role during physiological and pathological processes. Recent studies have indicated that autophagy is involved in the pathophysiological process of sepsis-induced ALI, including cell apoptosis, inflammation, and mitochondrial dysfunction, which indicates that regulating autophagy may be beneficial for this disease. However, the role of autophagy in the etiology and treatment of sepsis-induced ALI is not well characterized. This review summarizes the autophagy-related signaling pathways in sepsis-induced ALI, as well as focuses on the dual role of autophagy and its regulation by non-coding RNAs during disease progression, for the development of potential therapeutic strategies in this disease.

Calculated inflammatory markers derived from complete blood count results, along with routine laboratory and clinical data, predict treatment failure of acute peritonitis in chronic peritoneal dialysis patients.

BACKGROUND & AIMS: Complete blood count (CBC)-derived inflammatory markers are predictive biomarkers for the prognosis of many diseases. However, there was no study on patients with peritoneal dialysis-associated peritonitis (PDAP). We aimed to investigate the value of these markers in predicting treatment failure of acute peritonitis in chronic PD patients. METHODS: The records of 138 peritonitis episodes were reviewed and divided into treatment success or failure groups in a single center for 10 years. CBC-derived markers and other routine data were recorded before peritonitis treatment was initiated. Univariate and multivariate regression analyses and the receiver operating characteristic (ROC) curve about the predictors of treatment outcomes were performed. RESULTS: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and derived NLR were significantly higher in the failure group. Univariate logistic regression results showed that NLR and PLR were risk factors of treatment outcomes. The backward stepwise multivariate logistic regression results demonstrated that NLR [adjusted odds ratio (aOR), 1.376; 95% confidence intervals (CI), 1.105-1.713; p = .004], PLR (aOR, 1.010; 95%CI, 1.004-1.017; p = .002) were risk factors, but hemoglobin-to-lymphocyte ratio (HLR) (aOR, 0.977; 95%CI, 0.963-0.991; p = .001), and SII (aOR, 0.999; 95%CI, 0.998-1.000; p = .040) were protective factors. A combination of age, PD vintage, Gram-positive peritonitis, staphylococcus aureus, culture-negative, NLR, PLR, HLR, and SII would improve prognostic performance. The area under this ROC curve was 0.85, higher than other factors. CONCLUSIONS: NLR, PLR, HLR, and SII were associated with PDAP outcomes. Age, PD vintage, NLR, and PLR were significant risk factors in PDAP patients.

Effect of national holidays on health outcomes of patients receiving peritoneal dialysis in a single center over a ten-year period.

BACKGROUND: National holidays are associated with high mortality in some diseases, but little is known about patients undergoing peritoneal dialysis (PD). The research aimed to investigate the impact of national holidays on the health outcomes of PD patients. METHODS: Over ten years, all episodes of unplanned hospitalization, death, and peritonitis in PD patients were collected in our center. Seven national holidays in China were chosen, and non-holiday days were selected as the control period. The effect of national holidays was observed by comparing the hospitalization, death, and peritonitis rates between holiday and non-holiday groups. RESULTS: There were 297 events in all holiday periods and 1247 in non-holiday periods. There is no significant difference in hospitalization rate between holiday and non-holiday groups (32.4% ± 6.4% vs. 29.2% ± 3.4%, p = 0.175). So is the death rate [6.3% (4.8-12.3%) vs.5.0% (4.2-8.9%), p = 0.324] and peritonitis rate [0.19 (0.13-0.53) vs. 0.22 (0.18-0.27), p = 0.445] between the two groups. Significant differences were observed in the distribution of peritonitis causes between the two groups (p = 0.017). The rate of secondary to other infections in the holiday group was significantly higher than in the non-holiday group (25.0 vs. 10.3%, p = 0.015). CONCLUSION: Our study suggested no national holiday effect on health outcomes of PD patients based on ten-year data in our center.

Sporoderm-broken spore powder of Ganoderma lucidum ameliorate obesity and inflammation process in high-fat diet-induced obese mice.

Objective: This study examined the anti-obesity and anti-inflammatory effects of sporoderm-broken spore powder of Ganoderma lucidum (SSPL) against obese mice fed with a high-fat diet. Methods: Four groups of C57BL/6J mice were randomly assigned to the following diets: control diet (CD); high-fat diet (HD); high-fat diet plus l-carnitine (HDL); and high-fat diet with sporoderm-broken spore powder of Ganoderma lucidum (HDG). They were subjected to 12 weeks of testing. Results: Supplementation with SSPL lowered weight gain caused by a high-fat diet and improved serum and liver lipid levels, and histological investigation indicated that the HDG group had a significant reduction in liver lipid deposits and adipocyte size in epididymal fat. SSPL administration decreased the expression of genes associated with inflammation and fat anabolism, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), peroxisome proliferator-activated receptorγ (PPARγ), sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FAS), acetyl-coenzyme A (CoA) carboxylase (ACC), and leptin. SSPL therapy raised the levels of PPARα, carnitine palmitoyl-transferase 1 (CPT-1), acyl-CoA oxidase1 (ACOX1), and adiponectin. Conclusion: In summary, SSPL protected mice against developing obesity caused by increased fat intake by regulating inflammatory factors and lipid metabolism. Our findings indicate that SSPL is a potentially beneficial healthy meal for treating obesity.

Production of aptamers by cell-SELEX and their applications in cancer biomarker identification.

Cancer is a major cause of disease-related deaths worldwide, and early diagnosis involving detecting biomarkers of tumors can improve the cure rate and prognosis of patients. Biomarkers are signature proteins that can distinguish diseased cells from healthy cells, facilitating the diagnosis and treatment of diseases, especially cancer. Aptamers are single-stranded oligonucleotides that can recognize target proteins with high affinity and specificity. The development of biomarkers identified by aptamers has experienced extensive progress in current applications. The combinatorial strategy of cell-SELEX technology and proteomics analysis makes targeted protein identification more cost-effective and efficient and improves the success rate of discovery of multiple biomarkers simultaneously. In this methodology, biomarkers are identified via a series of operations such as screening of aptamers, separation, extraction, and analysis of target proteins, which has brought about the discovery of a number of new biomarkers of cancer. This review summarizes the current strategies, challenges, and potential applications for biomarker discovery using aptamers engendered by cell-SELEX.

Advances of aptamers screened by Cell-SELEX in selection procedure, cancer diagnostics and therapeutics.

Aptamers are a class of short artificial single-stranded oligo(deoxy) nucleotides that can bind to different targets, which generated by Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Due to excellent selectivity and high affinity to targets, aptamers hold considerable potential as molecular probe in diverse applications ranging from ensuring food safety, monitoring environment, disease diagnosis to therapy. This review highlights recent development and challenges about aptamers screened by Cell-SELEX, and its application about cancer diagnostics and therapeutics. Advances about some operation methods such as seperation method and culture method in aptamers selection procedure were summarized in this paper. Some common challenges and technological difficulties such as nonspecific binding and biostability were discussed. Up to now, the recent endeavors about cancer diagnostic and therapeutic applications of aptamers are summarized and expatiated. Most of aptamers screened by Cell-SELEX took tumor cells as target cells, and such aptamers have been assembled to various aptasensor for cancer diagnosis. Aptamers conjugated various drugs or nanomaterials are functioned for cancer target therapy to improve drugs delivery efficiency and reduce side effects. Furthermore, the duplexed aptamer is discussed to be applied for cancer cells detection and some conflicts of theories about duplexed aptamer designs are analyzed.

Chchd2 regulates mitochondrial morphology by modulating the levels of Opa1.

The mitochondrion is a highly dynamic organelle that is critical for energy production and numerous metabolic processes. Drosophila Chchd2, a homolog of the human disease-related genes CHCHD2 and CHCHD10, encodes a mitochondrial protein. In this study, we found that loss of Chchd2 in flies resulted in progressive degeneration of photoreceptor cells and reduced muscle integrity. In the flight muscles of adult Chchd2 mutants, some mitochondria exhibited curling cristae and a reduced number of cristae compared to those of controls. Overexpression of Chchd2 carrying human disease-related point mutations failed to fully rescue the mitochondrial defects in Chchd2 mutants. In fat body cells, loss of Chchd2 resulted in fragmented mitochondria that could be partially rescued by Marf overexpression and enhanced by Opa1 RNAi. The expression level of Opa1 was reduced in Chchd2 mutants and increased when Chchd2 was overexpressed. The chaperone-like protein P32 co-immunoprecipitated with Chchd2 and YME1L, a protease known to processes human OPA1. Moreover, the interaction between P32 and YME1L enhanced YME1L activity and promoted Opa1 degradation. Finally, Chchd2 stabilized Opa1 by competing with P32 for YME1L binding. We propose a model whereby Chchd2 regulates mitochondrial morphology and tissue homeostasis by fine-tuning the levels of OPA1.

Tumor-Associated Macrophages (TAMs): A Critical Activator In Ovarian Cancer Metastasis.

Tumor-associated macrophages (TAMs) that appear in every stage of cancer progression are usually tumor-promoting cells and are present abundantly in the tumor-associated microenvironment. In ovarian cancer, the overall and intratumoral M1/M2 ratio is a relatively efficient TAM parameter for predicting the prognosis of patients, especially for serous tissue type cancer. TAMs exhibit immunological checkpoint modulators, such as the B7 family and programmed death-ligand 1 (PD-L1), and play a key role in the development, metastasis and invasion of ovarian cancer, but the underlying mechanism is barely understood. Ovarian cancer is a severe gynecological malignancy with high mortality. Ovarian cancer-associated death can primarily be attributed to cancer metastasis. The majority of patients are diagnosed with wide dissemination in the peritoneum and omentum, limiting the effectiveness of surgery and chemotherapy. In addition, unlike other well-documented cancers, metastasis through vasculature is not a usual dissemination pathway in ovarian cancer. This review sheds light on TAMs and the main process and mechanism of ovarian cancer metastasis.

Large-scale RNAi screen identified Dhpr as a regulator of mitochondrial morphology and tissue homeostasis.

Mitochondria are highly dynamic organelles. Through a large-scale in vivo RNA interference (RNAi) screen that covered around a quarter of the Drosophila melanogaster genes (4000 genes), we identified 578 genes whose knockdown led to aberrant shapes or distributions of mitochondria. The complex analysis revealed that knockdown of the subunits of proteasomes, spliceosomes, and the electron transport chain complexes could severely affect mitochondrial morphology. The loss of Dhpr, a gene encoding an enzyme catalyzing tetrahydrobiopterin regeneration, leads to a reduction in the numbers of tyrosine hydroxylase neurons, shorter lifespan, and gradual loss of muscle integrity and climbing ability. The affected mitochondria in Dhpr mutants are swollen and have fewer cristae, probably due to lower levels of Drp1 S-nitrosylation. Overexpression of Drp1, but not of S-nitrosylation-defective Drp1, rescued Dhpr RNAi-induced mitochondrial defects. We propose that Dhpr regulates mitochondrial morphology and tissue homeostasis by modulating S-nitrosylation of Drp1.

Capsaicin reactivates hMOF in gastric cancer cells and induces cell growth inhibition.

Capsaicin (CAP) is the major pungent component of chili pepper and is being evaluated for use against numerous types of tumors. Although CAP is indicated to target multiple signaling pathways, exact mechanisms of how it disturb cancer cell metablism remain obscure. Recent studies revealed Sirtuin 1 (SIRT1) serves as a potential target of CAP in cancer cells, indicating a direct regulation of cancer cell histone acetylation by capsaicin. The present study evaluated the effect of CAP on gastric cancer (GC) cell lines to understand the mechanism of cell growth inhibition. The results showed that CAP could significantly suppress cell growth, while altering histone acetylation in GC cell lines. Further studies found that hMOF, a major histone acetyltranferase for H4K16, is central to CAP-induced epigenetic changes. Reduced hMOF activity was detected in GC tissues, which could be restored by CAP both in vivo and in vitro. These findings revealed an important role of hMOF-mediated histone acetylation in CAP-directed anti-cancer processes, and suggested CAP as a potential drug for use in gastric cancer prevention and therapy.

Negative Regulation of p21Waf1/Cip1 by Human INO80 Chromatin Remodeling Complex Is Implicated in Cell Cycle Phase G2/M Arrest and Abnormal Chromosome Stability.

We previously identified an ATP-dependent human Ino80 (INO80) chromatin remodeling complex which shares a set of core subunits with yeast Ino80 complex. Although research evidence has suggested that INO80 complex functions in gene transcription and genome stability, the precise mechanism remains unclear. Herein, based on gene expression profiles from the INO80 complex-knockdown in HeLa cells, we first demonstrate that INO80 complex negatively regulates the p21Waf1/Cip1 (p21) expression in a p53-mediated mechanism. In chromatin immunoprecipitation (ChIP) and a sequential ChIP (Re-ChIP) assays, we determined that the INO80 complex and p53 can bind to the same promoter region of p21 gene (-2.2 kb and -1.0 kb upstream of the p21 promoter region), and p53 is required for the recruitment of the INO80 complex to the p21 promoter. RNAi knockdown strategies of INO80 not only led to prolonged progression of cell cycle phase G2/M to G1, but it also resulted in abnormal chromosome stability. Interestingly, high expression of p21 was observed in most morphologically-changed cells, suggesting that negative regulation of p21 by INO80 complex might be implicated in maintaining the cell cycle process and chromosome stability. Together, our findings will provide a theoretical basis to further elucidate the cellular mechanisms of the INO80 complex.

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia.

Diabetes mellitus is known to cause kidney impairment; however, the mechanism remains elusive. The aim of this study was to investigate the role of C/EBP homologous protein (CHOP), an important protein in endoplasmic reticulum stress­mediated mesangial cell apoptosis in hyperglycemia. Mesangial cells were cultured in normal (control group) and high glucose medium (high glucose group). TUNEL staining was performed to assess apoptotic cells in the groups. The expression of CHOP and caspase­3 was also assayed by immunohistochemistry and western blot analysis. Following 24 h culture in high glucose medium, TUNEL­positive cells were observed to be significantly increased (P<0.01). The expression of CHOP and caspase­3 in mesangial cells was also found to be significantly enhanced under high glucose conditions compared with the normal group (P<0.01). The results indicate that CHOP mediates apoptosis in mesangial cells under hyperglycemia and may play a role in the development of diabetic nephropathy.

Investigation of thrombospondin-1 and transforming growth factor-ß expression in the heart of aging mice.

Elderly patients face the problems of morbidity and mortality due to age-mediated disabilities. The purpose of the present study was to investigate the expression of thrombospondin-1 (TSP-1) and transforming growth factor-ß (TGF-ß) in aging mice, and its probable mechanism in the pathological changes of aging myocardium. The aging model group (AM) comprised 30-month-old mice, while the control group comprised 2-month-old mice. The pathological changes were explored by H&E staining, and the contents of superoxide dismulase (SOD) and malondialdehyde (MDA) in the hearts were determined by xanthine oxidation or TBA colorimetry. TSP-1 and TGF-ß expression in the left ventricular myocardium was also measured by immunohistochemistry. The results showed that the activities of SOD decreased and the MDA content increased markedly in the hearts of the AM group compared to the control group. H&E staining showed that the control group myocardial cells lined up in order with clear structure and stained equably, while the AM group myocardial cells lined up in disorder with an augmented cell body and the appearance of many granules and interstitial fibrosis. Compared to the control group, in the hearts of the AM group, TSP-1 and TGF-ß protein expression in myocardial cells showed a significant increase (P<0.01). TSP-1 and TGF-ß expression increased in the myocardium, which may be related to pathological changes of age-related heart diseases, such as hypertrophy, fibrosis of myocardial cells and microvessel dissepiment thickening.