Alteration of Thyroid Hormones in Mouse Models of Alzheimer's Disease and Aging.

INTRODUCTION: Aging is characterized by the deterioration of a wide range of functions in tissues and organs, and Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Hypothyroidism occurs when there is insufficient production of thyroid hormones (THs) by the thyroid. The relationship between hypothyroidism and aging as well as AD is controversial at present. METHODS: We established an animal model of AD (FAD4T) with mutations in the APP and PSEN1 genes, and we performed a thyroid function test and RNA sequencing (RNA-Seq) of the thyroid from FAD4T and naturally aging mice. We also studied gene perturbation correlation in the FAD4T mouse thyroid, bone marrow, and brain by further single-cell RNA sequencing (scRNA-seq) data of the bone marrow and brain. RESULTS: In this study, we found alterations in THs in both AD and aging mice. RNA-seq data showed significant upregulation of T-cell infiltration- and cell proliferation-related genes in FAD4T mouse thyroid. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that upregulated genes were enriched in the functional gene modules of activation of immune cells. Downregulated energy metabolism-related genes were prominent in aging thyroids, which reflected the reduction in THs. GSEA showed a similar enrichment tendency in both mouse thyroids, suggesting their analogous inflammation state. In addition, the regulation of leukocyte activation and migration was a common signature between the thyroid, brain, and bone marrow of FAD4T mice. CONCLUSIONS: Our findings identified immune cell infiltration of the thyroid as the potential underlying mechanism of the alteration of THs in AD and aging.

METTL14 Regulates Intestine Cellular Senescence through m6A Modification of Lamin B Receptor.

N-6-Methyladenosine (m6A) modification is involved in multiple biological processes including aging. However, the regulation of m6A methyltransferase-like 14 (METTL14) in aging remains unclear. Here, we revealed that the level of m6A modification and the expression of METTL14 were particularly decreased in the intestine of aged mice as compared to young mice. Similar results were confirmed in Drosophila melanogaster. Knockdown of Mettl14 in Drosophila resulted in a short lifespan, associated disrupted intestinal integrity, and reduced climbing ability. In human CCD-18Co cells, knockdown of METTL14 accelerated cellular senescence, and the overexpression of METTL14 rescued senescent phenotypes. We also identified the lamin B receptor (LBR) as a target gene for METTL14-mediated m6A modification. Knockdown of METTL14 decreased m6A level of LBR, resulted in LBR mRNA instability, and thus induced cellular senescence. Our findings suggest that METTL14 plays an essential role in the m6A modification-dependent aging process via the regulation of LBR and provides a potential target for cellular senescence.

Analysis of clinicopathological features of papillary thyroid carcinoma in solid organ transplant recipients: a retrospective study.

Background: With the advances in organ transplantation technology and the increased number of organ recipients, more organ transplant recipients are living longer. However, many newly-onset thyroid cancer cases have been found among this population. The question remains in the uncertainty in whether the post-transplant thyroid cancer is more pathologically aggressive than the thyroid cancer in non-organ-transplant recipients. We compared the clinicopathological features of papillary thyroid carcinoma (PTC) between solid organ transplant recipients (SOTR) and the general population, in an attempt to improve the detection rate of post-transplant PTC in SOTR and overall survival prognosis of those patients. Methods: The clinical data of 408 PTC patients in the First Affiliated Hospital of Zhejiang University School of Medicine from July 2013 to April 2019 were retrospectively analyzed. The clinicopathological features were compared between non-organ-transplant recipients with PTC (group A, n=380) and SOTR with newly-onset PTC (group B, n=31) using Chi-square test, Fisher's exact test, Student's t-test, and logistic regression. Results: There were significant differences between these two groups in central compartment lymph node metastasis (P=0.005), multifocality (P=0.003), and maximum tumor diameter (P=0.007). Compared with group A, group B had a higher rate of tumor multifocality, higher rate of lymph node metastasis, and smaller tumor size. In addition, PTC in group B was more aggressive in biological behaviors such as tumor multifocality and lymph node metastasis. Conclusions: Compared with the general population, PTC after SORT demonstrate a more malignant pathological feature. The examination rate of thyroid cancer in SORT should be increased to improve the overall prognosis after solid organ transplant.

Effects of solid organ transplantation on the risk of developing thyroid cancer: a systematic review and meta-analysis.

Background: Solid organ transplantation (SOT), which is the best remedy for end-stage organ failure, is accompanied by the risk of developing a postoperative malignant tumor. To date, assessments of the changes in the increased risk of thyroid cancer (TC) after SOT remain controversial. This study sought to reevaluate the risk of TC after SOT based on the latest literature. Our findings could improve the early diagnosis of tumors and the overall prognosis of patients after SOT. Methods: A computerized search of four major English-language databases (i.e., PubMed, EMBASE, Cochrane Library, and Web of Science) was performed to retrieve cohort studies on the risk of developing TC after SOT. The standardized incidence ratio (SIR) was used as the pooled-effect size and expressed as the 95% confidence interval (CI). Results: In total, 20 cohort studies, comprising 362,079 patients who underwent SOT, were included in the meta-analysis. We found that the patients all had an increased risk of developing TC after the transplantation of different solid organs, including the kidney, heart, lung, and liver (P<0.05), and patients had the highest risk of developing TC after kidney transplantation (SIR =5.28, 95% CI: 4.03-6.92, P<0.01). Conclusions: Patients have an increased risk of developing TC after SOT. Aggressive and regular tumor screenings after SOT for early detection and timely treatment may improve patient prognosis.

ENO3 promotes colorectal cancer progression by enhancing cell glycolysis.

BACKGROUND: Colorectal cancer (CRC) is among the leading cause of cancer-related morbidity and mortality worldwide. Aerobic glycolysis, as a metabolic hallmark of cancer, plays an important role in CRC progression. Enolase 3 (ENO3) is a glycolytic enzyme that catalyzes 2-phosphoglycerate into phosphoenolpyruvate, while its role in CRC is still unknown. METHODS: Bioinformatics analysis was performed to examine the expression changes and roles of ENO3 in CRC patients from public databases. Then, ENO3 expression was validated in CRC tissues using Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) analysis, and western blot. Overexpression and silencing models were constructed using plasmid and lentivirus transfection. Cell viability, proliferation, and migration in vitro were applied to evaluate the protumoral effects of ENO3 on CRC. RNA sequencing and GO enrichment analysis of differentially expressed genes (DEGs) were performed to explore the underlying molecular mechanisms of ENO3 in CRC progression. The ATP and lactate production level were detected to assess cell glycolysis. RESULTS: ENO3 was significantly up-regulated in CRC. High ENO3 expression was positively correlated with poor prognosis and higher clinical stages of CRC patients. ROC curve demonstrated the diagnostic value of ENO3 for CRC with the AUC of 0.802. Gain- and loss-of function experiments demonstrated that ENO3 significantly enhanced the proliferation and migration ability of CRC cells in vitro. After ENO3 knockdown, RNA sequencing screened out a list of DEGs which were enriched in the regulation of the glycolytic process. The detection of lactate production and ATP level verified the role of ENO3 in the glycolytic process. CONCLUSION: Our findings illustrate that ENO3 could promote the progression of CRC by the enhancement of cell glycolysis, indicating the potential value of ENO3 as a novel biomarker and therapeutic target for CRC.

GDC-0326 Enhances the Effects of 5-Fu in Colorectal Cancer Cells by Inducing Necroptotic Death.

AIM: Chemoresistance to 5-fluorouracil (5-Fu) is common in colorectal cancer (CRC). Programmed necrosis (necroptosis) is an alternative form of programmed cell death regulated by receptor-interacting protein kinase (RIPK) 1 and 3, assumed as a novel target of cancer therapy. In this study, we aimed to explore whether a novel small molecular agent GDC-0326 could facilitate the effect of 5-Fu through necroptosis. MAIN METHODS: Cell Counting Kit-8 (CCK-8) assay and colony formation were performed to confirm the function of GDC-0326 in CRC cells. Western blot and immunofluorescence were conducted to measure the altered expressions of RIPK1/RIPK3 induced by GDC-0326. Subcutaneous tumor models were used to evaluate the chemotherapeutic effects and concomitant side effects of GDC-0326 in vivo. KEY FINDINGS: We found that GDC-0326 effectively suppressed the growth of CRC cells in a dose-dependent manner. The induction of necroptosis by GDC-0326 was correlated with the modulation of RIPK1 and RIPK3. Necrostatin-1 and GSK-872, inhibitors of RIPK1 and RIPK3, respectively, could rescue the cell death induced by GDC-0326. In addition, in vitro and in vivo studies showed that 5-Fu plus GDC-0326 evinced a better antitumor efficacy by suppressing tumor growth and increasing tumor necrosis with no increased toxicity. SIGNIFICANCE: This study demonstrates that GDC-0326 plus 5-Fu has augmented antitumor efficacy and acceptable safety, which might be a promising therapeutic strategy for CRC patients in the future.