Mesenchymal to epithelial transition (MET), whereby mesenchymal cells become more epithelial like in phenotype, was observed to occur during normal development and in cancers. Numerous investigations have been conducted on MET in carcino-mas. In addition, accumulating evidence also suggests the critical function of MET in sarcomas. Integrated analyses reveal that MET may be an important biological and clinical process in sarcomas, and transcription factors such as Slug may also perform central func-tions in epithelial differentiation in several sarcomas such as leiomyo-sarcoma and synovial sarcoma. Given the scarcity of investiga-tions and evidence, several important issues about MET, such as its molecular markers, signaling mechanisms, micro RNA regulations, and clinical significance, need to be clarified. In this article, we review several important questions about MET in sarcomas, including molecular markers, signaling mechanisms, regulation by miRNAs, and therapeutic implications.

Objective To performed microarray-based comparative genomic hybridization (aCGH) detection and carried out pathway analysis to gain a systemic view on the pathway alterations of the genetically altered genes in human osteosarcoma.Methods aCGH experiments were carried on 10 fresh osteosarcoma samples to obtain recurrent copy number change pattern,then the samples were further subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify the altered pathways in the osteosarcoma.To validate the aberrations of these key pathways,the alterations of VEGF pathway were selected to confirm by the methods of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) osteosarcoma archival tissues.Results The KEEG analysis of aCGH data identified 33 genetically altered pathways in osteosarcomas.Among them 20 pathways were identified genetic amplifications,such as VEGF and mTOR signaling pathways.Thirteen pathways were genetic deletions,such as Wnt and Hedgehog signaling pathways.The genetic aberrations of cell-cell-matrix pathway such as CAMs,Adherens junction and Tight junction pathways implied the genetically alterations of these pathways which are associated with the tumor invasion and metastasis.Validation the aberrations of VEGF pathway showed that VEGFA gene was significantly amplified.The positive protein expression of VEGFA had a significant association with microvessel density (MVD).Conclusion There are genetic aberrations which involved the component genes of VEGF,mTOR,CAMs,Adherens junction,Wnt,Hedgehog and other 26 signaling pathways.The alterations of these pathways which are significantly associated with tumor invasion,metastasis and progression suggest that the genetic aberrations of these key pathways might contribute to the tumorigenesis and progression in human osteosarcoma,and provide molecular genetic evidence for targeted therapy.

Background: Based on the theory of"five Zang-organs corresponding to the seasons"in traditional Chinese medicine (TCM), physiological functions including emotions vary with the seasons. We aimed to investigate the seasonal photoperiod effects of melatonin (MT) released from the pineal gland on the MT receptor (MTR)-Gs/Gi-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling pathway in the hippocampus.Methods: Rats were divided into three groups: control, operation (surgery with pineal gland removal), and pseudo-operation groups (same surgery as operation group but without removing pineal gland), and fed at specific time across the four seasons. The levels of MTR, adenylate cyclase (AC), cAMP, PKA, and CREB in the hippocampus were analyzed using ELISA. The concentrations of Gs and Gi were analyzed using Western blot. The expression of CREB mRNA was detected by PCR. Results: For intragroup comparisons, compared with spring, the levels of Gs/Gi in the control group were higher in summer, autumn, and winter (P=.009 in summer;P<.001 in autumn and winter);the levels of MTR, cAMP, PKA, and CREB in the control group were significantly higher in autumn and winter than in spring (all P<.001). The levels of MTR, cAMP, PKA, and CREB in each season were significantly lower in the operation group than in the control group (all P < .05). Significant differences were noted in Gs/Gi levels between the operation group and control group in spring, autumn, and winter (all P<.05). Conclusion: Our findings suggest that MTR-Gs/Gi-cAMP-PKA-CREB signaling pathway is involved in the seasonal photoperiod effects of the pineal gland on the hippocampus and may underpin seasonal changes in emotions. It can support the prevention and treatment of the seasonal onset of mental dis-orders, and enrich the theory of"five Zang-organs corresponding to the seasons".

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy-lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.

Acetaminophen (APAP) overdose is a major cause of liver injury. Neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases; however, its role in APAP-induced liver injury (AILI) is unclear. Thus, this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI. We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes. Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury, while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro. Additionally, hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1 (VDAC1) and increased VDAC1 oligomerization. Furthermore, VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency. Mechanistically, NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1. Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.