Alzheimer's disease (AD) is the most common type of dementia. Almost two-thirds of patients with AD are female. The reason for the higher susceptibility to AD onset in women is unclear. However, hormone changes during the menopausal transition are known to be associated with AD. Most recently, we reported that follicle-stimulating hormone (FSH) promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein (C/EBPβ)/asparagine endopeptidase (AEP) pathway. This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players, including APP and Tau, explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females. The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.
Female ; Humans ; Male ; Alzheimer Disease/pathology* ; CCAAT-Enhancer-Binding Protein-beta/metabolism* ; Cognitive Dysfunction/metabolism* ; Signal Transduction ; Follicle Stimulating Hormone

OBJECTIVETo explore the expression of CCAAT/enhancer binding protein beta (CEBPB) in gastric carcinoma tissues and its association with clinicopathological features and prognosis.

METHODSCEBPB protein expression level was detected by immunohistochemistry method in resected gastric carcinomas and adjacent gastric mucosa tissues (n=81), and its association with clinicopathological features and prognosis was analyzed.

RESULTSThe immunohistochemical staining of CEBPB was predominantly in the nucleus with some cytoplasmic staining. As a result, 16% (13/81) of the gastric carcinomas were stained positively, whereas there was hardly positive expression in adjacent gastric mucosa tissues. There was a significant association between the expression of CEBPB and distant metastasis on univariate analysis (P<0.05). The median survival time in patients with positive CEBPB expression was significantly lower than those with negative CEBPB expression (19.4 months vs. 45.2 months, P=0.024). Multivariable analysis showed that CEBPB was independently associated with prognosis (HR=2.544, 95%CI:1.154-5.610, P=0.021).

CONCLUSIONUp-regulation of CEBPB suggests poor prognosis in patients with gastric cancer.

Adult ; Aged ; Aged, 80 and over ; CCAAT-Enhancer-Binding Protein-beta ; metabolism ; Female ; Gastric Mucosa ; metabolism ; pathology ; Humans ; Male ; Middle Aged ; Prognosis ; Stomach Neoplasms ; metabolism ; pathology

Cancer is a highly aggressive and devastating disease, and impediments to a cure arise not just from cancer itself. Targeted therapies are difficult to achieve since the majority of cancers are more intricate than ever imagined. Mainstream methodologies including chemotherapy and radiotherapy as routine clinical regimens frequently fail, eventually leading to pathologies that are refractory and incurable. One major cause is the gradual to rapid repopulation of surviving cancer cells during intervals of multiple-dose administration. Novel stress-responsive molecular pathways are increasingly unmasked and show promise as emerging targets for advanced strategies that aim at both de novo and acquired resistance. We highlight recent data reporting that treatments particularly those genotoxic can induce highly conserved damage responses in non-cancerous constituents of the tumor microenvironment (TMEN). Master regulators, including but not limited to NF-kB and C/EBP-β, are implicated and their signal cascades culminate in a robust, chronic and genome-wide secretory program, forming an activated TMEN that releases a myriad of soluble factors. The damage-elicited but essentially off target and cell non-autonomous secretory phenotype of host stroma causes adverse consequences, among which is acquired resistance of cancer cells. Harnessing signals arising from the TMEN, a pathophysiological niche frequently damaged by medical interventions, has the potential to promote overall efficacy and improve clinical outcomes provided that appropriate actions are ingeniously integrated into contemporary therapies. Thereby, anticancer regimens should be well tuned to establish an innovative clinical avenue, and such advancement will allow future oncological treatments to be more specific, accurate, thorough and personalized.
Antineoplastic Agents ; therapeutic use ; CCAAT-Enhancer-Binding Protein-beta ; metabolism ; Humans ; Models, Biological ; Molecular Targeted Therapy ; methods ; trends ; NF-kappa B ; metabolism ; Neoplasms ; drug therapy ; metabolism ; Precision Medicine ; methods ; trends ; Signal Transduction ; drug effects ; Tumor Microenvironment ; drug effects

The CRES (cystatin-related epididymal spermatogenic) protein defines a new subgroup in the family 2 cystatins of the cystatin superfamily of cysteine protease inhibitors. However, unlike the ubiquitous expression of cystatin C, the Cres gene is preferentialy expressed in postmeiotic germ cells, the proximal caput epididymidis, and anterior pituitary gonadotrophs. Furthermore, CRES protein lacks two of the three consensus sites necessary for the cystatin inhibition of C1 cysteine proteases. Therefore, CRES may perform unique and tissue-specific functions in the reproductive and neuroendocrine systems. In the present review, we describe our studies on: 1. the Cres gene promoter and the transcriptional regulatory protein and their associated DNA binding sites that may be important for tissue-specific expression; and 2. the biochemical function of CRES protein. In brief, Northern blot, gel shift analyses, and transient transfection assays demonstrated that the C/EBP beta (CCAAT/enhancer binding protein) transcription factor is the predominant C/EBP family member expressed in the epididymis and gonadotroph cells and is necessary for high levels of Cres expression in these two tissues. In other studies, analyses of transgenic mice expressing a CAT reporter gene driven by 1.6 kb of Cres promoter revealed CAT mRNA and protein only in the germ cells. These studies suggest that the 1.6 kb of Cres 5' flanking sequence contains the required DNA elements for expression in the testis, but lacks the elements to correctly target expression of the reporter gene in the epididymis. Alternatively, repressor elements may be present. Finally, in vitro protease assays were performed to determine if CRES functions as a protease inhibitor. In contrast to cystain C, CRES did not inhibit the C1 cysteine protease papain but rather inhibited at nanomolar concentrations the serine protease PC2, a prohormone processing enzyme. Therefore, CRES is a new cross-class inhibitor that may regulate PC2 of PC2-like proteases and suggests a role for CRES in the regulation of prohormone and proprotein processing.
Amino Acid Sequence ; Animals ; CCAAT-Enhancer-Binding Protein-beta ; biosynthesis ; Cystatins ; classification ; genetics ; physiology ; Epididymis ; metabolism ; Gene Expression Regulation ; Humans ; Male ; Mice ; Mice, Transgenic ; Promoter Regions, Genetic ; genetics ; Sequence Homology, Amino Acid ; Spermatogenesis ; physiology

BACKGROUNDCCAAT/enhancer-binding protein beta (C/EBPbeta) is required for mitotic clonal expansion (MCE) during adipogenesis. It is still unclear how C/EBPbeta regulates MCE in the earlier differentiation programs of 3T3-L1 preadipocytes. The purpose of this paper was to understand why C/EBPbeta is required for preadipocyte proliferation, and identify new target genes of C/EBPbeta with chromatin immunoprecipitation (ChIP)-on-chip.

METHODSPostconfluent growth-arrested 3T3-L1 preadipocytes were induced to differentiation using a standard differentiation protocol. ChIP was performed at 20 hours after induction with specific anti-C/EBPbeta antibodies. The precipitated DNA was amplified, labeled and hybridized with a mouse promoter microarray. Compared with the control in which the ChIP experiment was performed with non-specific antibody, only the genes with a signal increasing more than 2 fold were considered as candidate genes.

RESULTSA total of 110 candidate genes were identified. BTG3 associated nuclear protein (SMAR1, Banp) and tripartite motif-containing 35 (Hls5, trim35) were two target genes among the 110 candidate genes which are involved in cell cycle regulation; the binding of C/EBPbeta to the promoter of banp and trim35 was verified by ChIP-PCR.

CONCLUSIONC/EBPbeta may regulate preadipocyte proliferation through activation of banp and trim35.

3T3-L1 Cells ; Adipocytes ; cytology ; Animals ; Apoptosis Regulatory Proteins ; genetics ; metabolism ; CCAAT-Enhancer-Binding Protein-beta ; genetics ; metabolism ; Cell Cycle Proteins ; genetics ; metabolism ; Cell Differentiation ; genetics ; physiology ; Cell Proliferation ; Chromatin Immunoprecipitation ; DNA-Binding Proteins ; genetics ; metabolism ; Mice ; Nuclear Proteins ; genetics ; metabolism ; Oligonucleotide Array Sequence Analysis ; Polymerase Chain Reaction ; Protein Binding

OBJECTIVETo investigate the expressions of inflammation- and fibrosis-related genes in perinephric and subcutaneous adipose tissues in patients with adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome.

METHODSThe perinephric and subcutaneous adipose tissues adipose tissues were obtained from 8 patients with ACTH-independent Cushing's syndrome undergoing laparoscopic retroperitoneal adrenalectomy. Real-time PCR was used to detect the mRNA expression levels of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), matrix metallopeptidase 2 (MMP-2), TIMP metallopeptidase inhibitor 1 (TIMP-1), early growth response 1 (EGR1), CCAAT/enhancer binding protein &beta;(CEBP&beta;), uncoupling protein 1(UCP-1), PPARγ coactivator 1 alpha (PGC1α) and cell death-inducing DFFA-like effector a (CIDEA).

RESULTSThe mRNA level of CIDEA was significantly higher in the perinephric adipose tissue (peri-N) than in the subcutaneous adipose tissue (subQ) (P<0.05). The expressions of CEBP&beta;, UCP-1, and PGC1α mRNA in the peri-N were similar with those in the subQ. The expressions of IL-6, TIMP1 and EGR1 mRNA in the subQ were significantly higher than those in the peri-N (P<0.05). No significant difference in TNF-α and MMP-2 mRNA levels was found between peri-N and subQ.

CONCLUSIONThe expression levels of the inflammation- and fibrosis-related genes are higher in the subQ than in the peri-N of patients with ACTH-independent Cushing's syndrome, suggesting that chronic exposure to endogenous hypercortisolism may cause adipose tissue dysfunction.

Adrenalectomy ; Adrenocorticotropic Hormone ; CCAAT-Enhancer-Binding Protein-beta ; metabolism ; Cushing Syndrome ; metabolism ; surgery ; Early Growth Response Protein 1 ; metabolism ; Humans ; Matrix Metalloproteinase 2 ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; metabolism ; Real-Time Polymerase Chain Reaction ; Subcutaneous Fat ; metabolism ; Tissue Inhibitor of Metalloproteinase-1 ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism ; Uncoupling Protein 1 ; metabolism