Ckip-1 Mediates P. gingivalis–Suppressed Cementoblast Mineralization

Porphyromonas gingivalis is responsible for the destruction of cementum in patients with periodontitis and periapical periodontitis. However, research about the effects of P. gingivalis on cementoblast mineralization and the underlying mechanism is still lacking. Casein kinase 2 interacting protein 1 (Ckip-1) is a scaffold protein that interacts with various proteins and signals to regulate different cell functions, such as cell morphology, apoptosis, and differentiation. In this study, we verified the suppressive effects of P. gingivalis and lipopolysaccharide (Pg-LPS) on OCCM-30 mineralization. We also showed that Ckip-1 gradually decreased during OCCM-30 mineralization but increased with the aggravation of Pg-induced inflammation. However, it remained unchanged when cells were stimulated with Pg-LPS, regardless of the concentration and incubation time. Then, more cellular cementum and enhanced Osterix expression were observed in Ckip-1 knockout mice when compared with the wild-type mice. Meanwhile, Ckip-1 silencing significantly enhanced cementoblast mineralization with or without P. gingivalis–associated inflammation. The trend was opposite when Ckip-1 was overexpressed. Finally, we found that the p38, Akt, and Wnt pathways were activated, while the Erk1/2 pathway was inhibited when Ckip-1 was silenced. The opposite results were also observed in the Ckip-1 overexpression group. Furthermore, we proved that cell mineralization was weakened when p38, Akt inhibitors were applied and strengthened when the Erk1/2 pathway was inhibited. In summary, Ckip-1 is upregulated under P. gingivalis–induced inflammation and negatively regulates cementoblast mineralization partially through mitogen-activated protein kinases and Akt signaling pathways, which may contribute to the restoration of cementum destroyed by P. gingivalis.

Misregulation of Wnt Signaling Pathways at the Plasma Membrane in Brain and Metabolic Diseases

Wnt signaling pathways constitute a group of signal transduction pathways that direct many physiological processes, such as development, growth, and differentiation. Dysregulation of these pathways is thus associated with many pathological processes, including neurodegenerative diseases, metabolic disorders, and cancer. At the same time, alterations are observed in plasma membrane compositions, lipid organizations, and ordered membrane domains in brain and metabolic diseases that are associated with Wnt signaling pathway activation. Here, we discuss the relationships between plasma membrane components—specifically ligands, (co) receptors, and extracellular or membrane-associated modulators—to activate Wnt pathways in several brain and metabolic diseases. Thus, the Wnt–receptor complex can be targeted based on the composition and organization of the plasma membrane, in order to develop effective targeted therapy drugs.

Role of the bone marrow microenvironment in drug resistance of hematological malignances

: The unique features of the tumor microenvironment (TME) govern the biological properties of many cancers, including hematological malignancies. TME factors can trigger invasion, and protect against drug cytotoxicity by inhibiting apoptosis and activating specific signaling pathways (e.g. NF-ΚB). TME remodeling is facilitated due to the high self-renewal ability of the bone marrow. Progressing tumor cells can alter some extracellular matrix (ECM) components which act as a barrier to drug penetration in the TME. The initial progression of the cell cycle is controlled by the MAPK pathway (Raf/MEK/ERK) and Hippo pathway, while the final phase is regulated by the PI3K/Akt /mTOR and WNT pathways. In this review we summarize the main signaling pathways involved in drug resistance (DR) and some mechanisms by which DR can occur in the bone marrow. The relationship between autophagy, endoplasmic reticulum stress, and cellular signaling pathways in DR and apoptosis are covered in relation to the TME.

The genomic architecture of EBV and infected gastric tissue from precursor lesions to carcinoma

Background Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood. Methods We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments. Results Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function. Conclusions We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.

Identification and Characterization of lncRNA and mRNA in Testes of Landrace and Hezuo Boars

Chinese HZ boars are typical plateau miniature boars characterized by precocious puberty, which is closely related to testicular development and spermatogenesis. Accumulating evidence indicates that lncRNA is involved in the testicular development and regulation of spermatogenesis. However, little is known about the lncRNA precocious regulation in testicular development and spermatogenesis on early sexual maturity of HZ boars. Thus, we investigated the expression and characterization of lncRNA and mRNA in 30-day-old and 120-day-old HZ boar testes using transcriptome to explore precocious puberty. Landrace (LC) boar was treated as the control. Histological analyses indicated that HZ boar underwent puberty development at an earlier stage than LC boar and had achieved sexual maturity at 120 days old. RNA-Seq yielded a total of 187 lncRNAs and 984 mRNAs; these molecules were identified as possible candidates for precocious puberty. GO terms and KEGG pathways enrichment analyses revealed that the differentially expressed lncRNA and their targeted genes were involved in metabolic pathways regulating testis development and spermatogenesis, such as the PI3K-Akt, TGF-beta and Wnt pathways. Further screening, some lncRNA (such as LOC102166140, LOC110259451, and MSTRG.15011.2), and mRNA (such as PDCL2, HSD17B4, SHCBP1L, CYP21A2, and SPATA3) were found to be possibly associated with precocious puberty, which would add to our understanding of the molecular regulatory mechanisms of precocious puberty. This study provided valuable information for further study of the role of lncRNA and mRNA in the process of precocious puberty.

A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer

Genetic evidence suggests a role for the Wnt/β-catenin pathway in gastric cancer. However, Wnt5a, regarded as a prototypical non-canonical Wnt ligand, has also been extensively associated with this disease. Therefore, the roles of the Wnt signaling pathway in gastric cancer initiation and progression, and particularly the precise mechanisms by which the non-canonical Wnt pathway might promote the development and progression of gastric cancer, are not entirely well understood. This article analyzes publicly available gene and protein expression data and reveals the existence of a WNT5A/FZD2/FZD7/ROR2 signature, which correlates with tumor-infiltrating and mesenchymal cell marker expression. High expression of FZD7 and ROR2 correlates with a shared gene and protein expression profile, which in turn correlates with poor prognosis. In summary, the findings presented in this article provide an updated view of the relative contributions of the Wnt/β-catenin and non-canonical Wnt pathways in gastric cancer.