CT45A1-mediated MLC2 (MYL9) phosphorylation promotes natural killer cell resistance and outer cell fate in a cell-in-cell structure, potentiating the progression of microsatellite instability-high colorectal cancer.

Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) have high tumor mutation burden and tumor immunogenicity, exhibiting a higher response rate to immunotherapy and better survival. However, a portion of MSI-H CRC patients still experience adverse disease outcomes. We aimed to identify the tumor-autonomous regulators determining these heterogeneous clinical outcomes.

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

Background: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation.

Methods: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls.

Results: Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD.

Histone deacetylation-regulated cell surface Siglec-7 expression promoted megakaryocytic maturation and enhanced platelet-like particle release.

Background: Functioning as important hematologic cells for hemostasis, wound healing and immune defense platelets are produced before being released into the blood by cytoplasmic fragmentation at the end of the megakaryocyte (MK) differentiation, during which the involvement of both apoptosis and autophagy has been reported. Inhibitory sialic acid-binding immunoglobulin-like lectin-7 gene (Siglec-7) can be expressed on platelets and induce apoptosis on activation for uncharacterized function.

Objective: We aimed to investigate the regulatory mechanism for Siglec-7 activation along MK differentiation and its physiologic role during the MK maturation and platelet formation.

Molecular actions of exosomes and their theragnostics in colorectal cancer: current findings and limitations.

Extracellular vesicles (EVs) are cell-released, membranous structures essential for intercellular communication. The biochemical compositions and physiological impacts of exosomes, lipid-bound, endosomal origin EVs, have been focused on, especially on the tumor-host interactions in a defined tumor microenvironment (TME). Despite recent progress in targeted therapy and cancer immunotherapy in colorectal cancer (CRC), cancer patients still suffer from distal metastasis and tumor relapse, suggesting unmet needs for biomarkers directing therapeutic interventions and predicting treatment responsiveness.

Branched I antigen regulated cell susceptibility against natural killer cytotoxicity through its N-linked glycosylation and overall expression.

Cell surface glycosylation has been known as an important modification process that can be targeted and manipulated by malignant cells to escape from host immunosurveillance. We previously showed that the blood group branched I antigen on the leukemia cell surface can regulate the cell susceptibility against natural killer (NK) cell-mediated cytotoxicity through interfering target-NK interaction. In this work, we first identified N-linkage as the major glycosylation linkage type for branched I glycan formation on leukemia cells, and this linkage was responsible for cell sensitivity against therapeutic NK-92MI targeting.

Long-Term Exposure to Low-Dose Di-(2-ethylhexyl) Phthalate Impairs Cholesterol Metabolism in Hepatic Stellate Cells and Exacerbates Liver Librosis.

Phthalates are often added to plastic products to increase their flexibility. Di-(2-ethylhexyl) phthalate (DEHP) is one of the most common plasticizers. Previously, a major incident involving phthalate-contaminated foodstuffs occurred, where phthalates were deliberately added to foodstuffs as a substitute for emulsifiers, resulting in a threat to public health.

Antifibrotic Effects of a Barbituric Acid Derivative on Liver Fibrosis by Blocking the NF-κB Signaling Pathway in Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) are the major profibrogenic cells that promote the pathogenesis of liver fibrosis. The crosstalk between transforming growth factor-β1 (TGF-β1) signaling and lipopolysaccharide (LPS)-induced NF-κB signaling plays a critical role in accelerating liver fibrogenesis. Until now, there have been no FDA-approved drug treatments for liver fibrosis.

DNA methylation-mediated Siglec-7 regulation in natural killer cells via two 5' promoter CpG sites.

First discovered on the natural killer (NK) cell, the cell surface inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) is known for regulating many important biological activities. However, the detail regulatory mechanism for Siglec-7 expression in NK cells currently remains unclear. In this study, we aimed to investigate how cell surface Siglec-7 expression is regulated and found that, in both NK cell lines and peripheral NK cells, transcription was the main regulatory step.

HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. The aims of this study were to verify the mechanisms and therapeutic potential of the ketogenesis rate-limiting enzyme 3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in HCC.

TGF-β regulated leukemia cell susceptibility against NK targeting through the down-regulation of the CD48 expression.

Transforming growth factor-β (TGF-β) is known to function as a dual role regulatory cytokine for being either a suppresser or promoter during tumor initiation and progression. In solid tumors, TGF-β secreted from tumor microenvironment acts as a suppresser against host immunity, like natural killer (NK) cells, to favor tumor evasion. However, besides solid tumors, the underlying mechanism of how TGF-β regulates leukemogenesis, tumor progression, immunoediting, and NK function is still not clear in detail.

The molecular genetic background leading to the formation of the human erythroid-specific Xg/CD99 blood groups.

The Xg and CD99 antigens of the human Xg blood group system show a unique and sex-specific phenotypic relationship. The phenotypic relationship is believed to result from transcriptional coregulation of the and genes, which span the pseudoautosomal boundary of the X and Y chromosomes. However, the molecular genetic background responsible for these blood groups has remained undetermined.

Niemann-Pick Type C2 Protein Regulates Free Cholesterol Accumulation and Influences Hepatic Stellate Cell Proliferation and Mitochondrial Respiration Function.

Liver fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. A high-cholesterol diet is associated with liver fibrosis via the accumulation of free cholesterol in hepatic stellate cells (HSCs). Niemann-Pick type C2 (NPC2) plays an important role in the regulation of intracellular free cholesterol homeostasis via direct binding with free cholesterol.

A Developed NK-92MI Cell Line with Siglec-7 Phenotype Exhibits High and Sustainable Cytotoxicity against Leukemia Cells.

Altered sialic acid processing that leads to upregulation of cell surface sialylation is recognized as a key change in malignant tissue glycosylation. This cancer-associated hypersialylation directly impacts the signaling interactions between tumor cells and their surrounding microenvironment, especially the interactions mediated by immune cell surface sialic acid-binding immunoglobulin-like lectins (Siglecs) to relay inhibitory signals for cytotoxicity. First, we obtained a Siglec-7 NK-92MI cell line, NK-92MI-S7N, by separating a group of Siglec-7 cell population from an eight-month-long-term NK-92MI in vitro culture by fluorescence-activated cell sorting (FACS).

The differential expression of the blood group P -A4GALT and P -A4GALT alleles is stimulated by the transcription factor early growth response 1.

Background: The P /P phenotypic polymorphism is one of the earliest blood groups discovered in humans. These blood groups have been connected to different levels of expression of the A4GALT gene in P and P red blood cells; however, the detailed molecular genetic mechanism that leads to these two phenotypes has not been established.

Study Design And Methods: After our previous identification of an association between the single-nucleotide polymorphisms (SNPs) rs2143918 and rs5751348 in A4GALT gene and the P /P phenotype, we conduct a survey of transcription factors that might connect these SNPs with the differential expression of the P -A4GALT and P -A4GALT alleles.

Branched I antigens on leukemia cells enhanced sensitivity against natural killer-cell cytotoxicity through affecting the target-effector interaction.

Background: The aberrant glycosylation on proteins and lipids has been implicated in malignant transformations for promoting the tumorigenesis, metastasis, and evasion from the host immunity. The I-branching β-1,6-N-acetylglucosaminyltransferase, converting the straight i to branched I histo-blood group antigens, reportedly could influence the migration, invasion, and metastasis of solid tumors.

Study Design And Methods: We first chose the highly cytotoxic natural killer (NK)-92MI cells as effector against leukemia for this cell line has been used in several clinical trials.

Glycine N-methyltransferase deficiency in female mice impairs insulin signaling and promotes gluconeogenesis by modulating the PI3K/Akt pathway in the liver.

Background: Glycine N-methyltransferase (GNMT) is abundantly expressed in the normal liver but is down-regulated in liver cancer tissues. GNMT knockout (Gnmt-/-) mice can spontaneously develop chronic hepatitis, fatty liver, and liver cancer. We previously demonstrated that hepatic GNMT is decreased in high-fat-diet-induced type 2 diabetes mellitus, but its contribution to metabolic syndrome is unclear.

The SHP2-ERK2 signaling pathway regulates branched I antigen formation by controlling the binding of CCAAT/enhancer binding protein α to the IGnTC promoter region during erythroid differentiation.

Background: Phosphorylation status of the transcription factor CCAAT/enhancer binding protein α (C/EBPα) has been demonstrated in a human hematopoietic cell model to regulate the formation of branched I antigen by affecting its binding affinity to the promoter region of the IGnTC gene during erythroid and granulocytic differentiation.

Study Design And Methods: The K-562 cell line was induced to differentiate into red blood cells (RBCs) or granulocytes by sodium butyrate or retinoic acid, respectively, to study the involvement of three MAP kinase pathways in I antigen synthesis. The regulatory effects of the extracellular signal-regulated kinase (ERK)2-Src homology region 2 domain-containing phosphatase 2 (SHP2) pathway on phosphorylation status and binding affinities of C/EBPα as well as the subsequent activation of IGnTC and synthesis of surface I formation were studied in wild-type K-562 cells and in mutant cells that overexpress ERK2 and SHP2.

Niemann-Pick Type C2 Protein Mediates Hepatic Stellate Cells Activation by Regulating Free Cholesterol Accumulation.

In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and so it is important to identify the molecules that regulate HSCs activation and liver fibrosis. Niemann-Pick type C2 (NPC2) protein plays an important role in the regulation of intracellular cholesterol homeostasis by directly binding with free cholesterol.

The ThPOK transcription factor differentially affects the development and function of self-specific CD8(+) T cells and regulatory CD4(+) T cells.

The zinc finger transcription factor ThPOK plays a crucial role in CD4 T-cell development and CD4/CD8 lineage decision. In ThPOK-deficient mice, developing T cells expressing MHC class II-restricted T-cell receptors are redirected into the CD8 T-cell lineage. In this study, we investigated whether the ThPOK transgene affected the development and function of two additional types of T cells, namely self-specific CD8 T cells and CD4(+) FoxP3(+) T regulatory cells.

TNFR1 delivers pro-survival signals that are required for limiting TNFR2-dependent activation-induced cell death (AICD) in CD8+ T cells.

Members of the TNF and TNF receptor (TNFR) superfamily play important roles in the maintenance of homeostasis of the immune system. Furthermore, several members of the TNFR family participate in T-cell activation and sustaining T-cell responses. We have shown that TNFR2 regulates T-cell activation by lowering the activation threshold and providing costimulatory signaling.

Phosphorylation status of transcription factor C/EBPalpha determines cell-surface poly-LacNAc branching (I antigen) formation in erythropoiesis and granulopoiesis.

The cell-surface straight and branched repeats of N-acetyllactosamine (LacNAc) units, called poly-LacNAc chains, characterize the histo-blood group i and I antigens, respectively. The transition of straight to branched poly-LacNAc chain (i to I) is determined by the I locus, which expresses 3 IGnT transcripts, IGnTA, IGnTB, and IGnTC. Our previous investigation demonstrated that the i-to-I transition in erythroid differentiation is regulated by the transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha).

Expression of the human Sd(a) beta-1,4-N-acetylgalactosaminyltransferase II gene is dependent on the promoter methylation status.

It has been noted that the expression of Sd(a), including its antigenic structure, the beta-1,4-N-acetylgalactosyltransferase II (beta4GalNAcT-II) activity responsible for its formation, and the Sd(a) beta4GalNAcT-II mRNA transcript, is drastically reduced in oncogenetic processes in gastrointestinal tissues. Markedly reduced metastatic potential has been demonstrated in colon and gastric cancer cells transfected with the Sd(a) beta4GalNAcT-II gene. In this study, a putative CpG island encompassing the promoter and exon 1 regions in the human Sd(a) beta4GalNAcT-II gene was identified, and the investigation of DNA methylation of the Sd(a) gene promoter region demonstrated a clear association between the methylation status of the CpG island promoter and expression of the Sd(a) gene in gastrointestinal cancer cell lines.

I branching formation in erythroid differentiation is regulated by transcription factor C/EBPalpha.

The histo-blood group i and I antigens have been characterized as straight and branched repeats of N-acetyllactosamine, respectively, and the conversion of the straight-chain i to the branched-chain I structure on red cells is regulated to occur after birth. It has been demonstrated that the human I locus expresses 3 IGnT transcripts, IGnTA, IGnTB, and IGnTC, and that the last of these is responsible for the I branching formation on red cells. In the present investigation, the K-562 cell line was used as a model to show that the i-to-I transition in erythroid differentiation is determined by the transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha), which enhances transcription of the IGnTC gene, consequently leading to formation of the I antigen.