Genes to Cells : Devoted to Molecular & Cellular Mechanisms

Metformin is an anti-diabetic drug. Metformin mainly inhibits gluconeogenesis in the liver and reduces blood sugar. In addition to the anti-diabetic effects, many studies have revealed that metformin has anti-inflammatory effects. Various molecules were suggested to be the target of the metformin's anti-inflammatory effects. However, the conclusion is not clear. Metformin is related to a number of molecules and the identification of the main target in anti-inflammatory effects leads to the understanding of inflammation and metformin...

Low-grade neuroepithelial tumors are major causes of drug-resistant focal epilepsy. Clinically, these tumors are defined as low-grade epilepsy-associated neuroepithelial tumors (LEATs). The BRAF V600E mutation is frequently observed in LEAT and linked to poor seizure outcomes. However, its molecular role in epileptogenicity remains elusive. To understand the molecular mechanism underlying the epileptogenicity in LEAT with the BRAF V600E genetic mutation (BRAF V600E-LEAT), we conducted RNA sequencing (RNA-seq) analysis using surgical specimens of BRAF V600E-LEAT obtained and stored at a single institute...

The cell-assisted lipotransfer technique, integrating adipose-derived mesenchymal stem cells (ADMSCs), has transformed lipofilling, enhancing fat graft viability. However, the multipotent nature of ADMSCs poses challenges. To improve safety and graft vitality and to reduce unwanted lineage differentiation, this study refines the methodology by priming ADMSCs into preadipocytes-unipotent, self-renewing cells. We explored the impact of fibroblast growth factor-1 (FGF-1), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF), either alone or in combination, on primary human ADMSCs during the proliferative phase...

Transient receptor potential melastatin 2 (TRPM2) assembles into tetramers to function as an oxidative stress-sensitive Ca2+ channel at the surface membrane. Limited information is currently available on the 10 protein isoforms of mouse TRPM2 (mTRPM2) identified. This study investigated whether these isoforms function as Ca2+ channels and examined their effects on full-length mTRPM2 activity using the HEK 293 cell exogenous expression system. Only full-length mTRPM2, isoform 1 localized to the surface membrane and was activated by oxidative stress...

In eukaryotes, single cells in a population display different transcriptional profiles. One of the factors regulating this heterogeneity is the chromatin state in each cell. However, the mechanisms of epigenetic chromatin regulation of specific chromosomal regions remain unclear. Therefore, we used single-cell tracking system to analyze IMD2. IMD2 is located at the subtelomeric region of budding yeast, and its expression is epigenetically regulated by heterochromatin fluctuations. Treatment with mycophenolic acid, an inhibitor of de novo GTP biosynthesis, triggered a decrease in GTP, which caused heterochromatin fluctuations at the IMD2 locus...

α-Synuclein (α-Syn)-positive intracellular fibrillar protein deposits, known as Lewy bodies, are thought to be involved in the pathogenesis of Parkinson's disease (PD). Although recent lines of evidence suggested that extracellular α-Syn secreted from pathogenic neurons contributes to the propagation of PD pathology, the precise mechanism of action remains unclear. We have reported that extracellular α-Syn caused sphingosine 1-phosphate (S1P) receptor type 1 (S1PR1) uncoupled from Gi and inhibited downstream G-protein signaling in SH-SY5Y cells, although its patho/physiological role remains to be clarified...

Hypoxia-inducible factor 1 (HIF1) is a transcription factor that is stabilized under hypoxia conditions via post-translational modifications. HIF1 regulates tumor malignancy and metastasis by gene transcriptions, such as Warburg effect and angiogenesis-related genes, in cancer cells. However, the HIF1 downstream genes show varied expressional patterns in different cancer types. Herein, we performed the hierarchical clustering based on the HIF1 downstream gene expression patterns using 1406 cancer cell lines crossing 30 types of cancer to understand the relationship between HIF1 downstream genes and the metastatic potential of cancer cell lines...

Mitophagy is programmed selective autophagy of mitochondria and is important for mitochondrial quality control and cellular homeostasis. Mitochondrial dysfunction and impaired mitophagy are closely associated with various diseases, including heart failure and diabetes. To better understand the pathophysiological role of mitophagy, we generated doxycycline-inducible mitophagy mice using a synthetic mitophagy adaptor protein consisting of an outer mitochondrial membrane targeting sequence and an engineered LIR...

Insertion sequence (IS)-excision enhancer (IEE) promotes the excision of ISs in the genome of enterohemorrhagic Escherichia coli O157. Because IEE-dependent IS excision occurs in the presence of transposase, the process of IS transposition may be involved in IS excision; however, little is understood about the molecular mechanisms of IS excision. Our in vitro analysis revealed that IEE exhibits DNA-dependent ATPase activity, which is activated by branched DNA. IEE also catalyzes the branch migration of fork-structured DNA...

Blackcurrant (Ribes nigrum L.) is a classical fruit that has long been used to make juice, jam, and liqueur. Blackcurrant extract is known to relieve cells from DNA damage caused by hydrogen peroxide (H2 O2 ), methyl methane sulfonate (MMS), and ultraviolet (UV) radiation. We found that blackcurrant extract (BCE) stabilizes the ribosomal RNA gene cluster (rDNA), one of the most unstable regions in the genome, through repression of noncoding transcription in the intergenic spacer (IGS) which extended the lifespan in budding yeast...

Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor, promotes the proliferation and migration of bladder cancer cells. CD271 knockdown decreased proliferation in both adherent and spheroid cultures, and vice versa when CD271 was overexpressed in bladder cancer cell lines. CD271 depletion impaired tumorigenicity in vivo. Migration activity was reduced by CD271 knockdown and TAT-Pep5, a known CD271-Rho GDI-binding inhibitor...

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in the de novo GTP biosynthesis pathway. Recent studies suggest that IMPDH2, an isoform of IMPDH, can localize to specific subcellular compartments under certain conditions and regulate site-specific GTP availability and small GTPase activity in invasive cancer cells. However, it is unclear whether IMPDH2 plays a site-specific regulatory role in subcellular functions in healthy cells. In this study, we focused on brain cells and examined the localization pattern of IMPDH2...

Suppressor of cancer cell invasion (SCAI) acts as a transcriptional repressor of serum response factor (SRF)-mediated gene expression by binding to megakaryoblastic leukemia (MKL)/myocardin-related transcription factor (MRTF), which is an SRF transcriptional coactivator. Growing evidence suggests that SCAI is a negative regulator of neuronal morphology, whereas MKL2/MRTFB is a positive regulator. The mRNA expression of SCAI is downregulated during brain development, suggesting that a reduction in SCAI contributes to the reduced suppression of SRF-mediated gene induction, thus increasing dendritic complexity and developing neuronal circuits...

Assay for Transposase-Accessible Chromatin using high-throughput sequencing (ATAC-seq) is the popular technique using next-generation sequencing to measure chromatin accessibility and identify open chromatin regions. While read alignment shape information of next-generation sequencing data with intensity information has been used in various bioinformatics methods, few studies have focused on pure shape information alone. In this study, we investigated what types of ATAC-seq read alignment shapes are observed for the promoter region and whether the pure shape information was related or unrelated to other gene features...

The hydrogen peroxide (H2 O2 )-producing NADPH oxidase Nox4, forming a heterodimer with p22phox , is expressed in a variety of cells including those in the heart to mediate adaptive responses to cellular stresses such as hypoxia. Since Nox4 is constitutively active, H2 O2 production is controlled by its protein abundance. Hypoxia-induced Nox4 expression is observed in various types of cells and generally thought to be regulated at the transcriptional level. Here we show that hypoxia upregulates the Nox4 protein level and Nox4-catalyzed H2 O2 production without increasing the Nox4 mRNA in rat H9c2 cardiomyocytes...

Irgb6 is a priming immune-related GTPase (IRG) that counteracts Toxoplasma gondii. It is known to be recruited to the low virulent type II T. gondii parasitophorous vacuole (PV), initiating cell-autonomous immunity. However, the molecular mechanism by which immunity-related GTPases become inactivated after the parasite infection remains obscure. Here, we found that Thr95 of Irgb6 is prominently phosphorylated in response to low virulent type II T. gondii infection. We observed that a phosphomimetic T95D mutation in Irgb6 impaired its localization to the PV and exhibited reduced GTPase activity in vitro...

The mitotic cohesin complex necessary for sister chromatid cohesion and chromatin loop formation shows local and global association to chromosomes in response to DNA double-strand breaks (DSBs). Here, by genome-wide binding analysis of the meiotic cohesin with Rec8, we found that the Rec8-localization profile along chromosomes is altered from middle to late meiotic prophase I with cleavage-independent dissociation. Each Rec8-binding site on the chromosome axis follows a unique alternation pattern with dissociation and probably association...

The c-Jun N-terminal kinase-associated leucine zipper protein (JLP), a scaffold protein of mitogen-activated protein kinase signaling pathways, is a multifunctional protein involved in a variety of cellular processes. It has been reported that JLP is overexpressed in various types of cancer and is expected to be a potential therapeutic target. However, whether and how JLP overexpression affects non-transformed cells remain unknown. Here, we aimed to investigate the effect of JLP overexpression on chromosomal stability in human non-transformed cells and the mechanisms involved...

Glyoxalase I (GLO I), a major enzyme involved in the detoxification of the anaerobic glycolytic byproduct methylglyoxal, is highly expressed in various tumors, and is regarded as a promising target for cancer therapy. We recently reported that piceatannol potently inhibits human GLO I and induces the death of GLO I-dependent cancer cells. Pyruvate kinase M2 (PKM2) is also a potential therapeutic target for cancer treatment, so we evaluated the combined anticancer efficacy of piceatannol plus low-dose shikonin, a potent and specific plant-derived PKM2 inhibitor, in two GLO I-dependent cancer cell lines, HL-60 human myeloid leukemia cells and NCI-H522 human non-small-cell lung cancer cells...

Avians have thrombocytes in their blood circulation rather than mammalian platelets. However, many details of thrombocyte characteristics have not been determined. Here, chicken thrombocytes were isolated, and extracellular vesicle (EV) production was investigated. The thrombocyte-specific markers cd41 and cd61 were expressed in the yolk sac at 24 h. According to the embryonic developmental stage, the cd41-expressing tissues changed from the yolk sac to the bone marrow and spleen. Accordingly, the bone marrow and spleen were the main tissues producing thrombocytes in adult chickens...