Human Cell最新文献

Cerebral stroke is an acute cerebrovascular disease, which is characterized by significant morbidity, death, and disability rate. Ischemic stroke is more than hemorrhagic stroke and accounts for 60-70% of all strokes. The present study explored the mechanisms of Eucommia ulmoides extract (EUE) in the treatment of ischemic stroke. Middle cerebral artery occlusion (MCAO) mouse models and oxygen and glucose deprivation (OGD) SH-SY5Y cell models were constructed to mimic ischemic stroke, and mice and cells were treated with gradient concentrations of EUE. The neurological function and brain tissue damage in mice were assessed using multiple parameters. Then the iron contents in cerebral tissue samples and neuronal cells were examined, and the expression levels of reactive oxygen species-related indicators and iron metabolism-related proteins were detected. EUE alleviated the ferroptosis process within cerebral tissue samples of MCAO mice and OGD-triggered neuronal cells, thereby mitigating neurological function and brain tissue damage by activating PI3K/Akt pathway. The target drug genes of EUE were searched by network pharmacology and molecular docking and found that the ferroptosis-related gene DDIT4 is the potential EUE-targeted gene in the therapy of ischemic stroke. DDIT4 expression was upregulated within cerebral brain samples of MCAO mice and OGD-triggered neuronal cells, and EUE could inhibit DDIT4 expression. The protective effect of EUE on neuronal cells could be partially reversed by overexpression of DDIT4. Moreover, EUE alleviated ferroptosis and improved neurological function in MCAO mice by suppressing DDIT4 expression and modulating the PI3K/Akt pathway. In conclusion, EUE exerts its neuroprotective effect against cerebral stroke by inhibiting DDIT4 expression and ferroptosis by regulating the PI3K/Akt pathway, and DDIT4 has been predicted to be an underlying therapeutic target for the treatment of ischemic stroke.

Exportin-1 (XPO1) is fundamental in the regulation of nuclear-to-cytoplasm transportation. XPO1 has the ability to transport hundreds of proteins and several different types of mRNAs responsible for proper cellular biology. Deregulation of the XPO1 transportation system aberrantly translocates transcription factors promoting the pathogenesis of diseases including cancer. However, XPO1 has transport-independent functions that involve epigenetic modifications. XPO1 associates with chromatin, recruiting oncogenic fusion proteins to target genes affecting chromatin structure and function. That intriguing association also affects transcriptional activation resulting in oncogenesis. XPO1 also regulates other epigenetic pathways and is epigenetically regulated as well. Herein, we report most recent findings on that topic, and we discuss the mechanisms and the consequences of normal and aberrant XPO1 association with the epigenetic marks.

Wolf-Hirschhorn syndrome (WHS) is a devastating congenital disease caused by deletions on the short arm of chromosome 4 (4p), for which no curative treatments currently exist. To facilitate the development of therapeutic strategies, the development of experimental models of WHS is crucial for investigating its etiology and pathogenesis, which remain elusive. In this study, we successfully generated human induced pluripotent stem cells (hiPSCs) from three fibroblast lines from WHS patients. We then characterized these hiPSCs, along with one hiPSC line previously generated from peripheral blood mononuclear cells, as part of a Japanese nationwide project. All four hiPSC lines exhibited characteristics of self-renewal, pluripotency, and karyotypes with expected 4p deletions. Copy number variation microarray analysis revealed that these WHS-specific hiPSCs carried hemizygous deletions in p15.1-p16.3 regions, commonly encompassing 100 genes. Transcriptome analysis showed that the expression of these genes faithfully reflected hemizygous deletion in these WHS-specific hiPSCs and that these down-regulated genes were associated with the development of neural crest cells. These results indicate that WHS-specific hiPSCs can recapitulate the abnormal genomic structure genes related to and the gene expression profile observed in WHS patients. Given the limited understanding of the molecular pathogenesis of WHS, these cellular resources will be instrumental in modeling disease phenotypes and in advancing novel therapies for this syndrome.

tRNA-derived small RNAs (tsRNAs) are functional non-coding RNAs that play crucial roles in transcriptional, translational, and epigenetic regulation. Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation, and its core mechanisms involve dysregulated iron homeostasis, redox imbalance, and lipid peroxidation. Emerging evidence indicates that tsRNAs serve as pivotal regulators of ferroptosis by targeting key components of the ferroptosis pathway. This regulatory interplay critically influences the activation or suppression of ferroptosis in various human diseases, including non-alcoholic steatohepatitis, perioperative neurocognitive disorders, acute kidney injury, non-small cell lung cancer, gastric cancer, diabetic kidney disease, atrial fibrillation, acute pancreatitis, depression, and acute lung injury, thereby affecting disease pathogenesis, progression, and therapeutic responses. This review summarizes the mechanisms underlying the interplay between tsRNAs and ferroptosis in human diseases and highlights the potential of tsRNAs as novel regulators of ferroptosis, providing insights into disease mechanisms.

The excessive inflammatory cascade in sepsis represents a major cause of multiorgan injuries, including sepsis-associated acute kidney injury (SAKI). Following the bioinformatics prediction, this study aims to investigate the role of ornithine decarboxylase 1 (ODC1) in macrophage phenotype in SAKI. C57BL/6 J mice and mouse bone marrow-derived macrophages or THP-1 cells were subjected to lipopolysaccharide (LPS) treatments to generate septic models. RT-qPCR and western blot assays revealed a reduced expression pattern of ODC1 in the kidney of mice and the BMDMs following LPS challenges. Upregulation of ODC1 ameliorated kidney injury, reduced M1 polarization of macrophages, and alleviated inflammatory cytokine secretion. Moreover, this upregulation inactivated the nuclear factor-kappa B signaling and enhanced macrophage autophagy while reducing pyroptosis. KLF6, highly expressed in septic mice, was found to repress ODC1 transcription by binding to its promoter. Silencing of KLF6 similarly promoted macrophage autophagy and inhibited pyroptosis, ameliorating kidney injury and inflammation in mice. These effects were, however, negated by the additional ODC1 silencing. Collectively, this study suggests that KLF6-mediated ODC1 loss inhibits macrophage autophagy while promoting pyroptosis, thus resulting in inflammation and progression of SAKI.

The liver is the largest internal organ. Several critical functions are attributed to the liver which include metabolism, synthesis of serum proteins, excretion, detoxification, and various physiological processes essential for maintaining body homeostasis. Its unique regenerative capacity helps the liver to restore itself fully after injury. This process involves all hepatocytes with or without the involvement of stem cells. The function of the liver is known to be regulated by circadian rhythm, which includes feeding-fasting cycles and the maintenance of the suprachiasmatic nucleus (SCN) that regulates as a master clock. The normal functioning of the liver is critical to the overall maintenance of homeostasis as it serves as a peripheral clock, suggesting a potential link between the SCN and liver. Aberrations in these circadian rhythms have been linked to various chronic hepatic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), which can lead to Hepatocellular carcinoma (HCC). This mini review explores the significance of circadian rhythm in liver function, with a focus on the role of melatonin and nuclear receptors such as Retinoic acid receptor-related orphan receptor-alpha (RORα), which is a known melatonin receptor critical to sustaining these rhythms that can influence biological functions, including immune system functioning, cell growth, and differentiation. Further, RORα is identified as one of the key regulators of inflammation and acts as a potential tumor suppressor, particularly in the context of HCC. This review explores the interplay between RORα, melatonin, and circadian rhythm and discusses the underpinnings that offer insights into the role of circadian rhythm disruption in HCC development and novel therapeutic strategies targeting circadian rhythm modulations to mitigate HCC.

Angelman syndrome is a rare neurodevelopmental disorder caused by the loss of function of the maternally inherited UBE3A gene within the chr15q11-q13 region. This gene is subjected to a tissue-specific form of genomic imprinting leading to the silencing of the paternal allele in neurons. Angelman syndrome can result from various (epi)genetic mechanisms, with paternal uniparental disomy of chromosome 15 (patUPD15) being one of the rarest and least studied due to the absence of suitable models. To address this gap, we generated three independent induced pluripotent stem cell (iPSC) lines from individuals with Angelman syndrome caused by patUPD15, alongside genetically matched unaffected familial controls. Peripheral blood mononuclear cells (PBMCs) were reprogrammed into iPSCs using a non-integrative Sendai virus-based approach expressing the Yamanaka factors. All iPSC lines underwent rigorous quality control, confirming stem cell identity, trilineage differentiation potential, and genetic and epigenetic integrity. This newly established iPSC toolkit provides a powerful platform to investigate the molecular underpinnings of Angelman syndrome caused by patUPD15, paving the way for future translational research and therapeutic development tailored for this understudied form of the disorder.

Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare and aggressive subtype of cervical adenocarcinoma characterized by intrinsic resistance to chemotherapy and poor clinical outcomes due to the lack of effective treatment options. To address this critical unmet need, we established a novel GAS-derived cell line, KGAS, from ascitic fluid collected from a patient with recurrent GAS. Short tandem repeat (STR) analysis confirmed the genetic identity between the primary tumor and the cell line. Upon transplantation into immunocompromised mice, KGAS cells formed tumors that expressed Claudin-18 and MUC6, clinically recognized markers of GAS. Furthermore, KGAS cells exhibited marked resistance to paclitaxel and carboplatin, showing significantly reduced growth inhibition compared to HeLa cells. We also established a paclitaxel- and carboplatin-resistant subline, rKGAS, and performed microRNA (miRNA) sequencing to explore the molecular basis of acquired chemoresistance. Seventeen differentially expressed miRNAs were identified between KGAS and rKGAS cells. Upregulated miRNAs in rKGAS were predicted to target oncogenes such as BCL2, MET, SIRT1, and VEGFA, whereas downregulated miRNAs were associated with tumor suppressor genes, including IGF1R, TNFAIP3, and MTOR. The KGAS and rKGAS cell lines represent valuable preclinical models for elucidating the molecular mechanisms of chemoresistance and malignant progression in cervical GAS, and may contribute to the development of novel therapeutic strategies for this challenging cancer subtype.

The Switch/Sucrose Nonfermentable (SWI/SNF) complexes are chromatin remodeling factors that consist of multiple protein subunits. Each subunit plays a distinct role in gene regulation and is aberrantly expressed in tumors, such as neuroendocrine neoplasms (NENs). BRG1-associated factor 53B (BAF53B), which is also known as ACTL6B, is a neuron-specific subunit that acts as a regulator during neurogenesis. Because the BAF53B expression pattern in tumors is unknown, the present study investigated the expression in cell lines and tissues. Publicly available transcriptome data indicated that BAF53B mRNA was highly expressed in NEN-derived cell lines. We performed immunohistochemical staining on tissue microarrays of different types of NENs with neuroendocrine (NE) marker expression (n = 117) (small cell lung carcinoma (SCLC)lung carcinoid (LC), gastroenteropancreatic-NEN (GEP-NEN), esophageal neuroendocrine carcinoma (ENEC), medullary thyroid carcinoma (MTC), neuroblastoma (NB), and pheochromocytoma (PHEO)) and non-NENs (n = 178). While few positive cells were observed in many cases of non-NENs (e.g., lung adenocarcinoma), positive expression was found in cases of NENs (SCLC (14/19, 73.7%), LC (12/16, 75.0%), GEP-NEN (4/9, 44.4%), ENEC (1/2, 50.0%), MTC (24/27, 88.9%), NB (18/20, 90.0%), and PHEO (16/24, 66.7%)). In NCI-H889 cells, BAF53B knockdown did not affect the cellular viability, and its effect on NE marker expression was only marginal. However, a gene expression microarray analysis suggested that BAF53B-regulated genes were associated with the development and progression of NENs. Our analysis revealed that BAF53B was an immunohistochemical marker for specific NENs, indicating its potentially important role in the pathogenesis.

Myocardial fibrosis is a complex pathological process that often leads to myocardial dysfunction, heart failure, and ultimately, death. A critical contributor to the development of cardiac fibrosis is the endothelial-to-mesenchymal transition (EndMT). Apigenin, a natural compound derived from Matricaria chamomilla, has shown potential anti-fibrotic effects, although its precise mechanism of action is not fully understood. This study investigated the effects of apigenin (API) on EndMT and myocardial fibrosis using an in vitro human coronary artery endothelial cell EndMT model and an in vivo animal model of fibrosis. At appropriate concentrations, apigenin significantly inhibited TGF-β1-induced EndMT and myocardial fibrosis without affecting cell viability. Mechanistically, we found that apigenin suppressed ribosome biogenesis in coronary endothelial cells. Through differential gene screening, GTP-binding protein 4 (GTPBP4) was identified as a key target gene regulating ribosome biogenesis during the progression of myocardial fibrosis. Our results indicate that GTPBP4 plays a pivotal role in the apigenin-mediated inhibition of both ribosome biogenesis and EndMT in these cells. By downregulating GTPBP4 expression, apigenin suppressed EndMT, alleviated myocardial fibrosis, improved cardiac function, and reduced biomarkers of myocardial injury. These findings demonstrate for the first time that apigenin mitigates myocardial fibrosis and EndMT by inhibiting GTPBP4 expression, positioning apigenin as a promising therapeutic candidate for the prevention and treatment of myocardial fibrosis.