Human Cell最新文献

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.

Age-related eye diseases (AREDs) are the leading cause of visual impairment in the elderly, affecting the structure of the anterior and posterior segments of the eye, significantly reducing the quality of life of patients, and even leading to irreversible blindness. Typical AREDs include age-related cataract (ARC), dry eye disease (DED), age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR), the global prevalence of which continues to rise, becoming a serious public health concern. SIRT1 is an NAD + dependent deacetylase, which plays an important physiological regulatory role in ocular tissues, mainly affecting gene expression and various cellular processes by regulating the acetylation status of substrate proteins. Studies have shown that SIRT1 plays a key role in oxidative stress, inflammation, autophagy, apoptosis and metabolism, and its expression or activity decreases can accelerate cell senescence and promote the occurrence and development of AREDs. In addition, SIRT1 expression levels and changes in its activity have been shown to be strongly associated with AREDs, making it a potential target for disease intervention and therapy. Therefore, this review systematically summarizes the biological role and regulatory mechanism of SIRT1 in AREDs, and explored its potential value as a therapeutic target, providing theoretical basis for future drug development and clinical transformation.

B-cell non-Hodgkin lymphoma (B-NHL) is a diverse group of aggressive lymphoid malignancies characterized by its molecular complexity. This study investigated the role of the upstream stimulatory factor 1 (USF1)-ribosomal protein S6 kinase B2 (RPS6KB2) axis in B-NHL progression through the AKT/HDM2 (also known as MDM2)/p53 signaling pathway. Using data from the GEO database, RPS6KB2 was identified to be overexpressed in B-NHL, which was confirmed by RT-qPCR, immunohistochemistry, and western blotting in both B-NHL tissues and cell lines. Functional studies revealed that RPS6KB2 knockdown reduced cell proliferation, migration, and tumor growth, while promoting apoptosis, effects that could be reversed by the AKT activator SC79. Bioinformatics analysis showed that USF1 activated the transcription of RPS6KB2 by directly binding to its promoter region. USF1 downregulation inhibited B-NHL progression, which was rescued by RPS6KB2 overexpression. These findings suggest that the USF1-RPS6KB2 axis contributes to B-NHL progression by activating the AKT/HDM2/p53 pathway.

miR-487a-3p shows the potential of modulating adipose-derived stem cells (ADSCs) differentiation. This study aimed to investigate the mechanism of miR-487a-3p on the osteogenic differentiation of ADSCs. In this work, ADSCs were induced to differentiate into osteoblasts. miR-487a-3p were regulated by miRNA mimics or inhibitors in ADSCs. Wnt family member 5A (WNT5A) siRNA was used to reverse miR-487a-3p inhibitor-induced effects on WNT5A expression in ADSCs. Fat mass and obesity-associated protein (FTO) in ADSCs were altered by shRNAs or overexpression vectors. Calcium nodule, ALP activity, and biomarkers of osteogenic differentiation (OD) were investigated. Rats received ovariectomy (OVX) to construct osteoporosis (OP) model, followed by ADSCs transplantation. Histopathological changes, bone histomorphometry, and detection of OD biomarkers were performed. We found that osteogenesis induced a decrease in miR-487a-3p expression and an increase in FTO expression. miR-487a-3p upregulation inhibited the OD of ADSCs, including decreases in calcium nodule formation, ALP activity, and OD biomarkers. miR-487a-3p downregulation showed the opposite role in OD. miR-487a-3p negatively regulated WNT5A in ADSCs. WNT5A silence reversed the effect of miR-487a-3p downregulation on OD. FTO silence caused the increase in m6A of pri-miR-487a. FTO overexpression inhibited DGCR8 recruitment in pri-miR-487a, and reversed the effect of miR-487a-3p upregulation in OD. ADSCs transplantation improved OP symptom in rats, including improvement of femur tissue, increase in percent bone volume and trabecular number, and upregulation in OD biomarkers. miR-487a-3p downregulation enhanced the therapeutic role of ADSC in rats with OP. Collectively, FTO regulated pri-miR-487a maturation via m6A-dependent pathway, which altered the WNT5A-mediated osteogenesis of ADSCs.