Skeletal dysplasias (SDs) comprise a series of severe congenital disorders that have strong clinical heterogeneity and usually attribute to diverse genetic variations. The pathogenesis of more than half of SDs remains unclear. Additionally, the clinical manifestations of fetal SDs are ambiguous, which poses a big challenge for accurate diagnosis. In this study, eight unrelated families with fetal SD were recruited and subjected to sequential tests including chromosomal karyotyping, chromosomal microarray analysis (CMA), and trio whole-exome sequencing (WES). Sanger sequencing and quantitative fluorescence PCR (QF-PCR) were performed as affirmative experiments. In six families, a total of six pathogenic/likely pathogenic variations were identified in four genes including SLC26A2, FGFR3, FLNB, and TMEM38B. These variations caused disorders following autosomal dominant or autosomal recessive inheritance patterns, respectively. The results provided reliable evidence for the subsequent genetic counseling and reproductive options to these families. With its advantage in variation calling and interpreting, trio WES is a promising strategy for the investigation of fetal SDs in cases with normal karyotyping and CMA results. It has considerable prospects to be utilized in prenatal diagnosis.
Stem cells (SCs) receive inductive cues from the surrounding microenvironment and cells. Limited molecular evidence has connected tissue-specific mesenchymal stem cells (MSCs) with mesenchymal transit amplifying cells (MTACs). Using mouse incisor as the model, we discover a population of MSCs neibouring to the MTACs and epithelial SCs. With Notch signaling as the key regulator, we disclose molecular proof and lineage tracing evidence showing the distinct MSCs contribute to incisor MTACs and the other mesenchymal cell lineages. MTACs can feedback and regulate the homeostasis and activation of CL-MSCs through Delta-like 1 homolog (Dlk1), which balances MSCs-MTACs number and the lineage differentiation. Dlk1 ’s function on SCs priming and self-renewal depends on its biological forms and its gene expression is under dynamic epigenetic control. Our findings can be validated in clinical samples and applied to accelerate tooth wound healing, providing an intriguing insight of how to direct SCs towards tissue regeneration.
Abstract. Osteosarcoma (OS) is the most commonly diagnosed tumor of the bones in children and young adults. Even with conventional therapies the 5-year survival rate is ~65% in patients with OS. Considering the side effects and aggressiveness of malignant bone tumors, research is focussing on multi-targeted strategies in treatment. Cucurbitacin B, a triterpenoid compound has been demonstrated to induce apoptosis in various cancer cell types. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling cascades and mitogen activated protein kinases (MAPK) signalling cascades are critical regulators of tumorigenesis. The present study assessed the influence of cucurbitacin B on the viability and expression of MAPKs and proteins of the JAK2/STAT3 cascades in human OS cells (U-2 OS). Cucurbitacin B (20-100 µM) significantly reduced cell viability (P<0.05) and induced apoptosis, as assessed by MTT and Annexin V/propidium iodide staining, along with inhibiting cell migration. Gelatin zymography revealed supressed activities of matrix metalloproteinase (MMP-)2 and 9. Furthermore, cucurbitacin B effectively upregulated the apoptotic pathway and caused the effective inhibition of MAPK signalling and JAK2/STAT3 cascades. Multifold suppression of vascular endothelial growth factor by cucurbitacin B was also observed, indicating inhibition of angiogenesis. Thus, by downregulating major pathways-MAPK and JAK2/STAT3 and MMPs, cucurbitacin B has potent anti-proliferative and anti-metastatic effects that require further investigation with regards to cancer treatment.
Background Zhu‐Tokita‐Takenouchi‐Kim syndrome is a severe multisystem developmental disorder characterized by intellectual disability, developmental delay, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. This syndrome is caused by heterozygous pathogenic variants in the SON gene at chromosome 21q22.1. Objectives The aim of this study was to investigate the pathogenesis of a 4‐year‐old Chinese child who displayed severe intellectual disability, delayed psychomotor development, and facial dysmorphism. Methods A sequential detection including chromosome karyotyping, chromosome microarray analysis (CMA), and whole‐exome sequencing (WES) was performed on this child. The familial verification of WES result was conducted by Sanger sequencing. Results A de novo frameshift variant SON : c.5230delC (p.Arg1744ValfsTer29) was identified in the proband. The identical variant was not found in his family members. The frequencies of this variant in gnomAD/gnomAD_EAS databases were both none. Conclusions This study substantiates that SON : c.5230delC (p.Arg1744ValfsTer29) is a pathogenic variant of Zhu‐Tokita‐Takenouchi‐Kim syndrome and it is the first time to report Zhu‐Tokita‐Takenouchi‐Kim syndrome in China.
Long-term poor glycemic control negatively affects macrovascular and microvascular diseases, as well as wound restoration. Buckwheat is a good source of rutin (quercetin-3-O-rutoside) and has benefits in regulating blood sugar. This study was to evaluate the antioxidant and anti-inflammatory effects of rutin on wound healing in streptozotocin-induced hyperglycemic rats. Eighteen male Wistar rats were randomly divided into three groups: normal (NDM), hyperglycemic (DM), and hyperglycemic with rutin (DMR). After induction of hyperglycemia for 2 days, a 15 × 15 mm wound was induced on the back of each rat. Intraperitoneal injection of rutin significantly ameliorated diabetes-induced body weight loss and improved metabolic dysfunctions of hyperglycemic rats. Based on appearance and histopathological staining, rutin promotes wound healing and inhibits production of inflammatory cells. The immunoblotting data indicated that rutin promotes production of antioxidant enzymes induced by nuclear factor erythroid 2-related factor 2 (NRF2), inhibits the expression of matrix metalloproteinases (MMPs) regulated by NF-κB, and decreases the expression of vascular endothelial growth factor (VEGF). It also promotes the expression of neurogenic-related protein (UCH-L1). The aforementioned results indicated that rutin reduces oxidative stress and inflammatory response in hyperglycemic rats, promoting wound healing and subsequently reducing the risk of wound ulcers.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU) is one of a doctors’ first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF) is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL) and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU-mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC.
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