scholarly journals Bhlhe40/Sirt1 Axis-Regulated Mitophagy Is Implicated in All-Trans Retinoic Acid-Induced Spina Bifida Aperta

2021 ◽  
Vol 9 ◽  
Author(s):  
Lu Zhao ◽  
Dan Liu ◽  
Wei Ma ◽  
Hui Gu ◽  
Xiaowei Wei ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Spina Bifida ◽  
Neural Tube ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Neural Tube Closure ◽  
Luciferase Reporter ◽  
All Trans Retinoic Acid ◽  
Spina Bifida Aperta ◽  
First Time

Neural tube defects (NTDs) are the most severe congenital malformations that result from failure of neural tube closure during early embryonic development, and the underlying molecular mechanisms remain elusive. Mitophagy is the best-known way of mitochondrial quality control. However, the role and regulation of mitophagy in NTDs have not yet been elucidated. In this study, we used an all-trans retinoic acid (ATRA)-induced rat model to investigate mitophagy and its underlying mechanism in spina bifida aperta (SBA). The results of western blot, immunofluorescence and RT-qPCR analyses indicated that mitophagy was impaired and Sirt1 was downregulated in SBA. Administration of resveratrol-a strong specific Sirt1 activator-activated Sirt1, thus attenuating autophagy suppression and ameliorating SBA. RNA-sequencing and bioinformatics analysis results indicated that transcriptional regulation played an important role in NTDs. A luciferase reporter assay was performed to demonstrate that the transcription factor Bhlhe40 directly bound to and negatively regulated Sirt1 expression. Further, we discovered that the Bhlhe40/Sirt1 axis regulated mitophagy in neural stem cells. Collectively, our results for the first time demonstrate that Bhlhe40/Sirt1 axis regulated mitophagy is implicated in ATRA-induced SBA. Our findings provide new insights into pathogenesis of NTDs and a basis for potential therapeutic targets for NTDs.

scholarly journals All-Trans Retinoic Acid Enhances Chemosensitivity to 5-FU by Targeting miR-378c/E2F7 Axis in Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Ji Li ◽  
Qing Xiang ◽  
Mei Wang ◽  
Hongchang Zhang ◽  
Rong Liang
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Vital Role ◽  
Luciferase Reporter ◽  
Inhibitory Effects ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Diphenyltetrazolium Bromide ◽  
Life Threatening ◽  
Hct116 Cells

Colorectal carcinoma (CRC), a life-threatening malignancy, has been found to present resistance to 5-fluorouracil (5-FU) and cause a poor prognosis for patients. Previous studies have proved that all-trans retinoic acid (ATRA) could inhibit the development of CRC cells. In addition, miR-378c was discovered to exert a vital role in various cancers. In this study, we utilized MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), transwell assay, and flow cytometry to confirm that ATRA was able to enhance the inhibitory effects of 5-FU on HCT116 cells effectively by promoting cell apoptosis. Then, ENCORI database (http://starbase.sysu.edu.cn/) was employed to predict that miR-378c was downregulated dramatically in CRC and E2F7 was the direct target of miR-378c. QRT-PCR (quantitative real-time polymerase chain reaction) was conducted to verify that the expression level of miR-378c was decreased while E2F7 expression was upregulated in CRC tissues compared with para-carcinoma tissues. Additionally, treatment of 5-FU combined with ATRA could increase miR-378c expression, whereas it decreased the expression of E2F7. Dual-Luciferase Reporter assay results revealed that miR-378c could regulate the load of E2F7 by binding to its 3′UTR directly. Furthermore, miR-378c inhibitor or vector with E2F7 partially counteracted the effects of 5-FU combined with ATRA on viability, migration, invasion, and apoptosis of HCT116 cells. In conclusion, our study aims to confirm that ATRA enhances chemosensitivity to 5-FU of patients with CRC and expound the potential molecular mechanisms.

Discontinuity of primary and secondary neural tube in spina bifida induced by retinoic acid in mice

Teratology ◽  
1990 ◽  
Vol 41 (3) ◽  
pp. 257-274 ◽  
Author(s):  
Yoshiko Yasuda ◽  
Hiroyoshi Konishi ◽  
Takahide Kihara ◽  
Takashi Tanimura
Keyword(s):  
Retinoic Acid ◽  
Spina Bifida ◽  
Neural Tube

Genesis and prevention of spinal neural tube defects in the curly tail mutant mouse: involvement of retinoic acid and its nuclear receptors RAR-beta and RAR-gamma

Development ◽  
1995 ◽  
Vol 121 (3) ◽  
pp. 681-691
Author(s):  
W.H. Chen ◽  
G.M. Morriss-Kay ◽  
A.J. Copp
Keyword(s):  
Retinoic Acid ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
In Situ Hybridisation ◽  
Tail Bud ◽  
Retinoic Acid Signalling ◽  
All Trans Retinoic Acid ◽  
Posterior Neuropore ◽  
Computerised Image Analysis ◽  
Curly Tail

A role for all-trans-retinoic acid in spinal neurulation is suggested by: (1) the reciprocal domains of expression of the retinoic acid receptors RAR-beta and RAR-gamma in the region of the closed neural tube and open posterior neuropore, respectively, and (2) the preventive effect of maternally administered retinoic acid (5 mg/kg) on spinal neural tube defects in curly tail (ct/ct) mice. Using in situ hybridisation and computerised image analysis we show here that in ct/ct embryos, RAR-beta transcripts are deficient in the hindgut endoderm, a tissue whose proliferation rate is abnormal in the ct mutant, and RAR-gamma transcripts are deficient in the tail bud and posterior neuropore region. The degree of deficiency of RAR-gamma transcripts is correlated with the severity of delay of posterior neuropore closure. As early as 2 hours following RA treatment at 10 days 8 hours post coitum, i.e. well before any morphogenetic effects are detectable, RAR-beta expression is specifically upregulated in the hindgut endoderm, and the abnormal expression pattern of RAR-gamma is also altered. These results suggest that the spinal neural tube defects which characterise the curly tail phenotype may be due to interaction between the ct gene product and one or more aspects of the retinoic acid signalling pathway.

Anesthesia for Neonatal Myelomeningocele

2021 ◽  
pp. 209-214
Author(s):  
Anna Clebone
Keyword(s):  
Spinal Cord ◽  
Cerebrospinal Fluid ◽  
Spina Bifida ◽  
Neural Tube ◽  
Fetal Development ◽  
Vertebral Column ◽  
Bony Defect ◽  
Spinal Nerves ◽  
Spina Bifida Aperta ◽  
Human Fetal Development

Myelomeningocele, also known as spina bifida aperta (often shortened to the nonspecific name “spina bifida”) is a congenital disorder of the spine. In infants with a myelomeningocele, the neural tube has not closed, and the vertebral arches have not fused during development, leading to spinal cord and meningeal herniation through the skin. Because of the high potential for injury and infection of the exposed spinal cord, which could lead to lifetime disability, these lesions are typically repaired within 24 to 48 hours after birth. A myelomeningocele occurs before day 28 of human fetal development and is an abnormality in which the posterior neural tube closes incompletely. The outcome is a vertebral column deformity, through which the meningeal-lined sac herniates. After the bony defect is created, the hypothesized mechanism of meningeal herniation is that the pulsations of cerebrospinal fluid act progressively to balloon out the spinal cord. If the sac is filled with spinal nerves or the spinal cord, it is known as a myelomeningocele; if the sac is empty, it is called a meningocele.

scholarly journals LncRNA DANCR functions as a competing endogenous RNA to regulate RAB1A expression by sponging miR-634 in glioma

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Dawei Xu ◽  
Jian Yu ◽  
Guojun Gao ◽  
Guangjian Lu ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Tumor Grade ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Biological Functions ◽  
Advanced Tumor ◽  
Rna Immunoprecipitation

Long noncoding RNA (lncRNA) differentiation antagonizing nonprotein coding RNA (DANCR) plays important regulatory roles in many solid tumors. However, the effect of DANCR in glioma progression and underlying molecular mechanisms were not entirely explored. In the present study, we determined the expression of DANCR in glioma tissues and cell lines using qRT-PCR and further defined the biological functions. Furthermore, we used luciferase reporter assay, Western blot, and RNA immunoprecipitation (RIP) to explore the underlying mechanism. Our results showed that DANCR was significantly up-regulated in glioma tissues and cell lines (U251, U118, LN229, and U87MG). High DANCR expression was correlated with advanced tumor grade. Inhibition of DANCR suppressed the glioma cells proliferation and induced cells arrested in the G0/G1 phase. In addition, we verified that DANCR could directly interact with miR-634 in glioma cells and this interaction resulted in the inhibition of downstream of RAB1A expression. The present study demonstrated that DANCR/miR-634/RAB1A axis plays crucial roles in the progression of glioma, and DANCR might potentially serve as a therapeutic target for the treatment of glioma patients.

scholarly journals From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6425-6437 ◽  
Author(s):  
Sai-Juan Chen ◽  
Guang-Biao Zhou ◽  
Xiao-Wei Zhang ◽  
Jian-Hua Mao ◽  
Hugues de Thé ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Magic Bullet ◽  
Therapeutic Effects ◽  
New Paradigm ◽  
Therapeutic Benefits ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia–retinoic acid receptor α (PML-RARα) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARα, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RARα for degradation through its RARα moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine.

scholarly journals Retinoic acid-induced spina bifida: evidence for a pathogenetic mechanism

Development ◽  
1990 ◽  
Vol 108 (1) ◽  
pp. 73-81 ◽  
Author(s):  
A.J. Alles ◽  
K.K. Sulik
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Spina Bifida ◽  
Nile Blue ◽  
Vital Staining ◽  
Primitive Streak ◽  
Histological Techniques ◽  
Stage Of Development ◽  
Spina Bifida Aperta ◽  
Posterior Neuropore

Treatment of C57Bl/6J mice with three successive doses of all-trans retinoic acid (28 mg kg-1 body weight) on 8 day, 6 h (8d,6h), 8d,12h, and 8d,18h of gestation resulted in a high incidence (79%, 31/39 fetuses) of spina bifida with myeloschisis (spina bifida aperta) in near term fetuses. Twelve hours following the last maternal dose (9d,6h), the caudal aspects of treated embryos, were abnormal, with eversion of the neural plate at the posterior neuropore, as compared to its normal concavity in comparably staged control specimens. This eversion persisted in affected embryos through the time that the posterior neuropore should normally close. The distribution of cell death in control and experimental embryos was determined using vital staining with Nile blue sulphate and with routine histological techniques. Twelve hours following the maternal dosing regimen, experimental embryos showed evidence of excessive cell death, predominantly in the mesenchyme associated with the primitive streak and in the endoderm of the tail gut, both of which are readily identifiable sites of physiological cell death at this stage of development. In addition, the presumptive trunk neural crest cells located in the dorsal midline, cranial to the posterior neuropore, exhibited a marked amount of cell death in the experimental embryos. We propose that the major factor in the generation of spina bifida in this model is excessive cell death in the tail gut and mesenchyme ventral to the neuroepithelium of the posterior neuropore.(ABSTRACT TRUNCATED AT 250 WORDS)

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