Retinoic acid (RA) is an oxidative metabolite of vitamin A (retinol, ROH) and plays an important role in the spermatogenesis (as in meiosis) of mammals. In mammalian testes, RA, in combination with its retinoic acid receptor (RAR), regulates the expressions of related target genes in various types of cells at different times. It activates meiosis by up-regulating the expressions of the genes that promote meiosis and down-regulate those that inhibit it during spermatogenesis in a specific stage. The results of researches on mammalian spermatogenesis have a great application value in reproductive biology, developmental biology, and reproductive engineering. Therefore, it is of considerable significance to study the signaling pathway of RA-induced meiosis during mammalian spermatogenesis. This article presents an introduction of the RA signal transduction system and its action mechanisms, as well as an overview on the signaling pathway of RA-activated meiosis during spermatogenesis.
Animals ; Humans ; Male ; Meiosis ; Signal Transduction ; Spermatogenesis ; Tretinoin ; metabolism

Meiotic initiation is a critical step in gametogenesis. Recently, some genes required for meiotic initiation have been identified. However, meiosis-initiating factors and the underlying mechanisms are far from being fully understood. We have established a long-term culture system of spermatogonial stem cells (SSCs) and an in vitro model of meiotic initiation using mouse SSCs. Our previous study revealed that the RNA-binding protein RBFOX2 may regulate meiotic initiation, but the role and the mechanism need to be further elucidated. In this study, we constructed RBFOX2 knockdown SSC lines by using lentivirus-mediated gene delivery method, and found that the knockdown SSCs underwent normal self-renewal, mitosis and differentiation. However, they were unable to initiate meiosis when treated with retinoic acid, and they underwent apoptosis. These results indicate that RBFOX2 plays an essential role in meiotic initiation of spermatogonia. This work provides new clues for understanding the functions of RNA-binding proteins in meiotic initiation.
Mice ; Male ; Animals ; Spermatogonia/metabolism* ; Meiosis/genetics* ; Cell Differentiation ; Tretinoin/pharmacology* ; Mitosis ; Testis/metabolism*

Male meiosis is a complex process whereby spermatocytes undergo cell division to form haploid cells. This review focuses on the role of retinoic acid (RA) in meiosis, as well as several processes regulated by RA before cell entry into meiosis that are critical for proper meiotic entry and completion. Here, we discuss RA metabolism in the testis as well as the roles of stimulated by retinoic acid gene 8 (STRA8) and MEIOSIN, which are responsive to RA and are critical for meiosis. We assert that transcriptional regulation in the spermatogonia is critical for successful meiosis.
Animals ; Cell Differentiation/genetics* ; Humans ; Meiosis/drug effects* ; Spermatogenesis/physiology* ; Tretinoin/metabolism*

OBJECTIVETo study the expression of gene associated with retinoid-interferon-induced mortality-19(GRIM-19) in preimplantation embryo of mice and explore its role in embryonic development.

METHODSThe protein and mRNA expressions of GRIM-19 in 2-cell, 4-cell, 8-cell, morula, and blastocyst phases of mice preimplantation embryo were detected by Western blot analysis and Real-time polymerase chain reaction (PCR).

RESULTSGRIM-19 was continuously expressed in every stage of preimplantation embryo of mice. Western blot analysis and Real-time PCR demonstrated a gradual increase of GRIM-19 expression from 2-cell, which reached a peak in 8-cell phase and then decreased progressively.

CONCLUSIONSThe expression of GRIM-19 in mouse preimplantation embryos changes as at different developmental phases. GRIM-19 may play an important role during embryonic development.

Animals ; Blastocyst ; drug effects ; metabolism ; Female ; Interferons ; pharmacology ; Mice ; NADH, NADPH Oxidoreductases ; genetics ; metabolism ; Pregnancy ; RNA, Messenger ; genetics ; Tretinoin ; pharmacology

Animals ; Keratolytic Agents ; pharmacology ; Neural Crest ; embryology ; metabolism ; Signal Transduction ; drug effects ; Tretinoin ; pharmacology ; Zebrafish ; Zebrafish Proteins ; genetics ; metabolism

OBJECTIVE: To investigate the expression of peptidylarginine deiminase 4 (PADI4) during the process of differentiation into granulocyte of NB4 cells induced by all-trans-retinoic acid (ATRA) and whether PADI4 is involved in the inflammatory cytokines expression. METHODS: Granulocyte differentiation model of NB4 cells induced by ATRA was established. The cell morphology changes were observed by Wright-Giemsa staining. The expression of cell differentiation marker CD11b was analyzed by flow cytometry. The mRNA and protein expression of PADI4 was detected by RT-PCR and Western blot, respectively. The expression of tumor necrosis factor (TNF) α and interleukin (IL) 1β was analyzed by ELISA, and also examined with the knockdown of PADI4 expression by siRNA. RESULTS: After NB4 cells induced by ATRA, the cytoplasm increased and the ratio of nuclear to cytoplasmic was reduced. Nuclear dented, and rod-shaped nucleus, lobulated phenomenon increased (P<0.05). Flow cytometry analysis results showed that the cell surface molecule CD11b expression increased (P<0.01). RT-PCR and Western blot showed the expression of PADI4 increased at both transcriptional and translational levels during the process of the differentiation. ELISA showed TNF-α and IL-1β secretion increased in differentiated macrophages, while they could be inhibited by PADI4-specific siRNA. CONCLUSION During the differentiation into granulocyte of NB4 cells induced by ATRA, PADI4 expression increased. Furthermore, PADI4 appeared to play a critical role in inflammatory cytokines secretion.
Cell Differentiation ; Cell Line, Tumor ; Cytokines/metabolism* ; Granulocytes ; Humans ; Leukemia, Promyelocytic, Acute ; Protein-Arginine Deiminase Type 4/metabolism* ; Tretinoin/pharmacology*

OBJECTIVETo explore the mechanism of Alpha-fetoprotein (AFP) effects on hepatocellular carcinoma cells (HCC) resistances apoptosis induced by tumor necrosis factor-related apoptosis inducing-ligand (TRAIL).

METHODSThe expressed alteration of TRAIL receptor-2 (DR5) after the human hepatoma cells line Bel 7402 (AFP-producing) and HLE cells (non-AFP producing) were treated with all trans retinoic acid (ATRA) were determined by Western blot; Interaction of AFP with RAR-beta was analyzed by co-immunoprecipitation (Co-IP); Laser confocal microscopy was used to observe co-localization of AFP and RAR-beta; Short small RNA interfering (RNAi) was applied to knock down the expression of AFP in Bel 7402 cells; The full AFP gene cDNA was inserted into pcDNA3.1 vector and constructed the expressed vector of AFP (named pcDNA3.1-afp); The growth of hepatoma cells was analyzed by MTT.

RESULTSBel 7402 and HLE cells expressed DR5, lowed dosage of ATRA (40mumol/L) had no influence on the expression of DR5 in Bel 7402 cells, but ATRA (160mumol/L) could inhibit the expression of AFP and promote the expression of DR5 significantly; Co-IP indicated that AFP had a property for interacting with RAR-beta; The results also demonstrated AFP co-localization with RAR-beta in cytoplasm of Bel 7202 cells; The expression of DR5 was enhanced while the expression of AFP was knocked down by RNAi. pcDNA3.1-afp vector was transfected into HLE cells, the growth of HLE cells were stimulated and TRAIL cytotoxicity of HLE cells were reduced. But when the expression of AFP was knocked down the sensitivity of Bel 7402 cells to TRAIL was enhanced.

CONCLUSIONSThese data provided that AFP had a capability to interact with RAR-beta and suppressed the expression of DR5. AFP could play pivotal role on hepatoma cells resistance-induced apoptosis by TRAIL.

Apoptosis ; Cell Line, Tumor ; metabolism ; Humans ; Receptors, Retinoic Acid ; metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; metabolism ; TNF-Related Apoptosis-Inducing Ligand ; metabolism ; Tretinoin ; pharmacology ; alpha-Fetoproteins ; metabolism

OBJECTIVE: To explore the effect of cytokine levels on early death and coagulation function of patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: Routine examination was performed on 69 newly diagnosed APL patients at admission. Meanwhile, 4 ml fasting venous blood was extracted from the patients. And then the supernatant was taken after centrifugation. The concentrations of cytokines, lactate dehydrogenase (LDH) and ferritin were detected by using the corresponding kits. RESULTS: It was confirmed that cerebral hemorrhage was a major cause of early death in APL patients. Elevated LDH, decreased platelets (PLT) count and prolonged prothrombin time (PT) were high risk factors for early death (P <0.05). The increases of IL-5, IL-6, IL-10, IL-12p70 and IL-17A were closely related to the early death of newly diagnosed APL patients, and the increases of IL-5 and IL-17A also induced coagulation disorder in APL patients by prolonging PT (P <0.05). In newly diagnosed APL patients, ferritin and LDH showed a positive effect on the expression of IL-5, IL-10 and IL-17A, especially ferritin had a highly positive correlation with IL-5 (r =0.867) and IL-17A (r =0.841). Moreover, there was a certain correlation between these five high-risk cytokines, among which IL-5 and IL-17A (r =0.827), IL-6 and IL-10 (r =0.823) were highly positively correlated. CONCLUSION Elevated cytokine levels in newly diagnosed APL patients increase the risk of early bleeding and death. In addition to the interaction between cytokines themselves, ferritin and LDH positively affect the expression of cytokines, thus affecting the prognosis of APL patients.
Humans ; Leukemia, Promyelocytic, Acute/diagnosis* ; Cytokines/metabolism* ; Interleukin-10 ; Interleukin-17/metabolism* ; Interleukin-6/metabolism* ; Interleukin-5/metabolism* ; Blood Coagulation Disorders ; Ferritins ; Tretinoin

In 1932, Harris, et al., reported that vitamin A had an anti-keratinizing effect on acne vulgaris, and in 1948, Straumfjord, somewhat over-enthusiastically reported that oral use of vitamin A also had a beneficial effect on acne. In spite of studies by Lynch and Cook (1947), and Andrew and Stokoe (1963), which questioned its effectiveness, the original enthusiasm for this regimen has not been completely dampened. Kligman (1969) reported that vitamin A acid (VAA), a metabolic end-product of vitamin A metabolism, produced a peeling effect and when applied topically, was effective in tbe treatment of acne. The mechanism of action of VAA is incompletely understood, however, it is observed to cause, arnong other things, an increase in the speed of proliferation of the cells of the epidermis; dissolution of the intracellular lysosomes; increase in the rate of keratin formation and the conversion of hard keratin to soft keratin; and an increase in the secretion of the sebaceous glands. The effect of VAA in acne treatment is due to the increase in the secretion of the sebaceous glands which prevents the formation of comedones. It is believed that the increased speed of cell division, increased keratinization and softening of the keratin cause a weakening of the intercellular adhesion. These processes cause an acceleration of the flow of cells out of the sebaceoua glands which prevents the formation of comedones and forces existing comedones to the surface of the skin. For this study, thirt:y eight patients with acne vulgaris were selected from among the outpatients of Severance Hospital. They were divided into two groups. The first group was treated with application of vitamin A acid alone. The second group was treated concurrently with topical vitamin A acid and oral tetracycline.
Acceleration ; Acne Vulgaris ; Cell Division ; Epidermis ; Humans ; Lysosomes ; Metabolism ; Outpatients ; Sebaceous Glands ; Skin ; Striae Distensae* ; Tetracycline ; Tretinoin ; Vitamin A

BACKGROUND AND OBJECTIVES: All-trans retinoic acid (RA) is a form of vitamin A analogue that has shown chemopreventive activities in many types of malignancy with the properties that regulate cellular differentiations and suppress malignant proliferations. It is thought that the catabolism of RA is mediated by cytochrome P450RAI (CYP26) and its absorption, effects and catabolism are related to cellular retinol binding proteins (CRBP-I and II) and cellular retinoic acid binding proteins (CRABP-I and II). With eight different squamous cell carcinoma cell lines (AMC-HN-1~-8), we investigated the effects of RA and roles of these proteins in the metabolism and regulatory activity of RA. MATERIALS AND METHODS: Survival fractions of eight AMC-HN cells were analyzed six days after the treating them with 1 nM of RA. Reverse transcription-polymerase chain reactions (RT-PCR) were performed before and 24 hours after the load of 1 nM of RA to detect the expressions of CRBP-I, CRABP-I, CRABP-II, and CYP26. RESULTS: Resistances to RA were detected in AMC-HN-1, -2, -5, and -6 cell lines after RA treatment, and AMC-HN-3, -4, -7, and -8 cell lines showed sensitive responses to RA. Before the addition of RA, expressions of CYP26 were detected in AMC-HN-1, -2, -4, -5, -6, and -7 cell lines and CRBP-I was expressed in AMC-HN-3, 4, 5, 7, and -8. After RA addition, the expressions of CYP26 were enhanced in AMC-HN-2, -5, -6, and -7. In six of eight cell lines, CRABP-I was suppressed and CRABP-II was enhanced after RA treatment. CONCLUSION: These results suggest that CYP26 has a direct correlation with the cellular metabolism of RA in the head and neck squamous cell carcinomas and that CRABP-I and CRABP-II have distinct roles in the regulatory effects of RA. CRBP-I might be an indicator that implies the responsiveness to RA.
Absorption ; Carcinoma, Squamous Cell* ; Cell Line ; Cytochromes ; Head* ; Metabolism* ; Neck* ; Receptors, Retinoic Acid ; Retinol-Binding Proteins, Cellular ; Tretinoin* ; Vitamin A