RESUMO
Accumulation of advanced glycation end-products (AGEs) in the brain contributes significantly to cognitive impairment in patients with diabetes by disrupting the post-mitotic state of neuronal cells, thereby triggering ectopic cell cycle re-entry (CCR) and subsequent neuronal apoptosis. Cinnamaldehyde (CINA), a potential mitigator of cognitive impairment due to its blood glucose-lowering properties, warrants exploration for its role in counteracting diabetes-related neurological damage. In this study, we examined the neuroprotective effect of CINA on AGE-damaged SH-SY5Y human neuroblastoma cells differentiated in vitro. We investigated the impact of CINA on AGE-induced neuronal CCR and apoptosis, finding that it substantially suppressed aberrant DNA replication, precluded cells from entering the mitotic preparatory phase, and diminished apoptosis. Additionally, CINA inhibited the expression of eIF4E without altering S6K1 phosphorylation. These findings indicate that CINA safeguards neuronal cells from AGE-related damage by preventing abnormal CCR, preserving the post-mitotic state of neuronal cells, and reducing AGE-induced apoptosis, potentially through the inhibition of eIF4E-controlled cell proliferation. Our results highlight the prospective utility of CINA in managing diabetic neuropathy.
Assuntos
Acroleína , Apoptose , Ciclo Celular , Produtos Finais de Glicação Avançada , Neurônios , Fármacos Neuroprotetores , Acroleína/análogos & derivados , Acroleína/farmacologia , Humanos , Produtos Finais de Glicação Avançada/metabolismo , Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ciclo Celular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Linhagem Celular Tumoral , Neuropatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Replicação do DNA/efeitos dos fármacos , Fosforilação/efeitos dos fármacosRESUMO
Amyloid ß-protein(Aß) deposition in the brain is directly responsible for neuronal mitochondrial damage of Alzheimer's disease(AD) patients. Mitophagy, which removes damaged mitochondria, is a vital mode of neuron protection. Ginsenoside Rg_1(Rg_1), with neuroprotective effect, has displayed promising potential for AD treatment. However, the mechanism underlying the neuroprotective effect of Rg_1 has not been fully elucidated. The present study investigated the effects of ginsenoside Rg_(1 )on the autophagy of PC12 cells injured by Aß_(25-35) to gain insight into the neuroprotective mechanism of Rg_1. The autophagy inducer rapamycin and the autophagy inhi-bitor chloroquine were used to verify the correlation between the neuroprotective effect of Rg_1 and autophagy. The results showed that Rg_1 enhanced the viability and increased the mitochondrial membrane potential of Aß-injured PC12 cells, while these changes were blocked by chloroquine. Furthermore, Rg_(1 )treatment increased the LC3â ¡/â protein ratio, promoted the depletion of p62 protein, up-regulated the protein levels of PINK1 and parkin, and reduced the amount of autophagy adaptor OPTN, which indicated the enhancement of autophagy. After the silencing of PINK1, a key regulatory site of mitophagy, Rg_1 could not increase the expression of PINK1 and parkin or the amount of NDP52, whereas it can still increase the LC3â ¡/â protein ratio and promote the depletion of OPTN protein which indicated the enhancement of autophagy. Collectively, the results of this study imply that Rg_1 can promote autophagy of PC12 cells injured by Aß, and may reduce Aß-induced mitochondrial damage by promoting PINK1-dependent mitophagy, which may be one of the key mechanisms of its neuroprotective effect.
Assuntos
Ginsenosídeos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Ginsenosídeos/farmacologia , Humanos , Mitofagia/fisiologia , Células PC12 , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ratos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk) F. H. Chen is a well-known traditional Chinese medicine with a long history and is widely used in the treatment of cerebrovascular disease. Panax notoginseng saponins (PNS) are the main active ingredients in Panax notoginseng (Burk) F. H. Chen, and its injection is used to treat nerve damage caused by cerebral ischemia and other conditions. PNS is thought to alleviate cognitive impairment in patients with Alzheimer's disease; however, its mechanism of action is unclear. AIM OF THE STUDY: We elucidated the role of PNS in attenuating cellular mitochondrial damage caused by amyloid ß (Aß) protein and in protecting cell viability from the perspective of regulating autophagy. By investigating the effects of PNS on the targets regulating mitophagy, we wanted to reveal the autophagy related mechanism by which PNS attenuated Aß damage in neuronal cells. MATERIALS AND METHODS: The effect of PNS on the mitochondrial membrane potential of Aß-injured PC12 cells was detected using flow cytometry, which reflected the alleviating effect of PNS on mitochondrial damage. Using mRFP-GFP-LC3-transfected PC12 cells, the effect of PNS on cellular autophagy flux was observed using laser confocal microscopy. Formation of the intracellular autophagosome was observed using transmission electron microscopy, which reflected the activation of autophagy by PNS. The siPINK1 lentivirus was used to silence the PINK1 gene in PC12 cells to obtain siPINK1-PC12 cells. The effects of PNS on the expression of the PINK1 gene and on the autophagy-related proteins LC3II/â , p62, PINK1, parkin, NDP52, and OPTN were observed to reveal the possible targets of PNS in regulating autophagy. RESULTS: After PNS treatment, the viability of Aß-injured PC12 cells improved and the mitochondrial membrane potential was restored. PNS treatment significantly enhanced the autophagy flux of damaged cells and increased the levels of LC3II/â protein and decreased p62 protein, while significantly improving the structure and mitochondrial morphology of PC12 cells injured by Aß. These changes led to more autophagosomes wrapping around the damaged mitochondria and promoting the depletion of OPTN, a mitophagy receptor. After silencing the PINK1 gene, PNS could not alter the PINK1 gene and protein levels, but could still increase LC3II/â , decrease p62 and OPTN, and significantly increase the amount of parkin. CONCLUSIONS: PNS could enhance the autophagic activity of cells, alleviate mitochondrial damage caused by Aß injury, and protect the activity of PC12 cells. It is possible that enhanced autophagy was achieved by promoting the recruitment of parkin protein to the mitochondrial receptors in a non-PINK1-dependent manner.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Panax notoginseng/química , Fitoterapia , Saponinas/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Células PC12 , Interferência de RNA , Ratos , Saponinas/química , Ubiquitina-Proteína Ligases/genéticaRESUMO
Oocyte in vitro maturation (IVM) is a technology with a long history that was established before IVF. Although it has been studied extensively, the efficiency of IVM has been poor for almost 30 years. In terms of the benefits of IVM, the efficiency and adoption of IVM are being improved by some notable improvements that have occurred in recent years. The establishment of biphasic IVM is the most important advancement in recent years. Biphasic IVM includes the pre-IVM culturing phase and IVM phase. The CNP-mediated pre-IVM culturing system is specifically tailored for non/minimally stimulated immature oocytes, and its efficiency has been shown. This is the most significant improvement made in recent decades in this area. In the clinic, IVM can be used for PCOS patients to avoid the occurrence of ovarian hyperstimulation syndrome (OHSS). Additionally, this method can solve the reproductive problems of some patients with special diseases (resistant ovary syndrome) that cannot be solved by IVF. In most fertility preservation procedures, oocytes in small antral follicles are lost. However, IVM has the ability to capture this kind of oocyte and save reproductive potential. IVM can be easily combined with fertility preservation strategies that have been applied in the clinic and improve the efficiency of fertility preservation. IVM is a useful and attractive technology and may be used widely worldwide in the near future.
Assuntos
Preservação da Fertilidade , Síndrome de Hiperestimulação Ovariana , Síndrome do Ovário Policístico , Feminino , Fertilização in vitro/métodos , Humanos , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/fisiologia , Folículo Ovariano , Síndrome do Ovário Policístico/terapiaRESUMO
PURPOSE: To report a case of successful ovarian stimulation and pregnancy in an infertile woman with Rathke's cleft cyst (RCC). METHODS: This is a case report of a 32-year-old infertile woman with RCC presenting with secondary amenorrhea and hypogonadotropic hypogonadism (HH). Three rounds of ovarian stimulation and ovulation induction by means of HMG and HCG were performed (two before HSG and one after HSG). HSG was performed after two rounds of ovulation induction without pregnancy to assess the fallopian tubes and uterine cavity of the patient. Serum beta-human chorionic gonadotropin (ß-HCG) and ultrasound examination were performed after the third round of ovulation induction to confirm successful pregnancy. RESULTS: HSG revealed that the uterine cavity was normal and that the bilateral fallopian tubes were unobstructed. Four weeks after the third round of ovulation induction, the ß-HCG test was positive (10261 µg/L), and ultrasound examination showed an intrauterine early gestational sac with an embryo (10*7 mm) and a primitive heart tube pulse. CONCLUSIONS: Infertility accompanied by RCC is rare in the clinic. Clarifying the cause of infertility and secondary amenorrhea is very important for achieving a successful pregnancy. This case demonstrates that such infertility can be treated effectively with ovarian stimulation and ovulation induction using HMG and HCG. To the best of our knowledge, this is the first case report of infertility accompanied by RCC.
RESUMO
China and the rest of the world are experiencing an outbreak of the 2019 novel coronavirus disease (COVID-19). Patients with cancer are more susceptible to viral infection and are more likely to develop severe complications, as compared to healthy individuals. The growing spread of COVID-19 presents challenges for the clinical care of patients with gynecological malignancies. Ovarian debulking surgery combined with the frequent need for chemotherapy is most likely why ovarian cancer was rated as the gynecologic cancer most affected by COVID-19. Therefore, ovarian cancer presents a particular challenging task. Concerning the ovarian cancer studies with confirmed COVID-19 reported from large-scale general hospitals in Wuhan, we hold that the treatment plan was adjusted appropriately and an individualized remedy was implemented. The recommendations discussed here were developed mainly based on the experience from Wuhan. We advise that the management strategy for ovarian cancer patients should be adjusted in the light of the local epidemic situation and formulated according to the pathological type, tumor stage and the current treatment phase. Online medical service is an effective and convenient communication platform during the pandemic.
Assuntos
COVID-19/prevenção & controle , Neoplasias Ovarianas/terapia , SARS-CoV-2/isolamento & purificação , COVID-19/epidemiologia , COVID-19/virologia , China/epidemiologia , Feminino , Ginecologia/métodos , Hospitais Gerais , Humanos , Oncologia/métodos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Pandemias , SARS-CoV-2/fisiologiaRESUMO
BACKGROUND: Panax notoginseng saponins (PNS) have been used for neurodegenerative disorders such as cerebral ischemia and Alzheimer's disease (AD). Although increasing evidences show the neuron protective effects of PNS, the vital compounds and their functional targets remain elusive. To explore the potential functional ingredients of PNS for the AD treatment and their molecular mechanisms, an in vitro neuron injured model induced by Aß was investigated, and the potential mechanism was predicted by network pharmacology approach and validated by molecular biology methods. METHODS: Network pharmacology approach was used to reveal the relationship between ingredient-target disease and function-pathway of PNS on the treatment of AD. The active ingredients of PNS were collected from TCMSP, PubChem database, and literature mining in PubMed database. DrugBank and GeneCards database were used to predict potential targets for AD. The STRING database was performed to reveal enrichment of these target proteins, protein-protein interactions, and related pathways. Networks were visualized by utilizing Cytoscape software. The enrichment analysis was performed by the DAVID database. Finally, neuroprotective effect and predictive mechanism of PNS were investigated in an in vitro AD model established by Aß 25-35-treated PC12 cells. RESULTS: An ingredient-target disease and function-pathway network demonstrated that 38 active ingredients were derived from PNS modulated 364 common targets shared by PNS and AD. GO and KEGG analysis, further clustering analysis, showed that mTOR signaling targets were associated with the neuroprotective effects of PNS. In Aß-treated PC12 cells, PNS treatment improved neuroprotective effect, including mTOR inhibition and autophagy activation. CONCLUSIONS: Collectively, the protective effects of PNS on AD-neuron injury are related to the inhibition of mTOR and autophagy activation.
RESUMO
The expression of annexin A5 (ANXA5) was shown to affect the pathogenesis of recurrent pregnancy loss (RPL). In this study, the effects of two haplotypes, M1 and M2, on the transcription efficiency of ANXA5 promoter were explored. Correlation analysis was used to investigate the association between the single-nucleotide polymorphism haplotypes in ANXA5 promoter and the risk of RPL. And a luciferase reporter assay was carried out to study the effects of haplotypes M1 and M2 on the transcription efficiency of the ANXA5 promoter. To study the association between ANXA5 haplotypes and the risk of RPL, real-time polymerase chain reaction, western blot analysis, and immunohistochemistry assays were conducted to observe the expressions of ANXA5 messenger RNA (mRNA) and protein. Compared to M1 haplotype carriers, M2 haplotype carriers were associated with a higher risk of RPL. Additionally, compared to GATGTC haplotype carriers, GATGGC haplotype carriers were associated with a higher risk of RPL. Compared with RPL cases, the incidences of M2 haplotype were lower in both the population control and parous control cases. Furthermore, M2 carriers showed more significantly decreased activity of ANXA5 promoter compared to the carriers of other haplotypes, indicating that the haplotypes of ANXA5 promoter may be used as a potential biomarker to predict the prognosis of RPL. Moreover, the activity of ANXA5 as well as the mRNA/protein expression of ANXA5 was significantly downregulated in RPL patients, indicating that the M2 haplotype significantly increased the risk of RPL. Therefore, haplotype M2 increased the risk of RPL by inhibiting the expression of ANXA5.
Assuntos
Aborto Habitual/genética , Anexina A5/genética , Predisposição Genética para Doença/genética , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Linhagem Celular , Feminino , Genótipo , Células Endoteliais da Veia Umbilical Humana , Humanos , Gravidez , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Fatores de Risco , Adulto JovemRESUMO
The aim of this study is to investigate the potential role of attenuated anti-Müllerian hormone signaling in the pathogenesis of ovarian hyperstimulation syndrome (OHSS). To analyze the expression of AMH and its receptors in human follicular fluid (FF) and granulosa cells (GCs), this study included consenting patients with moderate to severe OHSS (n = 83) and non-OHSS patients (control population, n = 108) undergoing IVF/ICSI treatment between March 2013 and March 2014. AMH concentrations in single FF samples from the OHSS patients were significantly lower than concentrations in samples from the control group. A negative correlation was found between the E2 level and the AMH level in single FF samples. Similarly, a negative correlation was found between the FF AMH level and the number of oocytes retrieved. Although the mRNA expression level of AMH was hardly detectable in GCs, the mRNA expression level of AMHR2 in GCs from OHSS patients was significantly lower than the AMHR2 mRNA expression level in the control population. Based on these results, we established a murine model of controlled ovarian hyperstimulation (COH) using AMHR2-down-regulated mice to demonstrate the potential role of AMH signaling in the progression of OHSS. The knockdown of AMHR2 is capable of significantly increasing the ovarian response to exogenous gonadotropins, leading to several major clinical manifestations of OHSS in the murine model. In conclusion, attenuated AMH signaling increases ovarian sensitivity to COH and the incidence of OHSS in individuals undergoes IVF/ICSI.
RESUMO
To investigate the possible relationship between single nucleotide polymorphisms (SNPs) in the anti-Müllerian hormone (AMH) signaling pathway and the incidence of early OHSS, the genomic DNA was isolated from peripheral blood leukocytes of 122 participants (62 patients with early OHSS and 60 patients without OHSS who underwent IVF/ICSI), and SNPs of the AMH and AMHR2 exons were detected directly. Further more, genotype distribution and allele frequency were analyzed. We found seven types of SNPs in the AMH exons, and two of them were missense mutations (rs10407022 and rs182295886). However, these two missense mutations did not increase the risk of early OHSS (rs10407022, P=0.307, OR=1.552, CI 0.668, 3.608; rs182295886, P=0.442, OR=0.359, CI 0.026, 4.883). While it was observed that participants with the SNP (rs10407022) had a relatively higher ovarian response than those without the SNP. Further more, we did not find any SNPs in exons of AMHR2. In conclusion, we analyzed the pathogenesis of OHSS by first investigating the SNPs in the AMH signaling pathway. There is no association between SNPs in the AMH/AMHR2 signaling pathway and early OHSS in Han Chinese women.