RESUMO
Depression, recognized globally as a primary cause of disability, has its pathogenesis closely related to neuroinflammation and neuronal damage. Arctiin (ARC), the major bioactive component of Fructus arctii, has various pharmacological activities, such as anti-inflammatory and neuroprotective effects. Building on previous findings that highlighted ARC's capability to mitigate depression by dampening microglial hyperactivation and thereby reducing neuroinflammatory responses and cortical neuronal damage in mice, the current study delves deeper into ARC's therapeutic potential by examining its impact on hippocampal neuronal damage in depression. Utilizing both chronic unpredictable mild stress (CUMS)-induced depression model in mice and corticosterone (CORT)-stimulated PC12 cell model of neuronal damage, the techniques including Nissl staining, immunohistochemistry, western blotting, ELISA, lactate dehydrogenase assays, colony formation assays, immunofluorescence staining and molecular docking were employed to unravel the mechanisms behind ARC's neuroprotective effects. The findings revealed that ARC not only mitigates hippocampal neuropathological damage and reduces serum CORT levels in CUMS-exposed mice but also enhances cell activity while reducing lactate dehydrogenase release in CORT-stimulated PC12 cells. ARC attenuated neuroinflammatory responses and neuronal apoptosis by inhibiting the overactivation of the P2X7 receptor (P2X7R)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, similar to the effect of A438079 (P2X7R antagonist). Interestingly, pretreatment with A438079 blocked the neuroprotective effect of ARC. Computer modeling predicted that both ARC and A438079 have strong binding with P2X7R and they have the same binding site. These results suggested that ARC may exert a neuroprotective role by binding to P2X7R, thereby inhibiting the P2X7R/NLRP3 inflammasome signaling pathway.
RESUMO
OBJECTIVE: To assess the efficacy and safety of Sanjie Analgesic Capsule (SAC) in Chinese patients with endometriosis-associated pain. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 15 centers between November 2013 and July 2017 in China. Eligible 323 patients with endometriosis were randomized at a 3:1 ratio to the SAC group (241 cases) and placebo group (82 cases) by stratified block randomization. Patients in the SAC or placebo groups were given SAC or placebo 1.6 g 3 times per day, orally, respectively since the first day of menstruation for 3 consecutive menstrual cycles. The primary endpoint was clinical response to dysmenorrhea evaluated using a 10-point Visual Analogue Scale at 3 and 6 months. The secondary endpoint was the pain score evaluated by VAS (chronic pelvic pain, defecation pain, and dyspareunia) at 3 and 6 months, and the pain recurrence rate at 6 months. Adverse events (AEs) were recorded during the study. RESULTS: A total of 241 women were included in the SAC group, and 82 were in the placebo group. Among these women, 217 (90.0%) and 71 (86.6%) completed the intervention, respectively. At 3 months, overall response rate (ORR) was significantly higher in women administered SAC (80.1%) compared with those who received a placebo (30.5%, P<0.01). Six months after treatment, the ORR for dysmenorrhea was 62.7% in the SAC group and 31.7% in the placebo group (P<0.01). Chronic pelvic pain and defecation pain were significantly improved by SAC compared with placebo (both P<0.05). The incidence rates of total AEs events in the SAC and placebo groups were 6.6% and 9.8%, respectively, and no significant difference was shown between the two groups (P=0.339). CONCLUSION: SAC is well-tolerated and may improve dysmenorrhea in women with endometriosis-associated pain. (Trial registration: ClinicalTrials.gov, No. NCT02031523).
Assuntos
Analgésicos , Cápsulas , Medicamentos de Ervas Chinesas , Endometriose , Humanos , Feminino , Endometriose/tratamento farmacológico , Endometriose/complicações , Método Duplo-Cego , Adulto , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/efeitos adversos , Analgésicos/uso terapêutico , Analgésicos/efeitos adversos , Resultado do Tratamento , Dismenorreia/tratamento farmacológico , Dor/tratamento farmacológico , Dor/etiologia , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Medição da Dor , Adulto Jovem , PlacebosRESUMO
In brief: Genes expressed in cumulus cells might be used as markers for competent oocytes/embryos. This study identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos. Abstract: Studies on the mechanisms behind cumulus expansion and cumulus cell (CC) apoptosis are essential for understanding the mechanisms for oocyte maturation. Genes expressed in CCs might be used as markers for competent oocytes and/or embryos. In this study, both in vitro (IVT) and in vivo (IVO) mouse oocyte models with significant difference in cumulus expansion and CC apoptosis were used to identify and validate new genes regulating cumulus expansion and CC apoptosis of mouse oocytes. We first performed mRNA sequencing and bioinformatic analysis using the IVT oocyte model to identify candidate genes. We then analyzed functions of the candidate genes by RNAi or gene overexpression to select the candidate cumulus expansion and CC apoptosis-regulating genes. Finally, we validated the cumulus expansion and CC apoptosis-regulating genes using the IVO oocyte model. The results showed that while Spp1, Sdc1, Ldlr, Ezr and Mmp2 promoted, Bmp2, Angpt2, Edn1, Itgb8, Cxcl10 and Agt inhibited cumulus expansion. Furthermore, Spp1, Sdc1 and Ldlr inhibited CC apoptosis. In conclusion, by using both IVT and IVO oocyte models, we have identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos and for elucidating the molecular mechanisms behind oocyte maturation.
Assuntos
Apoptose , Células do Cúmulo , Perfilação da Expressão Gênica , Oócitos , Animais , Células do Cúmulo/metabolismo , Oócitos/metabolismo , Oócitos/fisiologia , Camundongos , Feminino , Técnicas de Maturação in Vitro de Oócitos , Sindecana-1/metabolismo , Sindecana-1/genética , Oogênese/genética , OsteopontinaRESUMO
Understanding how stress hormones induce apoptosis in oviductal epithelial cells (OECs) and mural granulosa cells (MGCs) can reveal the mechanisms by which female stress impairs embryonic development and oocyte competence. A recent study showed that tissue plasminogen activator (tPA) ameliorates corticosterone-induced apoptosis in MGCs and OECs by acting on its receptors low-density lipoprotein receptor-related protein 1 (LRP1) and Annexin A2 (ANXA2), respectively. However, whether tPA is involved in corticotropin-releasing hormone (CRH)-induced apoptosis and whether it uses the same or different receptors to inhibit apoptosis induced by different hormones in the same cell type remains unknown. This study showed that CRH triggered apoptosis in both OECs and MGCs and significantly downregulated tPA expression. Moreover, tPA inhibits CRH-induced apoptosis by acting on ANXA2 in both OECs and MGCs. While ANXA2 inhibits apoptosis via phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling, LRP1 reduces apoptosis via mitogen-activated protein kinase (MAPK) signaling. Thus, tPA used the same receptor to inhibit CRH-induced apoptosis in both OECs and MGCs, however used different receptors to inhibit corticosterone-induced apoptosis in MGCs and OECs. These data helps understand the mechanism by which female stress impairs embryo/oocyte competence and proapoptotic factors trigger apoptosis in different cell types.
Assuntos
Apoptose , Hormônio Liberador da Corticotropina , Células Epiteliais , Células da Granulosa , Ativador de Plasminogênio Tecidual , Animais , Feminino , Apoptose/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Camundongos , Ativador de Plasminogênio Tecidual/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Oviductos/metabolismo , Oviductos/efeitos dos fármacos , Anexina A2/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Tubas Uterinas/metabolismo , Tubas Uterinas/efeitos dos fármacosRESUMO
BACKGROUND: Infection by Toxoplasma gondii can lead to severe pneumonia, with current treatments being highly inadequate. The NLRP3 inflammasome is one member of the NOD-like receptor family with a pyrin domain, which is crucial in the innate immune defense against T. gondii. Research has shown that resveratrol (RSV) prevents lung damage caused by this infection by inhibiting the T. gondii-derived heat shock protein 70/TLR4/NF-κB pathway, thus reducing the macrophage-driven inflammatory response. However, it should be mentioned that the participation of NLRP3 inflammasome in the immune response to the lung injuries caused by T. gondii infections is not entirely clear. PURPOSE: This study aims to clarify how RSV ameliorates lung damage triggered by Toxoplasma gondii infection, with a particular focus on the pathway involving TLR4, NF-κB, and the NLRP3 inflammasome. METHODS: Both in vitro and in vivo models of infection were developed by employing the RH strain of T. gondii in BALB/c mice and RAW 264.7 macrophage cell lines. The action mechanism of RSV was explored using techniques such as molecular docking, surface plasmon resonance, ELISA, Western blot, co-immunoprecipitation, and immunofluorescence staining. RESULTS: Findings indicate that the suppression of TLR4 or NF-κB impacts the levels of proteins associated with the NLRP3 inflammasome pathway. Additionally, a significant affinity for binding between RSV and NLRP3 was observed. Treatment with RSV led to a marked reduction in the activation and formation of the NLRP3 inflammasome within lung tissues and RAW 264.7 cells, alongside a decrease in IL-1ß concentrations in the bronchoalveolar lavage fluid. These outcomes align with those seen when using the NLRP3 inhibitor CY-09. Moreover, the application of CY-09 prior to RSV negated the latter's anti-inflammatory properties. CONCLUSION: Considering insights from previous research alongside the outcomes of the current investigation, it appears that the TLR4/NF-κB/NLRP3 signaling pathway emerges as a promising target for immunomodulation to alleviate lung injury from T. gondii infection. The evidence gathered in this study lays the groundwork for the continued exploration and potential future clinical deployment of RSV as a therapeutic agent with anti-Toxoplasma properties and the capability to modulate the inflammatory response.
Assuntos
Inflamassomos , Camundongos Endogâmicos BALB C , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pneumonia , Resveratrol , Receptor 4 Toll-Like , Toxoplasma , Resveratrol/farmacologia , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Células RAW 264.7 , Receptor 4 Toll-Like/metabolismo , Pneumonia/tratamento farmacológico , Pneumonia/parasitologia , Toxoplasma/efeitos dos fármacos , NF-kappa B/metabolismo , Toxoplasmose/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/parasitologia , Simulação de Acoplamento Molecular , Feminino , Transdução de Sinais/efeitos dos fármacos , Macrófagos/efeitos dos fármacosRESUMO
Molecular hybridization is a well-established strategy for developing new drugs. In the pursuit of promising photosensitizers (PSs) with enhanced photodynamic therapy (PDT) efficiency, a series of novel 5-fluorouracil (5FU) gallium corrole conjugates (1-Ga-4-Ga) were designed and synthesized by hybridizing a chemotherapeutic drug and PSs. Their photodynamic antitumor activity was also evaluated. The most active complex (2-Ga) possesses a low IC50 value of 0.185 µM and a phototoxic index of 541 against HepG2 cells. Additionally, the 5FU-gallium corrole conjugate (2-Ga) exhibited a synergistic increase in cytotoxicity under irradiation. Excitedly, treatment of HepG2 tumor-bearing mice with 2-Ga under irradiation could completely ablate tumors without harming normal tissues. 2-Ga-mediated PDT could disrupt mitochondrial function, cause cell cycle arrest in the sub-G1 phase, and activate the cell apoptosis pathway by upregulating the cleaved PARP expression and the Bax/Bcl-2 ratios. This work provides a useful strategy for the design of new corrole-based chemo-photodynamic therapy drugs.
Assuntos
Apoptose , Fluoruracila , Gálio , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Fluoruracila/farmacologia , Fluoruracila/química , Fluoruracila/uso terapêutico , Humanos , Gálio/química , Gálio/farmacologia , Animais , Porfirinas/farmacologia , Porfirinas/química , Porfirinas/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêutico , Camundongos , Apoptose/efeitos dos fármacos , Células Hep G2 , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Information on long-term effects of postovulatory oocyte aging (POA) on offspring is limited. Whether POA affects offspring by causing oxidative stress (OS) and mitochondrial damage is unknown. Here, in vivo-aged (IVA) mouse oocytes were collected 9 h after ovulation, while in vitro-aged (ITA) oocytes were obtained by culturing freshly ovulated oocytes for 9 h in media with low, moderate, or high antioxidant potential. Oocytes were fertilized in vitro and blastocysts transferred to produce F1 offspring. F1 mice were mated with naturally bred mice to generate F2 offspring. Both IVA and the ITA groups in low antioxidant medium showed significantly increased anxiety-like behavior and impaired spatial and fear learning/memory and hippocampal expression of anxiolytic and learning/memory-beneficial genes in both male and female F1 offspring. Furthermore, the aging in both groups increased OS and impaired mitochondrial function in oocytes, blastocysts, and hippocampus of F1 offspring; however, it did not affect the behavior of F2 offspring. It is concluded that POA caused OS and damaged mitochondria in aged oocytes, leading to defects in anxiety-like behavior and learning/memory of F1 offspring. Thus, POA is a crucial factor that causes psychological problems in offspring, and antioxidant measures may be taken to ameliorate the detrimental effects of POA on offspring.
Assuntos
Comportamento Animal , Mitocôndrias , Oócitos , Estresse Oxidativo , Animais , Oócitos/metabolismo , Mitocôndrias/metabolismo , Feminino , Camundongos , Masculino , Ovulação , Ansiedade/metabolismo , Ansiedade/patologia , Antioxidantes/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Blastocisto/metabolismo , Senescência Celular , MemóriaRESUMO
Understanding the mechanisms for oocyte maturation and optimizing the protocols for in vitro maturation (IVM) are greatly important for improving developmental potential of IVM oocytes. The miRNAs expressed in cumulus cells (CCs) play important roles in oocyte maturation and may be used as markers for selection of competent oocytes/embryos. Although a recent study from our group identified several new CCs-expressed miRNAs that regulate cumulus expansion (CE) and CC apoptosis (CCA) in mouse oocytes, validation of these findings and further investigation of mechanisms of action in other model species was essential before wider applications. By using both in vitro and in vivo pig oocyte models with significant differences in CE, CCA and developmental potential, the present study validated that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes. We demonstrated that miR-149 and miR-31 targeted SMAD family member 6 (SMAD6) and transforming growth factor ß2 (TGFB2), respectively, in the transforming growth factor-ß (TGF-ß) signaling. Furthermore, both miR-149 and miR-31 increased CE and decreased CCA via activating SMAD family member 2 (SMAD2) and increasing the expression of SMAD2 and SMAD family member 4. In conclusion, the present results show that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes by activating the TGF-ß signaling, suggesting that they might be used as markers for pig oocyte quality.
Assuntos
Células do Cúmulo , Técnicas de Maturação in Vitro de Oócitos , MicroRNAs , Oócitos , Animais , Feminino , Células do Cúmulo/fisiologia , Técnicas de Maturação in Vitro de Oócitos/veterinária , Técnicas de Maturação in Vitro de Oócitos/métodos , MicroRNAs/genética , MicroRNAs/metabolismo , Oócitos/fisiologia , Suínos , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Study on corrole photosensitizers (PSs) for photodynamic therapy (PDT) has made remarkable progress. Targeted delivery of PSs is of great significance for enhancing therapeutic efficiency, decreasing the dosage, and reducing systemic toxicity during PDT. The development of PSs that can be specifically delivered to the subcellular organelle is still an attractive and challenging work. Herein, we synthesize a series of azide-modified corrole phosphorus and gallium complex PSs, in which phosphorus corrole 2-P could not only precisely target the endoplasmic reticulum (ER) with a Pearson correlation coefficient (PCC) up to 0.92 but also possesses the highest singlet oxygen quantum yields (ΦΔ = 0.75). This renders it remarkable PDT activity at a very low dosage (IC50 = 23 nM) towards HepG2 tumor cell line while ablating solid tumors in vivo with excellent biosecurity. Furthermore, 2-P exhibits intense red fluorescence (ΦF = 0.25), outstanding photostability, and a large Stokes shift (190 nm), making it a promising fluorescent probe for ER. This study provides a clinically potential photosensitizer for cancer photodynamic therapy and a promising ER fluorescent probe for bioimaging.
Assuntos
Neoplasias , Fotoquimioterapia , Porfirinas , Azidas , Fluorescência , Fósforo , Corantes Fluorescentes/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Retículo Endoplasmático , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológicoRESUMO
PURPOSE: The adverse health consequences of premarital sex and childhood sexual abuse (CSA) are both global public health problems. Based on a random sample of college students from a Chinese city, this study investigated the relationship between CSA severity and premarital sex among students, focusing on sex differences. METHODS: A total of 2722 college students from 4 schools in Luzhou were recruited by multistage random sampling. Self-administered questionnaires were used to measure CSA experiences and premarital sex. Binary logistic regression analyses were conducted to analyse the relationship between CSA and premarital sex. RESULTS: The prevalence of CSA was 9.39%, and that of mild, moderate and severe CSA was 4.04%, 2.90% and 2.46%, respectively. The premarital sex reporting rate was 22.42%. After adjusting for confounding variables, CSA was positively associated with premarital sex. Notably, a cumulative effect of CSA on premarital sex was observed among students. Further stratification analyses showed that males who experienced CSA had a higher premarital sex rate than females, and this sex difference was also observed among students with different CSA severities. CONCLUSION: CSA and its severity were associated with premarital sex among college students. Furthermore, this association was stronger for males than females. Therefore, it is important to emphasize CSA prevention, especially for boys. These findings can promote understanding of the effects of CSA on premarital sex, and CSA prevention and intervention strategies should consider CSA severity and sex differences.
Assuntos
Abuso Sexual na Infância , Caracteres Sexuais , Comportamento Sexual , Feminino , Humanos , Masculino , China/epidemiologia , Estudantes , População do Leste AsiáticoRESUMO
It is known that the oocyte has a limited capacity to acquire and metabolize glucose, and it must rely on cumulus cells (CCs) to take up glucose and produce pyruvate for use to produce ATP through oxidative phosphorylation. We therefore propose that miRNAs might regulate glucose metabolism (GM) in CCs and might be used as markers for oocyte quality assessment. Here, mouse CC models with impaired glycolysis or pentose phosphate pathway (PPP) were established, and miRNAs targeting the key enzymes in glycolysis/PPP were predicted using the miRNA target prediction databases. Expression of the predicted miRNAs was compared between CCs with normal and impaired glycolysis/PPP to identify candidate miRNAs. Function of the candidate miRNAs was validated by transfecting CCs or cumulus-oocyte-complexes (COCs) with miRNA inhibitors and observing effects on glucose metabolites of CCs and on competence of oocytes. The results validated that miR-23b-3p, let-7b-5p, 34b-5p and 145a-5p inhibited glycolysis, and miR-24-3p, 3078-3p,183-5p and 7001-5p inhibited PPP of CCs. Our observation using a more physiologically relevant model (intact cultured COCs) further validated the four glycolysis-targeting miRNAs we identified. Furthermore, miR-let-7b-5p, 34b-5p and 145a-5p may also inhibit PPP, as they decreased the production of glucose-6-phosphate. In conclusion, miRNAs play critical roles in GM of CCs and may be used as markers for oocyte quality assessment. Summary sentence: We identified and validated eight new miRNAs that inhibit glycolysis and/or pentose phosphate pathways in cumulus cells (CCs) suggesting that miRNAs play critical roles in glucose metabolism of CCs and may be used for oocyte quality markers.
Assuntos
Células do Cúmulo , Glucose , Glicólise , MicroRNAs , Animais , Células do Cúmulo/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Camundongos , Glucose/metabolismo , Feminino , Glicólise/fisiologia , Via de Pentose Fosfato , Oócitos/metabolismoRESUMO
Seeking an excellent electrocatalyst is the trickiest issue for the application of urea electro-oxidation and electro-detection. Phosphorus-doped nickel plating on carbon fibers (Ni-P/CF) is synthesized by simple electroless plating. SEM results exhibit that the Ni-P densely and uniformly grows onto the surface of carbon fibers (CF), forming carbon fibers-like nanoarchitectures. Benefiting from the carbon fibers-like nano architectures with abundant exposed active sites on the surface of CF, electron transfer can be synchronously facilitated, and Ni-P/CF displays superior urea electrooxidation (UOR) performance with potentials of 1.40 V to reach 100 mA cm-2. Impressively, it can maintain at 20 mA cm-2 for 48 h without evident activity attenuation, demonstrating robust durability. Cycle stability shows that the voltage has only increased by 10 mV at 300 mA cm-2 from the 10th to 20000th cycles. Most importantly, Ni-P/CF at a length of 100 cm with good reproducibility was successfully synthesized, denoting great potential for large-scale industrial production. Therefore, this work not only affords cost-effective tactics for urea-rich wastewater degradation but also can achieve practical medical applications.
RESUMO
There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the role of RNA-binding proteins (RBPs) in EGFR-associated metastasis of HNSCC remains unclear. In this study, we reveal that RBPs, specifically nucleolin (NCL) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), correlated with the mesenchymal phenotype of HNSCC. The depletion of RBPs significantly attenuated EGF-induced HNSCC metastasis. Intriguingly, the EGF-induced EMT markers, such as fibronectin, were regulated by RBPs through the ERK and NF-κB pathway, followed by the enhancement of mRNA stability of fibronectin through the 5' untranslated region (5'-UTR) of the gene. The upregulation of fibronectin triggered the integrin signaling activation to enhance tumor cells' attachment to endothelial cells and increase endothelial permeability. In addition, the concurrence of EGFR and RBPs or EGFR and fibronectin was associated with overall survival and disease-free survival of HNSCC. The in vivo study showed that depletion of NCL, hnRNPA2B1, and fibronectin significantly inhibited EGF-promoted extravasation of tumor cells into lung tissues. The depletion of fibronectin or treatment with integrin inhibitors dramatically attenuated EGF-induced HNSCC metastatic nodules in the lung. Our data suggest that the RBPs/fibronectin axis is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis.
Assuntos
Fibronectinas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fibronectinas/genética , Células Endoteliais , Fator de Crescimento Epidérmico , Receptores ErbB/genética , Regiões 5' não Traduzidas , Integrinas , Neoplasias de Cabeça e Pescoço/genéticaRESUMO
BACKGROUND: We previously reported that REBACIN effectively eliminates persistent high-risk human papillomavirus (hrHPV) infection. Here, we conducted a prospective multicenter cohort study to evaluate the safety and effectiveness of REBACIN, taking into account factors such as specific hrHPV subtype and patient's age. METHODS: According to inclusion/exclusion criteria and participant willingness, 3252 patients were divided into REBACIN group while 249 patients into control group. Patients in REBACIN group received one course treatment of intravaginal administration of REBACIN while no treatment in control group. After drug withdrawal, participants in both groups were followed up. RESULTS: The clearance rate of persistent hrHPV infection in REBACIN group was 60.64%, compared to 20.08% in control group. Specifically, the clearance rates for single-type infection of HPV16 or HPV18 were 70.62% and 69.23%, respectively, which was higher than that of HPV52 (59.04%) or HPV58 (62.64%). In addition, the single, double, and triple/triple+ infections had a clearance rate of 65.70%, 53.31%, and 38.30%, respectively. Moreover, 1635 patients under 40 years old had a clearance rate of 65.14%, while it was 55.08% for 1447 patients over 40 years old. No serious adverse effects were found. CONCLUSION: This study confirmed that REBACIN can effectively and safely eliminate persistent hrHPV infection, which the clearance rate of HPV16/18 is higher than that of HPV52/58, the clearance rate of single-type infection is higher than that of multiple-type infections, and the clearance rate in young patients is higher than that in elder patients, providing a guidance for REBACIN application in clearing hrHPV persistent infection in real-world settings. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry Registration Number: ChiCTR1800015617 http://www.chictr.org.cn/showproj.aspx?proj=26529 Date of Registration: 2018-04-11.
Assuntos
Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Humanos , Idoso , Adulto , Papillomavirus Humano , Estudos de Coortes , Estudos Prospectivos , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Infecções por Papillomavirus/tratamento farmacológico , Papillomaviridae , GenótipoRESUMO
Pulmonary fibrosis (PF) is a serious progressive fibrotic disease that is characterized by excessive accumulation of extracellular matrix (ECM), thus resulting in stiff lung tissues. Lysyl oxidase (LOX) is an enzyme involved in fibrosis by catalyzing collagen cross-linking. Studies found that the ingredients in schisandra ameliorated bleomycin (BLM)-induced PF, but it is unknown whether the anti-PF of schisandra is related to LOX. In this study, we established models of PF including a mouse model stimulated by BLM and a HFL1 cell model induced by transforming growth factor (TGF)-ß1 to evaluate the inhibition effects of Schisandrin C (Sch C) on PF. We observed that Sch C treatment decreased pulmonary indexes compared to control group. Treatment of Sch C showed a significant reduction in the accumulation of ECM as evidenced by decreased expressions of α-SMA, FN, MMP2, MMP9, TIMP1 and collagen proteins such as Col 1A1, and Col 3A1. In addition, the expression of LOX in the lung tissue of mice after Sch C treatment was effectively decreased compared with the MOD group. The inhibition effects in vitro were consistent with those in vivo. Mechanistic studies revealed that Sch C significantly inhibited TGF-ß1/Smad2/3 and TNF-α/JNK signaling pathways. In conclusion, our data demonstrated that Sch C significantly ameliorated PF in vivo and vitro, which may play an important role by reducing ECM deposition and inhibiting the production of LOX.
Assuntos
Lignanas , Compostos Policíclicos , Fibrose Pulmonar , Animais , Camundongos , Fibrose Pulmonar/tratamento farmacológico , Colágeno , Lignanas/farmacologia , Lignanas/uso terapêutico , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêuticoRESUMO
The mechanisms underlying postovulatory oocyte aging (POA) remain largely unknown. The expression of the calcium-sensing receptor (CaSR) in mouse oocytes and its role in POA need to be explored. Our objective was to observe CaSR expression and its role in the susceptibility to activating stimuli (STAS) in POA mouse oocytes. The results showed that, although none of the newly ovulated oocytes were activated, 40% and 94% of the oocytes recovered 19 and 25 h after human chorionic gonadotropin (hCG) injection were activated, respectively, after ethanol treatment. The level of the CaSR functional dimer protein in oocytes increased significantly from 13 to 25 h post hCG. Thus, the CaSR functional dimer level was positively correlated with the STAS of POA oocytes. Aging in vitro with a CaSR antagonist suppressed the elevation of STAS, and cytoplasmic calcium in oocytes recovered 19 h post hCG, whereas aging with a CaSR agonist increased STAS, and cytoplasmic calcium of oocytes recovered 13 h post hCG. Furthermore, the CaSR was more important than the Na-Ca2+ exchanger in regulating oocyte STAS, and T- and L-type calcium channels were inactive in aging oocytes. We conclude that the CaSR is involved in regulating STAS in POA mouse oocytes, and that it is more important than the other calcium channels tested in this connection.
Assuntos
Cálcio , Receptores de Detecção de Cálcio , Humanos , Animais , Camundongos , Oócitos , Ovulação , Envelhecimento , PolímerosRESUMO
Although ethanol treatment is widely used to activate oocytes, the underlying mechanisms are largely unclear. Roles of intracellular calcium stores and extracellular calcium in ethanol-induced activation (EIA) of oocytes remain to be verified, and whether calcium-sensing receptor (CaSR) is involved in EIA is unknown. This study showed that calcium-free ageing (CFA) in vitro significantly decreased intracellular stored calcium (sCa) and CaSR expression, and impaired EIA, spindle/chromosome morphology and developmental potential of mouse oocytes. Although EIA in oocytes with full sCa after ageing with calcium does not require calcium influx, calcium influx is essential for EIA of oocytes with reduced sCa after CFA. Furthermore, the extremely low EIA rate in oocytes with CFA-downregulated CaSR expression and the fact that inhibiting CaSR significantly decreased the EIA of oocytes with a full complement of CaSR suggest that CaSR played a significant role in the EIA of ageing oocytes. In conclusion, CFA impaired EIA and the developmental potential of mouse oocytes by decreasing sCa and downregulating CaSR expression. Because mouse oocytes routinely treated for activation (18 h post hCG) are equipped with a full sCa complement and CaSR, the present results suggest that, while calcium influx is not essential, CaSR is required for the EIA of oocytes.
Assuntos
Cálcio , Etanol , Camundongos , Animais , Cálcio/metabolismo , Etanol/farmacologia , Oócitos/fisiologia , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , EnvelhecimentoRESUMO
The widespread prevalence of Pelvic Organ Prolapse (POP) and the paucity of ongoing treatments prompted us to develop a unique rat model combining ovariectomy and simulated vaginal delivery. We hypothesized that the tissue changes caused by low hormone levels and mechanical stretch could complement each other. Thus, the combined model can potentially mimic the collagen metabolism of vaginal wall tissue as well as mechanical stretch properties to complement disease progression in POP. Ovariectomy with sequential simulated vaginal delivery was performed on rats in the modeling group. Sham surgeries were performed as control. At 2, 4, and 12 weeks after modeling, the vaginal tissues of rats were evaluated by Masson's trichrome staining, Picro-Sirius red staining, immunohistochemistry, western blotting, and uniaxial tensile tests. Compared to the control group, the vaginal tissues of the model rats showed an atrophic epithelial layer and loose collagen fibers. The smooth muscle fibers were ruptured, smaller in diameter, and disorganized. The ratio of collagen type I/III significantly increased, but the contents of both Collagen I and III decreased. The expression of metalloproteinases 2 and 9 in the tissues increased, and the expression of tissue inhibitors of metalloproteinases 1 and 2 decreased. The tangent modulus of the tissues was significantly increased in the model rats. We verified a novel method to establish a pelvic organ prolapse model in rats. This approach combined the advantages of low hormone levels and mechanical stretch effects.
Assuntos
Prolapso de Órgão Pélvico , Feminino , Humanos , Ratos , Animais , Prolapso de Órgão Pélvico/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Ovariectomia , HormôniosRESUMO
Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that causes pulmonary toxoplasmosis, although its pathogenesis is incompletely understood. There is no cure for toxoplasmosis. Coixol, a plant polyphenol extracted from coix seeds, has a variety of biological activities. However, the effects of coixol on T. gondii infection have not been clarified. In this study, we infected a mouse macrophage cell line (RAW 264.7) and BALB/c mice with the T. gondii RH strain to establish infection models in vitro and in vivo, respectively, to explore protective effects and potential mechanisms of coixol on lung injury caused by T. gondii infection. Anti-T. gondii effects and underlying anti-inflammatory mechanisms of coixol were investigated by real-time quantitative PCR, molecular docking, localized surface plasmon resonance, co-immunoprecipitation, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence microscopy. The results show that coixol inhibits T. gondii loads and T. gondii-derived heat shock protein 70 (T.g.HSP70) expression. Moreover, coixol reduced inflammatory cell recruitment and infiltration, and ameliorated pathological lung injury induced by T. gondii infection. Coixol can directly bind T.g.HSP70 or Toll-like receptor 4 (TLR4) to disrupt their interaction. Coixol prevented overexpression of inducible nitric oxide synthase, tumor necrosis factor-α, and high mobility group box 1 by inhibiting activation of the TLR4/nuclear factor (NF)-κB signaling pathway, consistent with effects of the TLR4 inhibitor CLI-095. These results indicate that coixol improves T. gondii infection-induced lung injury by interfering with T.g.HSP70-mediated TLR4/NF-κB signaling. Altogether, these findings suggest that coixol is a promising effective lead compound for the treatment of toxoplasmosis.
Assuntos
Lesão Pulmonar , Toxoplasma , Toxoplasmose , Animais , Camundongos , Toxoplasma/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Lesão Pulmonar/tratamento farmacológico , Simulação de Acoplamento Molecular , Toxoplasmose/tratamento farmacológico , Transdução de Sinais , Proteínas de Choque Térmico HSP70/metabolismoRESUMO
Although studies indicate that female stress-increased secretion of glucocorticoids impairs oocyte competence and embryo development, by inducing apoptosis of ovarian and oviductal cells, respectively, the mechanisms by which glucocorticoids induce apoptosis of ovarian and oviductal cells are largely unclear. Tissue plasminogen activator (tPA) has been involved in apoptosis of different cell types. However, while some studies indicate that tPA is proapoptotic, others demonstrate its antiapoptotic effects. This study has explored the role and action mechanisms of tPA in corticosterone-induced apoptosis of mouse mural granulosa cells (MGCs) and oviductal epithelial cells (OECs). The results demonstrate that culture with corticosterone significantly increased apoptosis, while decreasing levels of tPA (Plat) mRNA and tPA protein in both MGCs and OECs. Culture with tPA ameliorated corticosterone-induced apoptosis of MGCs and OECs. Furthermore, while tPA protected MGCs from corticosterone-induced apoptosis by interacting with low-density lipoprotein receptor-related protein 1 (LRP1), it protected OECs from the apoptosis by acting on Annexin 2 (ANXA2). In conclusion, tPA is antiapoptotic in both MGCs and OECs, and it protects MGCs and OECs from corticosterone-induced apoptosis by interacting with LRP1 and ANXA2, respectively, suggesting that tPA may use different receptors to inhibit apoptosis in different cell types.