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Hepatocellular carcinoma (HCC) is one of the most common malignancy, presenting a formidable challenge to the medical community owing to its intricate pathogenic mechanisms. Although current prevention, surveillance, early detection, diagnosis, and treatment have achieved some success in preventing HCC and controlling overall disease mortality, the imperative to explore novel treatment modalities for HCC remains increasingly urgent. Epigenetic modification has emerged as pivotal factors in the etiology of cancer. Among these, RNA N6-methyladenosine (m6A) modification stands out as one of the most prevalent, abundant, and evolutionarily conserved post-transcriptional alterations in eukaryotes. The literature underscores that the dynamic and reversible nature of m6A modifications orchestrates the intricate regulation of gene expression, thereby exerting a profound influence on cell destinies. Increasing evidence has substantiated conspicuous fluctuations in m6A modification levels throughout the progression of HCC. The deliberate modulation of m6A modification levels through molecular biology and pharmacological interventions has been demonstrated to exert a discernible impact on the pathogenesis of HCC. In this review, we elucidate the multifaceted biological functions of m6A modifications in HCC, and concurrently advancing novel therapeutic strategies for the management of this malignancy.
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Adenosina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , RNA/metabolismo , RNA/genéticaRESUMO
BACKGROUND: The most significant cause of treatment failure in chronic myeloid leukemia (CML) is a persistent population of minimal residual cells. Emerging evidences showed that methylation of SHP-1 contributed to Imatinib (IM) resistance. Baicalein was reported to have an effect on reversal of chemotherapeutic agents resistance. However, the molecular mechanism of Baicalein on JAK2/STAT5 signaling inhibition against drug resistance in bone marrow (BM) microenvironment that had not been clearly revealed. METHODS: We co-cultured hBMSCs and CML CD34+ cells as a model of SFM-DR. Further researches were performed to clarify the reverse mechanisms of Baicalein on SFM-DR model and engraftment model. The apoptosis, cytotoxicity, proliferation, GM-CSF secretion, JAK2/STAT5 activity, the expression of SHP-1 and DNMT1 were analyzed. To validate the role of SHP-1 on the reversal effect of Baicalein, the SHP-1 gene was over-expressed by pCMV6-entry shp-1 and silenced by SHP-1 shRNA, respectively. Meanwhile, the DNMT1 inhibitor decitabine was used. The methylation extent of SHP-1 was evaluated using MSP and BSP. The molecular docking was replenished to further explore the binding possibility of Baicalein and DNMT1. RESULTS: BCR/ABL-independent activation of JAK2/STAT5 signaling was involved in IM resistance in CML CD34+ subpopulation. Baicalein significantly reversed BM microenvironment-induced IM resistance not through reducing GM-CSF secretion, but interfering DNMT1 expression and activity. Baicalein induced DNMT1-mediated demethylation of the SHP-1 promoter region, and subsequently activated SHP-1 re-expression, which resulted in an inhibition of JAK2/STAT5 signaling in resistant CML CD34+ cells. Molecular docking model indicated that DNMT1 and Baicalein had binding pockets in 3D structures, which further supported Baicalein might be a small-molecule inhibitor targeting DNMT1. CONCLUSIONS: The mechanism of Baicalein on improving the sensitivity of CD34+ cells to IM might be correlated with SHP-1 demethylation by inhibition of DNMT1 expression. These findings suggested that Baicalein could be a promising candidate by targeting DNMT1 to eradicate minimal residual disease in CML patients. Video Abstract.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Desmetilação , Flavonoides , Mesilato de Imatinib , Simulação de Acoplamento Molecular , Fator de Transcrição STAT5 , Microambiente TumoralRESUMO
The roles of nuclear receptor subfamily 1 group d member 1 (NR1D1) and the circadian clock in liver fibrosis remain unclear. Here, we showed that liver clock genes, especially NR1D1, were dysregulated in mice with carbon tetrachloride (CCl4)-induced liver fibrosis. In turn, disruption of the circadian clock exacerbated experimental liver fibrosis. NR1D1-deficient mice were more sensitive to CCl4-induced liver fibrosis, supporting a critical role of NR1D1 in liver fibrosis development. Validation at the tissue and cellular levels showed that NR1D1 was primarily degraded by N6-methyladenosine (m6A) methylation in a CCl4-induced liver fibrosis model, and this result was also validated in rhythm-disordered mouse models. In addition, the degradation of NR1D1 further inhibited the phosphorylation of dynein-related protein 1-serine site 616 (DRP1S616), resulting in weakened mitochondrial fission function and increased mitochondrial DNA (mtDNA) release in hepatic stellate cell (HSC), which in turn activated the cGMP-AMP synthase (cGAS) pathway. Activation of the cGAS pathway induced a local inflammatory microenvironment that further stimulated liver fibrosis progression. Interestingly, in the NR1D1 overexpression model, we observed that DRP1S616 phosphorylation was restored, and cGAS pathway was also inhibited in HSCs, resulting in improved liver fibrosis. Taken together, our results suggest that targeting NR1D1 may be an effective approach to liver fibrosis prevention and management.
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Relógios Circadianos , Células Estreladas do Fígado , Camundongos , Animais , Metilação , Cirrose Hepática/metabolismo , Fígado , Nucleotidiltransferases , Tetracloreto de Carbono/metabolismo , Tetracloreto de Carbono/farmacologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismoRESUMO
BACKGROUND: Stress urinary incontinence during pregnancy is closely related to the occurrence of postpartum and long-term urinary incontinence. Early pelvic floor management is of great significance in promoting the recovery of pelvic floor tissues in pregnant women. However, effective management of urinary incontinence is far from achievable owing to the low adherence of pregnant women in partaking in pelvic floor rehabilitation. As a comprehensive framework for behavioural theory, the Theoretical Domain Framework allows for comprehensive identification of behavioural determinants. Using Theoretical Domain Framework, this study aimed to identify barriers and enablers of pelvic floor rehabilitation behaviours in pregnant women with stress urinary incontinence. METHODS: A descriptive, qualitative design was used in this study. Face-to-face semi-structured interviews were conducted with pregnant women with stress urinary incontinence based on the Theoretical Domain Framework. The data were analysed using a combination of inductive and deductive methods. RESULTS: Twenty pregnant women with stress urinary incontinence were interviewed. Seven themes were summarised and used to explain the pelvic floor rehabilitation behaviours of pregnant women with stress urinary incontinence. The seven themes were (1) individual knowledge and experience of pelvic floor management, (2) judgments about expected outcomes, (3) interactions of interpersonal situations, (4) environment, resources, and decision-making processes, (5) personal goal-setting and efforts towards behaviour change, (6) emotional influences on decision-making, and (7) personal characteristics. Besides the "Optimism" domain, 13 of the 14 Theoretical Domains Framework domains were found to influence pregnant patients' pelvic floor rehabilitation behaviours after deductive mapping of themes to the Theoretical Domains Framework. In addition, the inductive analysis generated a theme of personal characteristics that did not map to any of the Theoretical Domains Framework domains. CONCLUSIONS: The pelvic floor rehabilitation behaviours of pregnant women with stress urinary incontinence are complex and are affected by many factors. The findings confirm the need for multiple interventions to support pelvic floor management in pregnant women with stress urinary incontinence, focusing on enhancing knowledge and skills in pelvic floor care and using appropriate behaviour change techniques (such as prompts) to provide a supportive environment.
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Incontinência Urinária por Estresse , Incontinência Urinária , Feminino , Humanos , Gravidez , Gestantes , Diafragma da Pelve , Período Pós-Parto , Terapia por Exercício/métodosRESUMO
Three polyphagous pest Liriomyza spp. (Diptera: Agromyzidae) have recently invaded Australia and are damaging horticultural crops. Parasitic wasps are recognized as effective natural enemies of leafmining species globally and are expected to become important biocontrol agents in Australia. However, the hymenopteran parasitoid complex of agromyzids in Australia is poorly known and its use hindered due to taxonomic challenges when based on morphological characters. Here, we identified 14 parasitoid species of leafminers based on molecular and morphological data. We linked DNA barcodes (5' end cytochrome c oxidase subunit I (COI) sequences) to five adventive eulophid wasp species (Chrysocharis pubicornis (Zetterstedt), Diglyphus isaea (Walker), Hemiptarsenus varicornis (Girault), Neochrysocharis formosa (Westwood), and Neochrysocharis okazakii Kamijo) and two braconid species (Dacnusa areolaris (Nees) and Opius cinerariae Fischer). We also provide the first DNA barcodes (5' end COI sequences) with linked morphological characters for seven wasp species, with three identified to species level (Closterocerus mirabilis Edwards & La Salle, Trigonogastrella parasitica (Girault), and Zagrammosoma latilineatum Ubaidillah) and four identified to genus (Aprostocetus sp., Asecodes sp., Opius sp. 1, and Opius sp. 2). Phylogenetic analyses suggest C. pubicornis, D. isaea, H. varicornis, and O. cinerariae are likely cryptic species complexes. Neochrysocharis formosa and Aprostocetus sp. specimens were infected with Rickettsia. Five other species (Cl. mirabilis, D. isaea, H. varicornis, Opius sp. 1, and Opius sp. 2) were infected with Wolbachia, while two endosymbionts (Rickettsia and Wolbachia) co-infected N. okazakii. These findings provide background information about the parasitoid fauna expected to help control the leafminers.
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Dípteros , Vespas , Animais , Filogenia , Vespas/genética , Dípteros/genética , Austrália , Produtos Agrícolas , DNARESUMO
Hypertrophic scar (HS) is a condition characterized by excessive synthesis and deposition of collagen. There are many clinical methods to alleviate HS, but most of them are accompanied by many complications. To investigate the effects of ß-Elemene, extracted from the ginger family plant Wenyujin, on human hypertrophic scar fibroblast (hHSFs). Cultured hHSFs and human normal fibroblasts, observed the effect of ß-Elemene on apoptosis, extracellular matrix, and endoplasmic reticulum stress (ERS) by western blot, Real Time-Polymerase Chain Reaction (RT-PCR), and flow cytometry. Based on our findings, it is clear that ß-Elemene could inhibit the expression of α-smooth muscle actin (α-SMA), collagen I, and fibronectin, reduced collagen deposition. Further studies had found that ß-Elemene could increase the expression of ERS-related proteins CHOP and Calnexin in a dose-dependent manner, thereby promoting the aggregation of cleaved-caspase-3 and inducing hHSFs to undergo poptosis. This process may depend on the regulation of P53. The results of our study indicates that ß-Elemene induced hHSFs to undergo apoptosis though ERS pathway in a P53-dependent manner, which means that our research provided a new strategy for the development of drugs for the treatment of HS.
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Cicatriz Hipertrófica , Apoptose , Células Cultivadas , Cicatriz Hipertrófica/tratamento farmacológico , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/metabolismo , Colágeno/metabolismo , Fibroblastos , Humanos , Sesquiterpenos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
INTRODUCTION AND HYPOTHESIS: Urinary incontinence is a common and burdensome problem amongst women. Although it can be prevented, little progress has been made. Identifying individuals at risk remains the key to the prevention of urinary incontinence. METHODS: Eligible women were enrolled in the obstetric wards of a tertiary maternity hospital in 2020. Urinary incontinence was measured using a well-accepted questionnaire. Logistic regression with a backward stepwise process was used for predictor selection. The discrimination and calibration of the nomogram were measured using the area under the ROC curve (AUC), Hosmer-Lemeshow test and calibration curve respectively. Bootstrapping procedure with 1000 resamples was used for internal validity. A temporal split (7:3) was made and data collected from the later period were used for temporal validation. RESULTS: Seven predictors including birth mode, urinary incontinence before and during pregnancy, place of residence, feeding pattern, parity, and age at first birth remained in the final model. The AUC was 0.757 (95% CI: 0.72-0.80) and 0.759 (95% CI: 0.70-0.82) in the derivation and validation cohorts respectively. No significant differences were detected in the Hosmer-Lemeshow test and calibration curve in both cohorts. CONCLUSIONS: The nomogram proved to be a convenient and reliable tool in the clinical setting for risk assessment of postpartum incontinence, which can be applied during pregnancy and the postnatal period for individual risk estimates of postpartum incontinence.
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Incontinência Urinária , Feminino , Humanos , Estudos Longitudinais , Paridade , Período Pós-Parto , Gravidez , Estudos Prospectivos , Incontinência Urinária/epidemiologia , Incontinência Urinária/prevenção & controleRESUMO
The excessive deposition of extracellular matrix (ECM) is the main characteristic of liver fibrosis, and hepatic stellate cells (HSCs) are the main source of ECM. The removal of activated HSCs has a reversal effect on liver fibrosis. Western blot and MTT analysis indicated that curcumol could relieve hepatic fibrosis by promoting HSCs receptor-interacting protein kinase 1/3 (RIP1/RIP3)-dependent necroptosis. Importantly, autophagy flow was monitored by constructing the mRFP-GFP-LC3 plasmid, and it was found that curcumol cleared activated HSCs in a necroptosis manner that was dependent on autophagy. Our study suggested that the activation of necrosome formed by RIP1 and RIP3 depended on Atg5, and that autophagosomes were also necessary for curcumol-induced necroptosis. Furthermore, microscale thermophoresis and co-immunoprecipitation assay results proved that curcumol could target Sirt1 to regulate autophagy by reducing the acetylation level of Atg5. The HSCs-specific silencing of Sirt1 exacerbated CCl4 -induced liver fibrosis in mice. The deacetylation of Atg5 not only accelerated the accumulation of autophagosomes but also enhanced the interaction between Atg5 and RIP1/RIP3 to induce necroptosis. Overall, our study indicated that curcumol could activate Sirt1 to promote Atg5 deacetylation and enhanced its protein-protein interaction function, thereby inducing autophagy and promoting the necroptosis of HSCs to reduce liver fibrosis.
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Células Estreladas do Fígado , Lisina , Animais , Autofagia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Lisina/metabolismo , Camundongos , Necroptose , Sesquiterpenos , Sirtuína 1/metabolismoRESUMO
Rhamnocitrin (RH) is a bioactive flavonoid of Astragali Radix, which exerts a wide variety of pharmacological effects. However, there are no reports focusing on the therapeutical effects and mechanisms of RH against neuropathic pain (NP). In this study, systematic pharmacology and in vivo experimental approaches were employed to identify the potential targets of RH for treating oxaliplatin-induced NP. Our findings indicated that the therapeutical effect of RH might be closely associated with key genes, including MAPK3, MAPK1, SRC, PTGS2, EGFR, MMP9, and MMP2, as well as potential signaling pathways such as PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and Rap1 signaling pathway. The in vivo experimental findings demonstrated that RH could suppress oxidative stress, inflammatory response, and down-regulate MMP2 and MMP9 expressions to exert its therapeutic effects against NP. This study used network pharmacology and experimental validation to elucidate the potential targets and underlying mechanisms by which RH improves oxaliplatin-induced NP and offer new insight on drug development for NP.
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Medicamentos de Ervas Chinesas , Neuralgia , Medicamentos de Ervas Chinesas/farmacologia , Receptores ErbB , Humanos , Quempferóis , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Farmacologia em Rede , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Oxaliplatina , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
Aedes mosquitoes harboring intracellular Wolbachia bacteria are being released in arbovirus and mosquito control programs. With releases taking place around the world, understanding the contribution of host variation to Wolbachia phenotype is crucial. We generated a Wolbachia transinfection (wAlbBQ) in Aedes aegypti and performed backcrossing to introduce the infection into Australian or Malaysian nuclear backgrounds. Whole Wolbachia genome sequencing shows that the wAlbBQ transinfection is nearly identical to the reference wAlbB genome, suggesting few changes since the infection was first introduced to A. aegypti over 15 years ago. However, these sequences were distinct from other available wAlbB genome sequences, highlighting the potential diversity of wAlbB in natural Aedes albopictus populations. Phenotypic comparisons demonstrate the effects of wAlbB infection on egg hatching and nuclear background on fecundity and body size but no interactions between wAlbB infection and nuclear background for any trait. The wAlbB infection was stable at high temperatures and showed perfect maternal transmission and cytoplasmic incompatibility regardless of the host background. Our results demonstrate the stability of wAlbB across host backgrounds and point to its long-term effectiveness for controlling arbovirus transmission and mosquito populations. IMPORTANCEWolbachia bacteria are being used to control the transmission of dengue virus and other arboviruses by mosquitoes. For Wolbachia release programs to be effective globally, Wolbachia infections must be stable across mosquito populations from different locations. In this study, we transferred Wolbachia (strain wAlbB) to Aedes aegypti mosquitoes with an Australian genotype and introduced the infection to Malaysian mosquitoes through backcrossing. We found that the phenotypic effects of Wolbachia are stable across both mosquito backgrounds. We sequenced the genome of wAlbB and found very few genetic changes despite spending over 15 years in a novel mosquito host. Our results suggest that the effects of Wolbachia infections are likely to remain stable across time and host genotype.
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Aedes/microbiologia , Wolbachia/genética , Animais , Feminino , Resposta ao Choque Térmico , Masculino , Fenótipo , TransfecçãoRESUMO
In November 2019, stem nematode was found on Codonopsis pilosula in Tanchang county, Gansu province, China. The population of stem nematode was identified on the basis of both molecular and morphological methods. The morphological and morphometric characteristics of this nematode population matched with Ditylenchus destructor Thorne, 1945. The sequences of rDNA-ITS and D2/D3 region of 28S-rRNA similarity with the D. destructor. The pathogenicity results revealed the symptom of dry rot on C. pilosula was caused by this nematode. To our knowledge, this is the first report that D. destructor on C. pilosula in China.
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A new cyst-forming nematode, Heterodera microulae sp. n., was isolated from the roots and rhizosphere soil of Microula sikkimensis in China. Morphologically, the new species is characterized by lemon-shaped body with an extruded neck and obtuse vulval cone. The vulval cone of the new species appeared to be ambifenestrate without bullae and a weak underbridge. The second-stage juveniles have a longer body length with four lateral lines, strong stylets with rounded and flat stylet knobs, tail with a comparatively longer hyaline area, and a sharp terminus. The phylogenetic analyses based on ITS-rDNA, D2-D3 of 28S rDNA, and COI sequences revealed that the new species formed a separate clade from other Heterodera species in Goettingiana group, which further support the unique status of H. microulae sp. n. Therefore, it is described herein as a new species of genus Heterodera; additionally, the present study provided the first record of Goettingiana group in Gansu Province, China.
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BACKGROUND & AIMS: Although ferroptosis holds promise as a new strategy for treating hepatocellular carcinoma (HCC), there are several obstacles that need to be overcome. One major challenge is the lack of understanding about the mechanisms underlying ferroptosis. Additionally, while the m6A modification has been shown to regulate various forms of cell death, its role in regulating ferroptosis in HCC has been largely overlooked. Bridging this knowledge gap, our study aimed to elucidate the regulatory influence of m6A modification on HCC ferroptosis. MATERIALS: Dot blot and EpiQuik m6A RNA Methylation Quantitative kit detected changes in overall m6A modification level during ferroptosis in HCC. MeRIP-qPCR and RIP-qPCR identified that the m6A modification of ATG5 mRNA was significant changed. BALB/c nude mice were used to construct xenograft tumor models to verify the phenotypes upon YTHDC2 silencing. In addition, patient-derived organoid models were used to demonstrate that induction of ferroptosis was an effective strategy against HCC. RESULTS: Our study has shown that inducing ferroptosis is a promising strategy for combatting HCC. Specifically, we have found a significant correlation between ferroptosis and high levels of m6A modification in HCC. Notably, we discovered that the elevation of ATG5 mRNA m6A modification mediated by WTAP is dependent on the reading protein YTHDC2. Importantly, inhibition of either WTAP or YTHDC2 effectively prevented ferroptosis and suppressed HCC development in both in vitro and in vivo models. CONCLUSION: Our study revealed that WTAP upregulates ATG5 expression post-transcriptionally in an m6A-YTHDC2-dependent manner, thereby promoting the translation of ATG5 mRNA during ferroptosis in HCC. These findings have significant implications for the development of innovative and effective therapeutic approaches for HCC treatment.
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Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/genética , Ferroptose/genética , Camundongos Nus , Neoplasias Hepáticas/genética , Autofagia/genética , Modelos Animais de Doenças , RNA MensageiroRESUMO
Background and Aims: Development of fibrosis in chronic liver disease requires activation of hepatic stellate cells (HSCs) and leads to a poor outcome. Artesunate (Art) is an ester derivative of artemisinin that can induce ferroptosis in HSCs, and activated transcriptional factor 3 (ATF3) is an ATF/CREB transcription factor that is induced in response to stress. In this study, we examined the role of the Rho-associated protein kinase 1 (ROCK1)/ATF3 axis in Art-induced ferroptosis in HSCs. Methods: HSC activation and ferroptosis were studied in vitro by western blotting, polymerase chain reaction, immunofluorescence, and other assays. ATF3 electrophoretic mobility and ROCK1 protein stability were assayed by western blotting. Immunoprecipitation was used to detect the interaction of ROCK1 and ATF3, as well as ATF3 phosphorylation. A ubiquitination assay was used to verify ROCK1 degradation. Atf3-interfering and Rock1-overexpressing mice were constructed to validate the anti-hepatic fibrosis activity of Art in vivo. Results: Art induced ferroptosis in HSCs following glutathione-dependent antioxidant system inactivation resulting from nuclear accumulation of unphosphorylated ATF3 mediated by ROCK1-ubiquitination in vitro. Art also decreased carbon tetrachloride-induced liver fibrosis in mice, which was reversed by interfering with Atf3 or overexpressing Rock1. Conclusions: The ROCK1/ATF3 axis was involved in liver fibrosis and regulation of ferroptosis, which provides an experimental basis for further study of Art for the treatment of liver fibrosis.
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INTRODUCTION: Urinary incontinence (UI) is one of the most common chronic diseases among women, which can endanger their physical and mental health and incur a heavy financial burden on both individuals and society. Web-based interventions (WBIs) have been applied to manage women's UI, but their effectiveness has remained inconclusive. This systematic review and meta-analysis aims to explore the effectiveness of WBIs on self-reported symptom severity, condition-specific quality of life, adherence to pelvic floor muscle training (primary outcomes) and other extensive secondary outcomes among women with UI. We also aimed to investigate whether intervention characteristics (format, interactivity and main technology) have impacts on the effectiveness of primary outcomes. METHODS AND ANALYSIS: This systematic review protocol was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. 10 electronic databases will be comprehensively searched from their inception to 1 May 2024, along with grey literature searches and manual reviews of relevant reference lists to identify eligible randomised controlled trials. The methodological quality of the included studies will be assessed by two reviewers based on the Cochrane Risk of Bias Tool. Meta-analyses will be conducted via Stata V.12.0. Leave-one-out sensitivity analyses will be performed, and publication bias will be evaluated using funnel plots and Egger's test. Subgroup analyses regarding intervention format, interactivity and main technology will be carried out. ETHICS AND DISSEMINATION: No ethics approval is needed for this review since no primary data are to be collected. The results of this review will help develop an optimal WBI for women with UI, thereby providing them with maximum benefits. The findings will be disseminated via a peer-reviewed journal or conference presentation. PROSPERO REGISTRATION NUMBER: CRD42023435047.
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Intervenção Baseada em Internet , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Incontinência Urinária , Humanos , Feminino , Incontinência Urinária/terapia , Qualidade de Vida , Terapia por Exercício/métodos , Diafragma da Pelve/fisiopatologiaRESUMO
BACKGROUND: LSECs (Liver sinusoidal endothelial cells) are the portal of liver, their pathological angiogenesis plays a constructive role in etiopathogenesis of liver fibrosis by affecting liver tissue repair and inflammatory drive. Although intervention in angiogenesis can effectively inhibit abnormal activation of LSEC, no effective drugs have been found to treat liver fibrosis. PURPOSE: We investigated the effect of the natural compound Curcumol on LSEC angiogenesis and elucidated the novel underlying mechanism, expecting to provide a scientific basis for exploring potential therapeutic drugs for liver fibrosis. METHODS: Various cellular and molecular assays, as well as genetic assays, were used to detect pathological angiogenesis and changes in glycolysis levels in cultured rat LSECs and mouse liver fibrosis models. RESULTS: Transcription factor KLF5 is able to influence the angiogenic properties of LSEC by regulating the glycolytic process, and affect the expression of LDH-A by transcriptionally binding to its promoter. In our study, we were surprised to find that LDH-A (the final step of glycolysis) has a strong regulatory effect on the glycolytic process of LSEC. Through in-depth study, we found that LDH-A could affect the transcriptional activity of KLF5, thus forming a positive feedback loop. Curcumol could break this positive feedback loop and inhibit the glycolysis-dependent angiogenic nature of LSEC, thus alleviating liver fibrosis. Curcumol reduced extracellular matrix (ECM) deposition, attenuated pathological angiogenesis in LSEC, and decreased the level of CCl4-induced liver fibrosis in mice. CONCLUSION: Our results demonstrated the great utilization potentiality of KLF5 in liver fibrosis, and the innovative discovery that LDH-A regulates the glycolytic process and forms a malignant feedback loop by exerting non-enzymatic effects. It also reveals the prospect of Curcumol-regulated KLF5/LDH-A feedback loop in the treatment of liver fibrosis, providing a new option for the future medicine of liver fibrosis.
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Células Endoteliais , Cirrose Hepática , Ratos , Camundongos , Animais , Lactato Desidrogenase 5/metabolismo , Lactato Desidrogenase 5/farmacologia , Retroalimentação , Cirrose Hepática/tratamento farmacológico , Fígado/metabolismo , Modelos Animais de Doenças , Glicólise , Neovascularização Patológica/tratamento farmacológico , Fatores de Transcrição Kruppel-Like/metabolismoRESUMO
Background and Aims: Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin. Methods: The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro. Results: Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis. Conclusions: Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.
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Background and Aim: Fear of childbirth (FOC) is one of the most common mental health concerns among expectant fathers, which can cause adverse consequences for themselves and their families. A valid and accurate tool is the key to the identification of FOC. This study aimed to translate and culturally adapt the fathers' fear of childbirth scale (FFCS) into simplified Chinese and test the scale's psychometric properties among expectant fathers in mainland China. Methods: Researchers obtained translation permission and followed the multiphase translation guidelines to develop the Chinese version of the fathers' fear of childbirth scale (C-FFCS). Relevant psychometric properties were selected for the scale's psychometric validation on the basis of the Consensus-based Standards for the Selection of Health Status Measurement Instruments checklist. In this cross-sectional study, two samples of expectant fathers were collected in a university-affiliated hospital in Hangzhou between September and October 2022. Results: A total of 381 expectant fathers completed the C-FFCS, resulting in an effective response rate of 95.6%. The C-FFCS is a 3-factor structure consisting of 16 items, which explained 66.374% of the total variance. The content validity index of items ranged from 0.833 to 1.00, and the scale-level content validity index was 0.931. The confirmatory factor analysis confirmed the scale's 3-factor structure. Evidence of convergent validity (average variance extracted = 0.508-0.780) as well as discriminant validity offered excellent psychometric support. The Cronbach's α coefficient, McDonald's ω coefficient, intraclass correlation coefficient, Spearman-Brown coefficient, and Guttman split-half coefficient are within the satisfactory range (> 0.80). Significant correlations between the scores of the C-FFCS and Childbirth Attitude Questionnaire (r = 0.658, p < 0.01) and Fear of Birth Scale (r = 0.555, p < 0.01) both revealed good concurrent validity. The structure of C-FFCS was invariant across different parity groups, with no floor and ceiling effect. Conclusion: The C-FFCS was demonstrated to be a sound instrument with good reliability and validity for measuring Chinese expectant fathers' FOC levels. However, further studies are advocated to verify the C-FFCS among a larger sample that is more representative of the Chinese expectant father population.
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This study aimed to screen and determine the value of AP004608.1 expression as a biomarker for Prostate cancer (PCa) survival. We investigated the expression and prognosis of AP004608.1 through bioinformatics analysis. Low AP004608.1 expression predicted favorable Overall survival (OS) and Progression-free survival (PFS) in PCa patients, according to the Cancer Genome Atlas (TCGA) database. Cox regression demonstrated that low AP004608.1 expression were in-dependent biomarkers for OS. Moreover, Gene Expression Omnibus (GEO) database was utilized to verify the prognostic role of AP004608.1 in PCa, and the similar results were reached. A meta-analysis revealed that low AP004608.1 expression was closely relevant to better OS. AP004608.1 could constitute a promising prognostic biomarker, and probably plays an important role in PCa.
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Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis.