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The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor ß1 (TGF-ß1)-activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle-promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor-controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-ß/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Transformación Celular Neoplásica , Genes ras , Proteína smad3 , Humanos , Transformación Celular Neoplásica/genética , Senescencia Celular/genética , Genes Supresores de Tumor , Proteína smad3/genética , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14âE16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12â20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.
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The development of resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib, but combination therapy with other drugs may have a positive effect. However, the effect of ropivacaine combined with sorafenib on the treatment of HCC cells and its potential regulatory mechanisms remain unclear. The proliferation and apoptosis of HCC cells treated with ropivacaine, sorafenib, and ropivacaine plus sorafenib were analyzed by cell-counting kit 8 and flow cytometry. The protein levels were measured by Western blot. The antitumor effect of ropivacaine, sorafenib, and their combination was verified by a tumor xenograft model. Ropivacaine and sorafenib markedly impeded the viability of HCC cells in a concentration-dependent manner. Compared with ropivacaine or sorafenib treatment alone, ropivacaine and sorafenib combination treatment impeded HCC cell proliferation, facilitated apoptosis, enhanced cleaved caspase-3, cleaved caspase-9, and cyclin D1 protein expression, while it reduced IL-6 and p-STAT3 expression and inhibited tumor growth in vivo. Importantly, the activation of the IL-6/STAT3 pathway could reverse the repressive or stimulative effects of ropivacaine and sorafenib on the proliferation and apoptosis in HCC cells. In summary, ropivacaine synergistically induces sorafenib-stimulated apoptosis of HCC cells via the IL-6/STAT3 pathway. Ropivacaine is a potential drug for the treatment of HCC when combined with sorafenib.
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BACKGROUND: This study compared the differences of microvesicles (MVs) and microvesicles-delivering Smad7 (Smad7-MVs) on macrophage M1 polarization and fibroblast differentiation in a model of Peyronie's disease (PD). METHODS: Overexpression of Smad7 in rat BMSCs was obtained by pCMV5-Smad7 transfection. MVs were collected from rat BMSCs using ultracentrifugation. In cells, 100 µg/mL of MVs or Smad7-MVs were used to treat the 100 ng/mL of lipopolysaccharide (LPS)-induced RAW264.7 cells or 10 ng/mL of recombinant transforming growth factor-ß1 (TGF-ß1)-induced fibroblasts. The pro-inflammatory cytokines and markers of M1 macrophages were measured in RAW264.7 cells, and the migration and markers of fibroblast differentiation were measured in fibroblasts. In rats, 50 µg of MVs or Smad7-MVs were used to treat the TGF-ß1-induced animals. The pathology of tunica albuginea (TA), the markers of M1 macrophages and fibroblast differentiation in the TA were measured. RESULTS: The MVs or Smad7-MVs treatment suppressed the LPS-induced macrophage M1 polarization and TGF-ß1-induced fibroblast differentiation. Moreover, the Smad7-MVs treatment decreased the fibroblast differentiation compared with the MVs treatment. In the TGF-ß1-induced TA of rats, MVs or Smad7-MVs treatment ameliorated the TA fibrosis by suppressing the macrophage M1 polarization and fibroblast differentiation. There was no significance on the M1-polarized macrophages between the MVs treatment and the Smad7-MVs treatment. Meanwhile, the Smad7-MVs treatment had an edge in terms of suppressing the fibroblast differentiation in the TGF-ß1-induced PD model compared with the MVs treatment. CONCLUSIONS: This study demonstrated that Smad7-MVs treatment had advantages over MVs treatment in suppressing of fibroblast differentiation in a model of PD.
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Diferenciación Celular , Micropartículas Derivadas de Células , Modelos Animales de Enfermedad , Fibroblastos , Macrófagos , Induración Peniana , Proteína smad7 , Factor de Crecimiento Transformador beta1 , Animales , Induración Peniana/metabolismo , Induración Peniana/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Ratas , Masculino , Proteína smad7/metabolismo , Proteína smad7/genética , Ratones , Micropartículas Derivadas de Células/metabolismo , Células RAW 264.7 , Factor de Crecimiento Transformador beta1/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratas Sprague-Dawley , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citologíaRESUMEN
BACKGROUND: Diabetes is a predominant driver of coronary artery disease worldwide. This study aims to unravel the distinct characteristics of oral and gut microbiota in diabetic coronary heart disease (DCHD). Simultaneously, we aim to establish a causal link between the diabetes-driven oral-gut microbiota axis and increased susceptibility to diabetic myocardial ischemia-reperfusion injury (MIRI). METHODS: We comprehensively investigated the microbial landscape in the oral and gut microbiota in DCHD using a discovery cohort (n = 183) and a validation chohort (n = 68). Systematically obtained oral (tongue-coating) and fecal specimens were subjected to metagenomic sequencing and qPCR analysis, respectively, to holistically characterize the microbial consortia. Next, we induced diabetic MIRI by administering streptozotocin to C57BL/6 mice and subsequently investigated the potential mechanisms of the oral-gut microbiota axis through antibiotic pre-treatment followed by gavage with specific bacterial strains (Fusobacterium nucleatum or fecal microbiota from DCHD patients) to C57BL/6 mice. RESULTS: Specific microbial signatures such as oral Fusobacterium nucleatum and gut Lactobacillus, Eubacterium, and Roseburia faecis, were identified as potential microbial biomarkers in DCHD. We further validated that oral Fusobacterium nucleatum and gut Lactobacillus are increased in DCHD patients, with a positive correlation between the two. Experimental evidence revealed that in hyperglycemic mice, augmented Fusobacterium nucleatum levels in the oral cavity were accompanied by an imbalance in the oral-gut axis, characterized by an increased coexistence of Fusobacterium nucleatum and Lactobacillus, along with elevated cardiac miRNA-21 and a greater extent of myocardial damage indicated by TTC, HE, TUNEL staining, all of which contributed to exacerbated MIRI. CONCLUSION: Our findings not only uncover dysregulation of the oral-gut microbiota axis in diabetes patients but also highlight the pivotal intermediary role of the increased abundance of oral F. nucleatum and gut Lactobacillus in exacerbating MIRI. Targeting the oral-gut microbiota axis emerges as a potent strategy for preventing and treating DCHD. Oral-gut microbial transmission constitutes an intermediate mechanism by which diabetes influences myocardial injury, offering new insights into preventing acute events in diabetic patients with coronary heart disease.
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Enfermedad de la Arteria Coronaria , Diabetes Mellitus , Microbioma Gastrointestinal , Humanos , Animales , Ratones , Ratones Endogámicos C57BL , Fusobacterium nucleatum/fisiología , Enfermedad de la Arteria Coronaria/etiologíaRESUMEN
Platelet-rich plasma (PRP) has significant potential for various applications and holds clinical value in regenerative medicine. Cryopreservation is used to extend the preservation period of PRP, facilitating its clinical application. However, the potential negative effects of long-term cryopreservation on platelet storage lesion are still uncertain. In this study, PRP was stored at - 30 °C or - 80 °C. Platelet count, apoptosis, reactive oxygen species (ROS) content, and CD62P expression were assessed on the 14th and 28th days. The study also evaluated platelet mitochondria morphology and function, serotonin (5-HT) secretion by platelets, and the inflammatory activating effect of cryopreserved platelets in PRP. The results showed that there were no significant differences in platelet count, the content of 5-HT, and inflammatory effects between fresh PRP and PRP cryopreserved at both - 30 °C and - 80 °C. However, there was an increase in ROS level, apoptosis, and CD62P level after cryopreservation at both temperatures. Additionally, the levels of ROS, apoptosis, and CD62P in platelets were similar after storage at - 30 °C and - 80 °C. The main difference observed was that the morphology and function of mitochondria were severely damaged after storage at - 30 °C, while they were less affected at - 80 °C. Based on these findings, it can be concluded that storing PRP at - 80 °C is more suitable for achieving a better therapeutic effect in clinical applications, but cryopreservation could not replace the current standard.
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Plasma Rico en Plaquetas , Serotonina , Humanos , Especies Reactivas de Oxígeno , Serotonina/metabolismo , Serotonina/farmacología , Conservación de la Sangre/métodos , Plaquetas/metabolismo , Criopreservación/métodosRESUMEN
OBJECTIVE: Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. METHODS: We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. RESULTS: Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. SIGNIFICANCE: Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.
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Epilepsia , Hipocampo , Interneuronas , Parvalbúminas , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Electroencefalografía , Epilepsia/patología , Epilepsia/genética , Hipocampo/patología , Hipocampo/metabolismo , Interneuronas/patología , Interneuronas/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/patología , Proteína 2 de Unión a Metil-CpG/genética , Ratones Transgénicos , Parvalbúminas/metabolismoRESUMEN
Antimony(V) substitution is common in secondary ferrihydrite, especially in mining areas and tailings. However, its impact on the adsorption behavior of ferrihydrite is still unclear. Therefore, this study investigated the influential mechanisms of Sb(V) substitution on the lattice structure and surface properties of Sb-substituted ferrihydrite (SbFh), and its adsorption of coexisting Sb(OH)6-. Antimony(V) is substituted at Fe1 sites and is primarily distributed on the surface. Substitution has opposing effects on the outer- and inner-sphere complexation of Sb(OH)6-. On one hand, substituted-Sb(V) transfers more positive charges to ≡FeOH, reducing the number of H bonds. Subsequently, the charge saturation of ≡FeOH decreases, surface charge increases, and outer-sphere complexation is promoted. On the other hand, the elevated bond valence of Sb-O increases charge saturation of ≡FeOH, reducing the charge capacity that ≡FeOH can accommodate from inner-sphere complexes. Thus, inner-sphere complexation is inhibited. Inner-sphere complexation plays a more important role, and Sb(OH)6- adsorption is inhibited. Additionally, the primary complexation modes of Sb(OH)6- transform from bidentate to monodentate complexation. This research has important implications for understanding the environmental behavior of ferrihydrite, as well as the fate and bioavailability of antimony in mining areas and tailings.
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Antimonio , Propiedades de Superficie , Antimonio/química , Adsorción , Compuestos Férricos/químicaRESUMEN
Volatile organic compounds (VOCs) are consumed by photochemical reactions during transport, leading to inaccuracies in estimating the local ozone (O3) formation mechanism and its subsequent strategy for O3 attainment. To comprehensively quantify the deviations in O3 formation mechanism by consumed VOCs (C-VOCs), a 5-month field campaign was conducted in a typical industrial city in Northern China over incorporating a 0-D box model (implemented with MCMv3.3.1). The averaged C-VOCs concentration was 6.8 ppbv during entire period, and Alkenes accounted for 62% dominantly. Without considering C-VOCs, the relative incremental reactivity (RIR) of anthropogenic VOCs (AVOC, overestimated by 68%-75%) and NOx (underestimated by 137%-527%) demonstrated deviations at multiple scenarios, and the RIR deviations for precursors in High-O3-periods (HOP) were lower than Low-O3-periods (LOP). The RIR deviations from individual species involved C-VOCs calculation did not impact the identification for the high-ranking-RIR AVOC species but non-negligible. Monthly comparisons showed that higher C-VOCs concentrations would lead to higher RIR deviations. The daily maximum of net Ox production rate (P(Ox)) and the regional transport Ox (Trans(Ox)) without C-VOCs were underestimated by 56%-194% and 81%-243%, respectively. After considering C-VOCs, the contribution of HO2+NO for Ox gross production (G(Ox)) decreased by 7% (LOP) and 7% (HOP), but OH + NO2 for Ox destruction (D(Ox)) decreased by 16% (LOP) and 23% (HOP), and alkenes + O3 increased for D(Ox) by 12% (LOP) and 22% (HOP). This implies that VOCs-NOx-O3 sensitivity was deviated between with/without C-VOCs, and severe O3 pollution rendered deviations in O3 formation, especially via NOx-driving chemistry. Based on RIR(NOx)/RIR(AVOC) with/without C-VOCs, the sensitivity regime shifted from VOCs-limited (-0.93) to transition (1.38) at LOP, and from VOCs-limited (0.19) to NOx-limited (3.79) at HOP. Our results reflected that the NOx limitation degree was underestimated without constraint C-VOCs, especially HOP, and provided implication to more precise O3 pollution control strategies.
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Contaminantes Atmosféricos , Ciudades , Monitoreo del Ambiente , Ozono , Compuestos Orgánicos Volátiles , Ozono/análisis , Ozono/química , Compuestos Orgánicos Volátiles/análisis , China , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/química , Monitoreo del Ambiente/métodos , Procesos FotoquímicosRESUMEN
OBJECTIVE: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide, and cervical incompetence (CIC) is a significant contribution. Cervical cerclage (CC) is an effective obstetric intervention. However, many clinical factors affect the success rate of surgery. The objective was to investigate and compare the pregnancy and neonatal outcomes of patients who underwent ultrasound- and physical examination-indicated cervical cerclage and to explore the influencing factors of preterm delivery before 34 weeks. METHODS: The sociodemographic characteristics and clinical data of patients with a diagnosis of cervical incompetence who underwent ultrasound- and physical examination-indicated transvaginal cervical cerclage at Nanjing Maternal and Child Health Hospital from January 2020 to December 2022 were retrospectively analyzed. The pregnancy and neonatal outcomes of the patients were evaluated. Continuous variables were compared using Student's t test (for normally distributed data) or the Mann-Whitney U test (for nonnormally distributed data). Categorical variables were analysed using the chi-square test or Fisher's exact test. Additionally, logistic regression analyses and receiver operating characteristic curves were used to evaluate the associations of inflammatory markers with maternal and neonatal outcomes. RESULTS: This study included 141 participants who underwent cervical cerclage, including 71 with ultrasound-indicated cerclage and 70 with physical examination-indicated cerclage. Compared to those in the ultrasound-indicated cerclage group, the duration from cerclage to delivery, birth weight, and APGAR score in the physical examination-indicated cerclage group were significantly lower, and the rates of delivery at < 28 weeks, < 32 weeks, < 34 weeks, and < 37 weeks of gestation and neonatal mortality were significantly higher (all P < 0.05). Compared to those in the physical ultrasound-indicated cerclage group, in the physical examination-indicated cerclage group, maternal blood inflammatory markers, such as C-reactive protein (CRP), the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI) were significantly higher (P < 0.05). Additionally, maternal blood inflammatory markers, such as the CRP, white blood cell count, platelet to lymphocyte ratio (PLR), SII, and SIRI were significantly higher in the group with delivery before 34 weeks of gestation. Furthermore, the results demonstrated that twin pregnancy had the highest OR for preterm delivery before 34 weeks of gestation (OR = 3.829; 95% CI 1.413-10.373; P = 0.008), as well as the following: the SII level (OR = 1.001; 95% CI 1.000-1.002; P = 0.003) and CRP level (OR = 1.083; 95% CI 1.038-1.131; P = 0.022). The risk factors for preterm delivery before 34 weeks of gestation were twin gestation, an increased SII level and an increased CRP level, which had good combined predictive value. CONCLUSION: In patients with cervical insufficiency, ultrasound-indicated cervical cerclage appears to lead to better pregnancy outcomes than physical examination-indicated cerclage. Twin pregnancy and maternal blood inflammatory markers, such as the CRP level and the SII, are associated with preterm delivery before 34 weeks of gestation.
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Cerclaje Cervical , Examen Físico , Resultado del Embarazo , Nacimiento Prematuro , Incompetencia del Cuello del Útero , Humanos , Femenino , Cerclaje Cervical/estadística & datos numéricos , Cerclaje Cervical/métodos , Embarazo , Estudios Retrospectivos , Adulto , Resultado del Embarazo/epidemiología , Incompetencia del Cuello del Útero/cirugía , Incompetencia del Cuello del Útero/diagnóstico por imagen , Examen Físico/métodos , Nacimiento Prematuro/prevención & control , Recién Nacido , Ultrasonografía Prenatal , ChinaRESUMEN
Dysregulation of microRNA (miRNA) expression in cancer is a significant factor contributing to the progression of chemoresistance. The objective of this study is to explore the underlying mechanisms by which miR-34b-3p regulates chemoresistance in cervical cancer (CC). Previous findings have demonstrated low expression levels of miR-34b-3p in both CC chemoresistant cells and tissues. In this study, we initially characterize the behavior of SiHa/DDP cells which are CC cells resistant to the chemotherapeutic drug cisplatin (DDP). Subsequently, miR-34b-3p mimics are transfected into SiHa/DDP cells. It is observed that overexpression of miR-34b-3p substantially inhibits the proliferation, migration, and invasion abilities of SiHa/DDP cells and also enhances their sensitivity to DDP-induced cell death. Quantitative RT-PCR and western blot analysis further reveal elevated expression levels of STC2 and FN1 in SiHa/DDP cells, contrary to the expression pattern of miR-34b-3p. Moreover, STC2 and FN1 contribute to DDP resistance, proliferation, migration, invasion, and decreased apoptosis in CC cells. Through dual-luciferase assay analysis, we confirm that STC2 and FN1 are direct targets of miR-34b-3p in CC. Finally, rescue experiments demonstrate that overexpression of either STC2 or FN1 can partially reverse the inhibitory effects of miR-34b-3p overexpression on chemoresistance, proliferation, migration and invasion in CC cells. In conclusion, our findings support the role of miR-34b-3p as a tumor suppressor in CC. This study indicates that targeting the miR-34b-3p/STC2 or FN1 axis has potential therapeutic implications for overcoming chemoresistance in CC patients.
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Proliferación Celular , Cisplatino , Resistencia a Antineoplásicos , Fibronectinas , MicroARNs , Neoplasias del Cuello Uterino , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Femenino , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Fibronectinas/metabolismo , Fibronectinas/genética , Movimiento Celular/genética , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Apoptosis/genética , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , GlicoproteínasRESUMEN
Focal segmental glomerulosclerosis (FSGS) is a leading kidney disease, clinically associated with proteinuria and progressive renal failure. The occurrence of this disease is partly related to gene mutations. We describe a single affected family member who presented with FSGS. We used high-throughput sequencing, sanger sequencing to identify the pathogenic mutations, and a systems genetics analysis in the BXD mice was conducted to explore the genetic regulatory mechanisms of pathogenic genes in the development of FSGS. We identified high urinary protein (++++) and creatinine levels (149 µmol/L) in a 29-year-old male diagnosed with a 5-year history of grade 2 hypertension. Histopathology of the kidney biopsy showed stromal hyperplasia at the glomerular segmental sclerosis and endothelial cell vacuolation degeneration. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous missense mutation (c.643C > T) in exon 2 of TRPC6, leading to the substitution of arginine with tryptophan at position 215 (p.Arg215Trp). Systems genetics analysis of the 53 BXD mice kidney transcriptomes identified Pygm as the upstream regulator of Trpc6. Those two genes are jointly involved in the regulation of FSGS mainly via Wnt and Hippo signaling pathways. We present a novel variant in the TRPC6 gene that causes FSGS. Moreover, our data suggested TRPC6 works with PYGM, as well as Wnt and Hippo signaling pathways to regulate renal function, which could guide future clinical prevention and targeted treatment for FSGS outcomes.
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Objective: This study aimed to investigate the impact of palliative care on the quality of life, depressive state, and physical and psychological symptoms of patients with end-stage cancer. Methods: A systematic literature search of PubMed, Embase, and Scopus databases was conducted for randomized controlled trials (RCTs) published from May 2000 to June 2023, focusing on the impact of palliative care on end-stage cancer patients. The search utilized terms such as "palliative care," "cancer/tumor/malignancy," "terminal/end-stage/advanced," to identify studies meeting our inclusion criteria. Selected RCTs were evaluated for quality, and relevant data were extracted for meta-analysis. Results: Meta-analysis of 16 RCTs revealed that palliative care significantly improved depressive states [OR=-0.88, 95%CI (-1.55, -0.20), P = .01] and alleviated physical and psychological symptoms [OR=-2.38, 95%CI (-3.95, -0.81), P = .003] in end-stage cancer patients compared to conventional oncology care. However, the improvement in overall quality of life was not statistically significant (P > .05). Conclusion: Palliative care significantly enhances the mental and physical well-being of end-stage cancer patients by reducing depressive states and symptom burden, although its impact on overall quality of life requires further exploration.
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OBJECTIVE: The development of drug resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib (Sor). However, the regulatory mechanisms underlying the effects of the combination Sor and ropivacaine (Rop) on HCC cells remain unclear. METHODS: miR-224 and HOXD10 mRNA expression in HCC cells was analyzed using qRT-PCR. CCK-8, Transwell assays and tumor formation experiments in nude mice were used to assess HCC cell proliferation, migration, and invasion. Migration of HCC cells was also analyzed using a cell scratch assay. Hematoxylin and eosin staining was used to detect tumor area. RESULTS: miR-224 expression profoundly increased in HepG2 and Huh7 cells. Treatment with Rop and/or Sor blocked miR-244 expression, especially the combination treatment. Transfection of miR-224 mimic increased HCC cell proliferation and tumor size in nude mice, and migration and invasion in vitro in the presence of Rop and Sor compared to the negative control mimic. Dual-luciferase reporter assays showed that HOXD10 was targeted by miR-224. HOXD10 protein expression and was markedly reduced in HepG2 and Huh7 cells. Rop and/or Sor treatment increased HOXD10 protein expression, particularly the combination treatment. miR-224 negatively regulated HOXD10 expression in HCC cells treated with Rop and Sor. Transfection-mediated silencing of HOXD10 increased HCC cell proliferation, migration, and invasion in the presence of Rop and Sor compared with negative control transfection. CONCLUSION: The combination of Rop and Sor attenuates HCC cell proliferation and metastasis via the miR-224/HOXD10 axis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Animales , Ratones , Carcinoma Hepatocelular/patología , Sorafenib/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Ratones Desnudos , Ropivacaína/farmacología , Línea Celular Tumoral , Proliferación Celular/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
Hyacinth bean [Lablab purpureus (L.) Sweet], a plant belonging to the leguminous family and traditionally used for medicinal purposes in China, is a valuable resource with a wide range of health benefits. This review examines the bioactive compounds, health-promoting properties and functional food potential of hyacinth bean, highlighting its role in protecting against metabolic diseases and the underlying molecular mechanisms. According to existing research, hyacinth bean contains a diverse array of bioactive compounds, Consumption of hyacinth beans and hyacinth bean-related processed food products, as well as their use in medicines, is associated with a variety of health benefits that are increasingly favoured by the scientific community. In light of these findings, we posit that hyacinth bean holds great promise for further research and food application. © 2024 Society of Chemical Industry.
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Prostate cancer (PCa) has a certain degree of heritability, and metastasis occurs as cancer progresses. However, its underlying mechanism remains largely unknown. We sequenced four cases of cancer without metastasis, four metastatic cancer, and four benign hyperplasia tissues as controls. A total of 1839 damaging mutations were identified. Pathway analysis, gene clustering, and weighted gene co-expression network analysis were employed to find characteristics associated with metastasis. Chr19 had the most mutation density and 1p36 had the highest mutation frequency across the genome. These mutations occurred in 1630 genes, including the most frequently mutated genes TTN and PLEC, and dozens of metastasis-related genes, such as FOXA1, NCOA1, CD34, and BRCA2. Ras signalling and arachidonic acid metabolism were uniquely enriched in metastatic cancer. Gene programmes 10 and 11 showed the signatures indicating the occurrence of metastasis better. A module (135 genes) was specifically associated with metastasis. Of them, 67.41% reoccurred in program 10, with 26 genes further retained as the signature genes related to PCa metastasis, including AGR3, RAPH1, SOX14, DPEP1, and UBL4A. Our study provides new molecular perspectives on PCa metastasis. The signature genes and pathways could be served as potential therapeutic targets for metastasis or cancer progression.
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Neoplasias de la Próstata , Masculino , Humanos , RNA-Seq , Neoplasias de la Próstata/patología , Perfilación de la Expresión Génica , Mutación , Secuencia de Bases , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción SOXB2/genética , Factores de Transcripción SOXB2/metabolismoRESUMEN
BACKGROUND: The ischemia-reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. METHODS: Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen-glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. RESULTS: We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-ß1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-ß1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. CONCLUSION: Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.
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Lesión Renal Aguda , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Ratas , Lesión Renal Aguda/metabolismo , Apoptosis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Riñón/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
To understand soil biodiversity we need to know how soil communities are assembled. However, the relationship between soil community assembly and environmental factors, and the linkages between soil microbiota taxonomic groups and their body sizes, remain unexplored in tropical seasonal rainforests. Systematic and stratified random sampling was used to collect 243 soil and organism samples across a 20-ha plot in a tropical seasonal rainforest in southwestern China. High-throughput sequencing, variation analysis and principal coordinates of neighbourhood matrices were performed. Soil community composition, spatial distribution and assembly processes based on propagule size (including archaea, bacteria, fungi and nematodes) were investigated. The results showed that: (i) the community assembly of small soil microorganisms (bacteria, fungi) was mostly influenced by stochastic processes while that of larger soil organisms (nematodes) was more deterministic; (ii) the independent effects of habitat (including soil and topographic variables) and its interaction with plant attributes for community structure significantly decreased with increasing body size; and (iii) plant leaf phosphorus directly influenced the spatial distribution of soil-available phosphorus, which indicates their indirect impact on the assembly of the soil communities. Our data suggest that the assembly of multitrophic soil communities can be explained to some extent by changes in above-ground plant attributes. This highlights the importance of above- and below-ground linkages in influencing multitrophic soil microbiota community assembly.
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Microbiota , Bosque Lluvioso , Suelo/química , Estaciones del Año , Plantas/microbiología , Biodiversidad , Microbiota/genética , Bacterias/genética , Hongos/genética , Tamaño Corporal , Microbiología del Suelo , FósforoRESUMEN
Low-light stress compromises photosynthetic and energy efficiency and leads to spikelet sterility; however, the effect of low-light stress on pollen tube elongation in the pistil remains poorly understood. The gene RGA1, which encodes a Gα-subunit of the heterotrimeric G-protein, enhanced low-light tolerance at anthesis by preventing the cessation of pollen tube elongation in the pistil of rice plants. In this process, marked increases in the activities of acid invertase (INV), sucrose synthase (SUS) and mitochondrial respiratory electron transport chain complexes, as well as the relative expression levels of SUTs (sucrose transporter), SWEETs (sugars will eventually be exported transporters), SUSs, INVs, CINs (cell-wall INV 1), SnRK1A (sucrose-nonfermenting 1-related kinase 1) and SnRK1B, were observed in OE-1 plants. Accordingly, notable increases in contents of ATP and ATPase were presented in OE-1 plants under low-light conditions, while they were decreased in d1 plants. Importantly, INV and ATPase activators (sucrose and Na2 SO3 , respectively) increased spikelet fertility by improving the energy status in the pistil under low-light conditions, and the ATPase inhibitor Na2 VO4 induced spikelet sterility and decreased ATPase activity. These results suggest that RGA1 could alleviate the low-light stress-induced impairment of pollen tube elongation to increase spikelet fertility by promoting sucrose unloading in the pistil and improving the metabolism and allocation of energy.
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Infertilidad , Oryza , Azúcares/metabolismo , Tubo Polínico , Plantas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Sacarosa/metabolismo , Adenosina Trifosfatasas/metabolismo , Oryza/genéticaRESUMEN
Microresonator soliton frequency combs offer unique flexibility in synthesizing microwaves over a wide range of frequencies. Therefore, it is very important to study the time jitter of soliton microcombs. Here, we fabricate optical microresonators with perfect transmission spectrum that characterizes highly uniform extinction ratio and absence of mode interactions by laser machining high-purity silica fiber preforms. Based on such perfect whispering-gallery-mode cavity, We demonstrate that K-band microwave with ultra-low phase noise (-83 dBc/Hz@100â Hz; -112 dBc/Hz@1kHz; -133 dBc/Hz@10kHz) can be generated by photo-detecting the repetition rate of a soliton microcomb. Also, with the Raman scattering and dispersive wave emission largely restricted, we show that ultra-low time jitter soliton has a wide existence range. Our work illuminates a pathway toward low-noise photonic microwave generation as well as the quantum regime of soliton microcombs.