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The transient receptor potential melastatin 7 channel (TRPM7) is a nonselective cation channel highly expressed in some human cancer tissues. TRPM7 is involved in the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cancer cells. Modulation of TRPM7 could be a promising therapeutic strategy for treating cancer; however, efficient and selective pharmacological TRPM7 modulators are lacking. In this study we investigated N- [4- (4, 6-dimethyl- 2-pyrimidinyloxy) - 3- methylphenyl] -N' - [2 -(dimethylamino)] benzoylurea (SUD), a newly synthesized benzoylurea derivative, for its effects on cancer cell migration and EMT and on functional expression of TRPM7. Our previous studies showed that SUD induces cell cycle arrest and apoptosis of MCF-7 and BGC-823 cells (human breast cancer and gastric cancer cell lines, respectively). Here, we show that SUD significantly decreased the migration of both types of cancer cells. Moreover, SUD decreased vimentin expression and increased E-cadherin expression in both cell types, indicating that EMT is also decreased by SUD. Importantly, SUD potentially reduced the TRPM7-like current in a concentration-dependent manner and decreased TRPM7 expression through the PI3K/Akt signaling pathway. Finally, molecular docking simulations were used to investigate potential SUD binding sites on TRPM7. In summary, our research demonstrated that SUD is an effective TRPM7 inhibitor and a potential agent to suppress the metastasis of breast and gastric cancer by inhibiting TRPM7 expression and function.
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Movimiento Celular , Transición Epitelial-Mesenquimal , Proteínas Serina-Treonina Quinasas , Canales Catiónicos TRPM , Urea , Humanos , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/antagonistas & inhibidores , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Urea/análogos & derivados , Urea/farmacología , Urea/química , Línea Celular Tumoral , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Antineoplásicos/farmacología , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Células MCF-7RESUMEN
RNA N6-methyladenosine (m6A) readers mediate cancer progression. However, the functional role and potential mechanisms of the m6A readers in prostate cancer tumorigenicity remain to be elucidated. In this study, we demonstrate that YTHDF3 expression is elevated in castration-resistant prostate cancer (CRPC) and positively correlated to high grade, bone metastasis and poor survival. YTHDF3 expression promoted CRPC cell proliferation, epithelial to mesenchymal transition (EMT) and tumour progression. Mechanistically, YTHDF3 promoted the RNA degradation of SPOP and NXK3.1 but stabilized RNA expressions of TWIST1 and SNAI2 dependent on m6A to facilitate cell proliferation and EMT. Additionally, YTHDF3 expression enhanced AKT activity via degrading SPOP in an m6A-dependent manner. Importantly, we found that melatonin can compete with m6A to occupy the m6A-binding cage of YTHDF3, leading to inhibition of YTHFD3 and its target expressions as well as CRPC tumour growth. Our findings uncover an essential role of YTHDF3 in the progression of CRPC and highlight the role of melatonin in anti-CRPC activity.
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Progresión de la Enfermedad , Neoplasias de la Próstata Resistentes a la Castración , Proteínas de Unión al ARN , Masculino , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Humanos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Animales , Línea Celular Tumoral , Adenosina/análogos & derivados , Adenosina/metabolismo , Proliferación Celular/genética , Ratones , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Melatonina/metabolismo , Ratones DesnudosRESUMEN
INTRODUCTION: Premature ovarian insufficiency (POI) is one of the causes of female infertility. Unexplained POI is increasingly affecting women in their reproductive years. However, the etiology of POI is diverse and remains elusive. We and others have shown that brain-derived neurotrophic factor (BDNF) plays an important role in adult ovarian function. Here, we report on a novel role of BDNF in the Developmental Origins of POI. METHODS: Placental BDNF knockout mice were created using CRISPR/CAS9. Homozygous knockout (cKO(HO)) mice didn't survive, while heterozygous knockout (cKO(HE)) mice did. BDNF reduction in cKO(HE) mice was confirmed via immunohistochemistry and Western blots. Ovaries were collected from cKO(HE) mice at various ages, analyzing ovarian metrics, FSH expression, and litter sizes. In one-month-old mice, oocyte numbers were assessed using super-ovulation, and oocyte gene expression was analyzed with smart RNAseq. Ovaries of P7 mice were studied with SEM, and gene expression was confirmed with RT-qPCR. Alkaline phosphatase staining at E11.5 and immunofluorescence for cyclinD1 assessed germ cell number and cell proliferation. RESULTS: cKO(HE) mice had decreased ovarian function and litter size in adulthood. They were insensitive to ovulation induction drugs manifested by lower oocyte release after superovulation in one-month-old cKO(HE) mice. The transcriptome and SEM results indicate that mitochondria-mediated cell death or aging might occur in cKO(HE) ovaries. Decreased placental BDNF led to diminished primordial germ cell proliferation at E11.5 and ovarian reserve which may underlie POI in adulthood. CONCLUSION: The current results showed decreased placental BDNF diminished primordial germ cell proliferation in female fetuses during pregnancy and POI in adulthood. Our findings can provide insights into understanding the underlying mechanisms of POI.
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Factor Neurotrófico Derivado del Encéfalo , Ratones Noqueados , Placenta , Insuficiencia Ovárica Primaria , Animales , Insuficiencia Ovárica Primaria/metabolismo , Insuficiencia Ovárica Primaria/genética , Insuficiencia Ovárica Primaria/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Femenino , Ratones , Embarazo , Placenta/metabolismo , Ovario/metabolismo , Ovario/patología , Modelos Animales de Enfermedad , Oocitos/metabolismoRESUMEN
BACKGROUND: Adequate bowel preparation is essential for successful colonoscopy and polypectomy procedures. However, a significant proportion of patients still exhibit suboptimal bowel preparation, ranging from 18% to 35%. The effectiveness of bowel preparation agents can be hampered by volume and taste, adversely affecting patient compliance and tolerance. Therefore, exploring strategies to minimise laxative volume and improve patient tolerance and adherence is imperative to ensure optimal bowel preparation quality. METHODS AND ANALYSIS: This study is a two-arm, single-blinded, parallel-group randomised controlled trial designed to compare the efficacy of 2 L polyethylene glycol (PEG) combined with linaclotide with 4 L PEG in bowel cleansing. A total of 422 participants will be randomly assigned in a 1:1 ratio to either the intervention group (2 L PEG combined with 580 µg linaclotide) or the control group (4 L PEG). The primary outcome measure is bowel cleansing efficacy, which is assessed using the Boston Bowel Preparation Scale. Secondary outcomes include evaluating the tolerability and safety of the bowel preparation regimens, bowel diary assessments, postpolypectomy complications (such as bleeding and perforation) and the size and number of removed polyps. ETHICS AND DISSEMINATION: The study has received approval from the Clinical Research Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine. The findings of this trial will serve as a valuable resource for clinicians and patients undergoing colonoscopy polypectomy by guiding the selection of appropriate bowel preparation regimens. Study findings will be disseminated to participants, presented at professional society meetings, and published in peer-reviewed journals. This trial was registered on the Chinese Clinical Trial Registry with registration number ChiCTR2300075410.
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Catárticos , Pólipos del Colon , Colonoscopía , Polietilenglicoles , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Catárticos/administración & dosificación , China , Pólipos del Colon/cirugía , Colonoscopía/métodos , Pueblos del Este de Asia , Péptidos/administración & dosificación , Polietilenglicoles/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Método Simple CiegoRESUMEN
Preclinical evidence has firmly established a bidirectional interaction among the lung, gut, and gut microbiome. There are many complex communication pathways between the lung and intestine, which affect each other's balance. Some metabolites produced by intestinal microorganisms, intestinal immune cells, and immune factors enter lung tissue through blood circulation and participate in lung immune function. Altered gut-lung-microbiome interactions have been identified in rodent models and humans of several lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, asthma, etc. Emerging evidence suggests that microbial therapies can prevent and treat respiratory diseases, but it is unclear whether this association is a simple correlation with the pathological mechanisms of the disease or the result of causation. In this review, we summarize the complex and critical link between the gut microbiota and the lung, as well as the influence and mechanism of the gut microbiota on respiratory diseases, and discuss the role of interventions such as prebiotics and fecal bacteria transplantation on respiratory diseases. To provide a reference for the rational design of large-scale clinical studies, the direct application of microbial therapy to respiratory-related diseases can reduce the incidence and severity of diseases and accompanying complications.
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Premature infants are often exposed to hyperoxia. However, there is limited data regarding the mechanistic underpinnings linking neonatal hyperoxia exposure and its contribution to cardio-renal dysfunction in adults born preterm. Our objective was to determine whether neonatal hyperoxia induces systemic vascular stiffness and cardio-renal dysfunction in adulthood. Newborn rats were randomly assigned to room air (RA) or hyperoxia (85% O2) from postnatal day 1 to 14, then recovered in RA until 1 year of life. Arterial stiffness, cardio-renal histomorphometry, and fibrosis in the aorta, heart, and kidney were assessed. RNA-sequencing (RNA-seq) of the aorta and kidney was also done. Adult rats exposed to neonatal hyperoxia had increased aortic and mesenteric artery stiffness as demonstrated by wire and pressure myography. They also had cardiomyocyte hypertrophy, glomerulomegaly, and tubular injury. Hyperoxia exposure altered the transcriptome profile associated with fibrosis and matrix remodeling in the aorta and kidney. There was also increased TGF-ß1 levels and fibrosis in the aorta, left ventricle, and kidney. In conclusion, neonatal hyperoxia exposure was associated with systemic vascular and cardio-renal alterations in 1-year-old rats. Further studies to determine how targeted therapies could reprogram cardio-renal injury after neonatal hyperoxia exposure are indicated.
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Animales Recién Nacidos , Hiperoxia , Enfermedades Renales , Animales , Hiperoxia/metabolismo , Ratas , Enfermedades Renales/etiología , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Riñón/metabolismo , Riñón/patología , Fibrosis , Rigidez Vascular , Masculino , Femenino , Ratas Sprague-Dawley , Aorta/patología , Aorta/metabolismoRESUMEN
It is important to ensure the nutritional quality and safe production of rice. Here, plot experiments were used to analyze the effects of three soil amendments-10 t ha-1 of biochar (BC), 1.5 t ha-1 of lime (LM), and 2.25 t ha-1 of silicon-calcium fertilizer (SC)-on the soil characteristics, rice yield and quality of double-cropping rice grown in mildly cadmium-polluted paddy fields. Compared with the control treatment (CK), the BC and SC treatments significantly improved rice processing, appearance and nutritional quality, but reduced cooking quality. All three soil amendments significantly reduced cadmium (Cd) content in brown rice. Soil amendments could significantly increase soil pH and reduce soil available Cd content. The application of the BC and SC treatments increased the content of each nutrient index in the soil (SOM, NN, AP, AK). Correlation analysis showed that the improvement in rice processing, appearance, and nutritional quality was mainly affected by the comprehensive effects of soil SOM, NN, AP and AK; the hygiene quality was mainly affected by soil pH and available Cd. In terms of benefit analysis combined with cost, the SC treatment had the highest benefit effect. Taken together, in mildly cadmium-polluted paddy fields, the application of silicon-calcium fertilizer improved the soil quality, thereby increased the yield and quality of rice, and had the best effect on increasing income.
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Cadmio , Calcio , Fertilizantes , Oryza , Silicio , Suelo , Oryza/crecimiento & desarrollo , Oryza/efectos de los fármacos , Fertilizantes/análisis , Silicio/química , Suelo/química , Calcio/análisis , Calcio/metabolismo , Cadmio/análisis , Contaminantes del Suelo/análisis , Compuestos de Calcio/química , Carbón Orgánico/química , Concentración de Iones de Hidrógeno , ÓxidosRESUMEN
Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and precancerous lesion in stomach cancer. Abnormal activation cellular ferroptosis further damages gastric tissue, which is susceptible to inflammation. Luteolin has powerful anti-inflammatory and regulatory potential for cellular ferroptosis. We aimed to clarify the involvement of luteolin in inflammation and ferroptosis during CAG. Luteolin targets were searched to identify intersecting genes in the chronic atrophic gastritis disease database. The AGE-RAGE pathway is a potential target of luteolin for the treatment of chronic atrophic gastritis and a binding site between luteolin and RAGE was predicted through a computer simulation of molecular docking. We established a CAG rat model using N-methyl-N-nitro-N-nitroguanidine. The therapeutic effect of luteolin on CAG was detected using western blotting, qPCR, hematoxylin and eosin staining, lipid oxidation (MDA), and Fe2+ assays. Luteolin inhibited the AGE-RAGE signaling pathway and reduced the inflammatory response in gastric tissues. Additionally, luteolin downregulated the concentration of (MDA) and Fe2+, and CAG downregulated the expression levels of ACSL4 and NOX1 and upregulated the expression levels of FIH1 and GPX4 ferroptosis-related proteins, thus inhibiting the ferroptosis of gastric tissue cells, which had a therapeutic effect on CAG.
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Ferroptosis , Gastritis Atrófica , Luteolina , Transducción de Señal , Ferroptosis/efectos de los fármacos , Luteolina/farmacología , Luteolina/uso terapéutico , Animales , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patología , Gastritis Atrófica/genética , Ratas , Transducción de Señal/efectos de los fármacos , Masculino , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Productos Finales de Glicación Avanzada/metabolismo , Modelos Animales de Enfermedad , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ratas Sprague-Dawley , Enfermedad Crónica , Simulación del Acoplamiento Molecular , Humanos , Antiinflamatorios/farmacologíaRESUMEN
BACKGROUND: This randomized controlled trial aimed to evaluate the efficacy of preoperative inhaled budesonide combined with intravenous dexamethasone on postoperative sore throat (POST) after general anesthesia in patients who underwent thyroidectomy. METHODS: Patients who underwent elective thyroidectomy were randomly divided into the intravenous dexamethasone group (group A) and budesonide inhalation combined with intravenous dexamethasone group (group B). All patients underwent general anesthesia. The incidence and severity of POST, hoarseness, and cough at 1, 6, 12, and 24 hours after surgery were evaluated and compared between the 2 groups. RESULTS: There were 48 and 49 patients in groups A and B, respectively. The incidence of POST was significantly lower at 6, 12, and 24 hours in group B than that in group A (Pâ <â .05). In addition, group B had a significantly lower incidence of coughing at 24 hours (Pâ =â .047). Compared with group A, the severity of POST was significantly lower at 6 (Pâ =â .027), 12 (Pâ =â .004), and 24 (Pâ =â .005) hours at rest, and at 6 (Pâ =â .002), 12 (Pâ =â .038), and 24 (Pâ =â .015) hours during swallowing in group B. The incidence and severity of hoarseness were comparable at each time-point between the 2 groups (Pâ >â .05). CONCLUSION: Preoperative inhaled budesonide combined with intravenous dexamethasone reduced the incidence and severity of POST at 6, 12, and 24 hours after extubation compared with intravenous dexamethasone alone in patients who underwent thyroidectomy. Additionally, this combination decreased the incidence of postoperative coughing at 24 hours.
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Budesonida , Dexametasona , Faringitis , Complicaciones Posoperatorias , Cuidados Preoperatorios , Tiroidectomía , Humanos , Masculino , Femenino , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Budesonida/administración & dosificación , Tiroidectomía/efectos adversos , Faringitis/prevención & control , Faringitis/etiología , Faringitis/epidemiología , Persona de Mediana Edad , Administración por Inhalación , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/epidemiología , Adulto , Cuidados Preoperatorios/métodos , Administración Intravenosa , Quimioterapia Combinada , Ronquera/prevención & control , Ronquera/etiología , Ronquera/epidemiología , Anestesia General/métodos , Anestesia General/efectos adversos , Glucocorticoides/administración & dosificación , Resultado del TratamientoRESUMEN
Introduction: The ratoon rice planting area is gradually expanding, but there has been relatively little research on ratoon rice grains contaminated with Cd. Methods: In this study, five ratoon rice varieties were selected and divided into three groups according to early-maturity (growth duration: 100-110 days), mid-maturity (growth duration: 110-120 days) and late-maturity (growth duration: 120-130 days) varieties. Field experiments were done to study the differences in Cd accumulation among ratoon rice varieties with different growth duration. Results: The results showed that the Cd accumulation and concentration of grains spikelet at each growth stage in the main crop were in the order of late-maturity > mid-maturity > early-maturity varieties. However, the trends in Cd concentration and accumulation in grains spikelet during the ratoon crop were the opposite. Analysis found that as the growth duration of the variety extended, the accumulated temperature and daily average temperature in the main crop increased, which significantly increased the translocation factors of Cd from root, stem, and leaf to grains spikelet, and increased the daily average Cd accumulation rate in grains spikelet. The daily average temperature in the ratoon crop increased as the growth duration shortened. The early-maturity variety had higher Cd accumulation in stubble, which promoted the translocation of Cd from the root, stem, and leaf of the plant to the grains spikelet. Discussion: Therefore, appropriately shortening the growth duration of the main crop and extending the growth duration of the ratoon crop are important ways to reduce Cd accumulation in ratoon rice in areas with mild Cd pollution.
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Background: There was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL. Methods: A total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival. Results: With a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)-containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT. Conclusion: ASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.
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Quimioterapia de Consolidación , Trasplante de Células Madre Hematopoyéticas , Quimioterapia de Inducción , Linfoma de Células T Periférico , Trasplante Autólogo , Humanos , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Adulto , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inducción de Remisión , Anciano , Estudios Retrospectivos , Adulto Joven , Resultado del Tratamiento , Pronóstico , Terapia CombinadaRESUMEN
Fossilized mating insects are irreplaceable material for comprehending the evolution of the mating behaviours and life-history traits in the deep-time record of insects as well as the potential sexual conflict. However, cases of mating pairs are particularly rare in fossil insects, especially aquatic or semi-aquatic species. Here, we report the first fossil record of a group of water striders in copulation (including three pairs and a single adult male) based on fossils from the mid-Cretaceous of northern Myanmar. The new taxon, Burmogerris gen. nov., likely represents one of the oldest cases of insects related to the marine environment, such as billabongs formed by the tides. It exhibits conspicuous dimorphism associated with sexual conflict: the male is equipped with a specialized protibial comb as a grasping apparatus, likely representing an adaptation to overcome female resistance during struggles. The paired Burmogerris show smaller males riding on the backs of the females, seemingly recording a scene of copulatory struggles between the sexes. Our discovery reveals a mating system dominated by males and sheds light on the potential sexual conflicts of Burmogerris in the Cretaceous. It indicates the mating behaviour remained stable over long-term geological time in these water-walking insects.
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Ámbar , Rasgos de la Historia de Vida , Animales , Femenino , Masculino , Insectos , Reproducción , Copulación , Fósiles , MianmarRESUMEN
Saposhnikoviae Radix (SR) may enhance the pharmacodynamics of Huangqi Chifeng Tang (HQCFT) in the treatment of cerebral infarction according to our previous research, but the underlying mechanism is unknown. Herein, an in vivo pharmacokinetic assay in rats and in vitro MDCK-MDR1 cell assays were used to investigate the possible mechanism of SR, its main components, and its interactions with Astragali Radix (AR) and Paeoniae Radix (PR). An ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLCâMS/MS)-based analytical method for quantifying astragaloside IV (ASIV) and paeoniflorin (PAE) in microdialysis and transport samples was developed. The pharmacokinetic parameters of SR were determined using noncompartmental analyses CCK-8 assays were used to detect the cytotoxicity of ASIV, PAE, cimifugin (CIM), prim-o-glucosylcimifugin (POG) and their combinations. Moreover, drug transport was studied using MDCK-MDR1 cells. Western blotting was performed to measure the protein expression levels of P-GP and MRP1. Claudin-5, ZO-1, and F-actin expression was determined via immunohistochemical staining of MDCK-MDR1 cells. harmacokinetic studies revealed that, compared with those of Huangqi Chifeng Tang-Saposhnikoviae Radix (HQCFT-SR), the Tmax of ASIV increased by 11.11 %, and the MRT0-t and Tmax of PAE increased by 11.19 % and 20 %, respectively, in the HQCFT group. Transport studies revealed that when ASIV was coincubated with 28 µM CIM or POG, the apparent permeability coefficient (Papp) increased by 71.52 % and 50.33 %, respectively. Coincubation of PAE with 120 µM CIM or POG increased the Papp by 87.62 % and 60.95 %, respectively. Moreover, CIM and POG significantly downregulated P-gp and MRP1 (P < 0.05), inhibited the expression of Claudin-5, ZO-1, and F-actin (P < 0.05), and affected intercellular tight junctions (TJs). In conclusion, our study successfully established a selective, sensitive and reproducible UPLCâMS/MS analytical method to detect drugâdrug interactions between SR, AR and PR in vivo and in vitro, which is beneficial for enhancing the therapeutic efficacies of AR and PR. Moreover, this study provides a theoretical basis for further research on the use of SR as a drug carrier.
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Medicamentos Herbarios Chinos , Glucósidos , Monoterpenos , Ratas Sprague-Dawley , Saponinas , Espectrometría de Masas en Tándem , Triterpenos , Animales , Glucósidos/farmacocinética , Glucósidos/análisis , Glucósidos/química , Glucósidos/farmacología , Saponinas/farmacocinética , Saponinas/farmacología , Saponinas/química , Saponinas/análisis , Monoterpenos/análisis , Triterpenos/farmacología , Triterpenos/farmacocinética , Triterpenos/química , Triterpenos/análisis , Perros , Ratas , Células de Riñón Canino Madin Darby , Espectrometría de Masas en Tándem/métodos , Masculino , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Apiaceae/química , Interacciones de Hierba-Droga , Interacciones Farmacológicas , Reproducibilidad de los ResultadosRESUMEN
Cuproptosis and disulfidptosis, recently discovered mechanisms of cell death, have demonstrated that differential expression of key genes and long non-coding RNAs (lncRNAs) profoundly influences tumor development and affects their drug sensitivity. Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, presently lacks research utilizing cuproptosis and disulfidptosis-related lncRNAs (CDRLRs) as prognostic markers. In this study, we analyzed RNA-seq data, clinical information, and mutation data from The Cancer Genome Atlas (TCGA) on ccRCC and cross-referenced it with known cuproptosis and disulfidptosis-related genes (CDRGs). Using the LASSO machine learning algorithm, we identified four CDRLRs-ACVR2B-AS1, AC095055.1, AL161782.1, and MANEA-DT-that are strongly associated with prognosis and used them to construct a prognostic risk model. To verify the model's reliability and validate these four CDRLRs as significant prognostic factors, we performed dataset grouping validation, followed by RT-qPCR and external database validation for differential expression and prognosis of CDRLRs in ccRCC. Gene function and pathway analysis were conducted using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) for high- and low-risk groups. Additionally, we have analyzed the tumor mutation burden (TMB) and the immune microenvironment (TME), employing the oncoPredict and Immunophenoscore (IPS) algorithms to assess the sensitivity of diverse risk categories to targeted therapeutics and immunosuppressants. Our predominant objective is to refine prognostic predictions for patients with ccRCC and inform treatment decisions by conducting an exhaustive study on cuproptosis and disulfidptosis.
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Carcinoma de Células Renales , Neoplasias Renales , ARN Largo no Codificante , Humanos , Carcinoma de Células Renales/genética , ARN Largo no Codificante/genética , Pronóstico , Reproducibilidad de los Resultados , Medicina de Precisión , Neoplasias Renales/genética , Apoptosis , Microambiente TumoralRESUMEN
The coronavirus disease-19 (COVID-19) pandemic, declared in early 2020, has left an indelible mark on global health, with over 7.0 million deaths and persistent challenges. While the pharmaceutical industry raced to develop vaccines, the emergence of mutant severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) strains continues to pose a significant threat. Beyond the immediate concerns, the long-term health repercussions of COVID-19 survivors are garnering attention, particularly due to documented cases of cardiovascular issues, liver dysfunction, pulmonary complications, kidney impairments, and notable neurocognitive deficits. Recent studies have delved into the pathophysiological changes in various organs following post-acute infection with murine hepatitis virus-1 (MHV-1), a coronavirus, in mice. One aspect that stands out is the impact on the skin, a previously underexplored facet of long-term COVID-19 effects. The research reveals significant cutaneous findings during both the acute and long-term phases post-MHV-1 infection, mirroring certain alterations observed in humans post-SARS-CoV-2 infection. In the acute stages, mice exhibited destruction of the epidermal layer, increased hair follicles, extensive collagen deposition in the dermal layer, and hyperplasticity of sebaceous glands. Moreover, the thinning of the panniculus carnosus and adventitial layer was noted, consistent with human studies. A long-term investigation revealed the absence of hair follicles, destruction of adipose tissues, and further damage to the epidermal layer. Remarkably, treatment with a synthetic peptide, SPIKENET (SPK), designed to prevent Spike glycoprotein-1 binding with host receptors and elicit a potent anti-inflammatory response, showed protection against MHV-1 infection. Precisely, SPK treatment restored hair follicle loss in MHV-1 infection, re-architected the epidermal and dermal layers, and successfully overhauled fatty tissue destruction. These promising findings underscore the potential of SPK as a therapeutic intervention to prevent long-term skin alterations initiated by SARS-CoV-2, providing a glimmer of hope in the battle against the lingering effects of the pandemic.
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There have been contradictory reports on the biological role of transforming growth factor-ßs (TGFßs) in breast cancer (BC), especially with regard to their ability to promote epithelial-mesenchymal transition (EMT). Here, we show that TGFß2 is preferentially expressed in mesenchymal-like BCs and maintains the EMT phenotype, correlating with cancer stem cell-like characteristics, growth, metastasis and chemo-resistance and predicting worse clinical outcomes. However, this is only true in ERα- BC. In ERα+ luminal-type BC, estrogen receptor interacts with p-Smads to block TGFß signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFß2 ) that is weakened in TGFß2-overexpressing BC cells. We discover that TGFß2-Snail1 recruits enhancer of zeste homolog-2 to convert miRNAsTGFß2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFß2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFß2 overexpression reverses the mesenchymal-like traits in agreement with the inhibition of TGFß2-Snail1 signalling in BC cells. These findings clarify the roles of TGFß2 in BC and suggest novel therapeutic strategies based on the TGFß2-Snail1-miRNAsTGFß2 loop for a subset type of human BCs.
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Neoplasias de la Mama , MicroARNs , Humanos , Femenino , Neoplasias de la Mama/genética , MicroARNs/genética , Receptor alfa de Estrógeno/genética , Factor de Crecimiento Transformador beta/genética , Transducción de Señal/genéticaRESUMEN
Introduction: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease characterized by excessive deposition of extracellular matrix. Cannabidiol, a natural component extracted from plant cannabis, has been shown to have therapeutic effects on lung diseases, but its exact mechanism of action is unknown, hindering its therapeutic effectiveness. Methods: To establish a pulmonary fibrosis model, combined with UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing, to explore cannabidiol's mechanism in treating pulmonary fibrosis. The rats were randomly divided into the control group, pulmonary fibrosis model group, prednisone treatment group, and cannabidiol low, medium, and high dose groups. The expression levels of HYP, SOD, and MDA in lung tissue and the expression levels of TNF-α, IL-1ß, and IL-6 in serum were detected. Intestinal microbiota was detected using UPLC-QTOF/MS analysis of metabolomic properties and 16S rDNA sequencing. Results: Pathological studies and biochemical indexes showed that cannabidiol treatment could significantly alleviate IPF symptoms, significantly reduce the levels of TNF-α, IL-1ß, IL-6, MDA, and HYP, and increase the expression level of SOD (p < 0.05). CBD-H can regulate Lachnospiraceae_NK4A136_group, Pseudomonas, Clostridia_UCG-014, Collinsella, Prevotella, [Eubacterium]_coprostanoligenes_group, Fusobacterium, Ruminococcus, and Streptococcus, it can restore intestinal microbiota function and reverse fecal metabolism trend. It also plays the role of fibrosis through the metabolism of linoleic acid, glycerol, linolenic acid, and sphingolipid. Discussion: Cannabidiol reverses intestinal microbiota imbalance and attenuates pulmonary fibrosis in rats through anti-inflammatory, antioxidant, and anti-fibrotic effects. This study lays the foundation for future research on the pathological mechanisms of IPF and the development of new drug candidates.
RESUMEN
Cardiovascular disease has become a major cause of death worldwide. Myocardial injury (MI) caused by myocardial infarction, myocarditis, and drug overdose can lead to impaired cardiac function, culminating in serious consequences such as angina pectoris, arrhythmias, and heart failure. Exosomes exhibit high biocompatibility and target specificity, rendering them an important non-cellular therapy for improving MI. Exosomes are diminutive vesicles that encapsulate nucleic acids and proteins. Exosomes derived from cardiac stem cells themselves have therapeutic effects, and they can also serve as carriers to deliver therapeutic drugs to recipient cells, thereby exerting a therapeutic effect. The molecules within exosomes are encapsulated in a lipid bilayer, allowing them to stably exist in body fluids without being affected by nucleases. Therefore, the utilization of exosomes as drug delivery systems (DDS) for disease treatment has been extensively investigated and is currently undergoing clinical trials. This review summarizes the therapeutic effects of exosomes on MI and provides an overview of current research progress on their use as DDS in MI.