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Heart failure is a leading cause of death in the elderly. Traditional Chinese medicine, a verified alternative therapeutic regimen, has been used to treat heart failure, which is less expensive and has fewer adverse effects. In this study, a total of 15 active ingredients of Astragalus membranaceus (Huangqi, HQ) were obtained; among them, Isorhamnetin, Quercetin, Calycosin, Formononetin, and Kaempferol were found to be linked to heart failure. Ang II significantly enlarged the cell size of cardiomyocytes, which could be partially reduced by Quercetin, Isorhamnetin, Calycosin, Kaempferol, or Formononetin. Ang II significantly up-regulated ANP, BNP, ß-MHC, and CTGF expressions, whereas Quercetin, Isorhamnetin, Calycosin, Kaempferol or Formononetin treatment partially downregulated ANP, BNP, ß-MHC and CTGF expressions. Five active ingredients of HQ attenuated inflammation in Ang II-induced cardiomyocytes by inhibiting the levels of TNF-α, IL-1ß, IL-18 and IL-6. Molecular docking shows Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol can bind with its target protein ESR1 in a good bond by intermolecular force. Quercetin, Calycosin, Kaempferol or Formononetin treatment promoted the expression levels of ESR1 and phosphorylated ESR1 in Ang II-stimulated cardiomyocytes; however, Isorhamnetin treatment had no effect on ESR1 and phosphorylated ESR1 expression levels. In conclusion, our results comprehensively illustrated the bioactives, potential targets, and molecular mechanism of HQ against heart failure. Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol might be the primary active ingredients of HQ, dominating its cardioprotective effects against heart failure through regulating ESR1 expression, which provided a basis for the clinical application of HQ to regulate cardiac hypertrophy and heart failure.
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Astragalus propinquus , Medicamentos Herbarios Chinos , Insuficiencia Cardíaca , Simulación del Acoplamiento Molecular , Miocitos Cardíacos , Farmacología en Red , Astragalus propinquus/química , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Quercetina/farmacología , Quercetina/química , Quercetina/análogos & derivados , Angiotensina II/metabolismo , Quempferoles/farmacología , Quempferoles/química , Ratas , Humanos , Isoflavonas/farmacología , Isoflavonas/químicaRESUMEN
Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n = 11) and healthy matched controls (n = 17) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.
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Trastorno de Personalidad Antisocial , Criminales , Tomografía de Emisión de Positrones , Receptores de Dopamina D2 , Violencia , Humanos , Receptores de Dopamina D2/metabolismo , Masculino , Trastorno de Personalidad Antisocial/diagnóstico por imagen , Trastorno de Personalidad Antisocial/metabolismo , Adulto , Tomografía de Emisión de Positrones/métodos , Receptores Opioides mu/metabolismo , Racloprida/farmacocinética , Adulto Joven , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Fentanilo/análogos & derivadosRESUMEN
BACKGROUND: Inflammatory Bowel Diseases (IBD), an autoimmune disease characterised by abnormal intestinal immunity, are related to vital morbidity around the world. However, therapeutic agents for IBD have not achieved desired benefit. Exploring new therapeutic targets for IBD, especially based on its abnormally intestinal immunity, could alleviate the flare-up and worsening of IBD. Tissue resident memory T cells (TRM) are core of multiple autoimmune diseases, including IBD. However, the mechanism of TRM differentiation remains to be investigated. METHODS: The alterations in mRNA and lncRNA profile of intestinal intraepithelial lymphocytes (IELs), the largest component of intestinal TRM, were analyzed in DSS-induced chronic colitis. Based on it, we examined the function of rectal insulin instillation in a dextran sodium sulfate (DSS) induced chronic colitis. Furthermore, we investigated the downstream-target of the insulin pathway-EZH2 and the crucial role of EZH2 in intestinal tissue resident memory T cell differentiation by utilizing EZH2fl/flCD4cre mice. RESULTS: Insulin receptor (INSR) expression was found to be significantly reduced. Activation of mucosal insulin pathway by rectal insulin instillation exacerbated colitis by disrupting IELs subgroups and up-regulating TNF-É and IL-17 expression. Rectal insulin instillation promoted EZH2 expression and EZH2 inhibition alleviated chronic colitis. EZH2fl/flCD4cre mice restored the normal IEL subgroups and suppressed TNF-É and IL-17 expression, exhibiting alleviated colitis. IELs from EZH2fl/flCD4cre mice exhibit significant changes in TRM related phenotype. CD4+TRM was significantly increased in chronic colitis and decreased in EZH2fl/flCD4cre mice. CONCLUSION: Insulin receptor of intestinal mucosal T-cells could promote intestinal TRM differentiation via EZH2. Our discoveries suggest that therapies targeting colonic INSR and EZH2 could be potential treatment for IBD based on its regulatory effects on TRM. Insulin receptor inhibitors rather than insulin should be applied during colitis-active phase. In addition, EZH2 shows to be a downstream signal of the insulin pathway and EZH2 inhibitor could alleviating intestinal inflammation. However, the critical role of EZH2 in TRM differentiation restricts the anti-tumor effects of EZH2 inhibitor in vivo.
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Colitis , Enfermedades Inflamatorias del Intestino , Insulinas , Ratones , Animales , Interleucina-17/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Receptor de Insulina/efectos adversos , Receptor de Insulina/metabolismo , Células T de Memoria , Colitis/inducido químicamente , Diferenciación Celular , Mucosa Intestinal/patología , Inflamación/patología , Insulinas/metabolismo , Sulfato de Dextran/efectos adversos , Modelos Animales de EnfermedadRESUMEN
PURPOSE: Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. METHODS: Based on a historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. Daylength at the time of scanning was used as a predictor for brain regional non-displaceable binding of the radiotracer, while controlling for age and sex. RESULTS: Daylength was negatively correlated with availability of D2/3 dopamine receptors in the striatum. The largest effect was found in the left caudate, and based on the primary sample, every 4.26 h (i.e., one standard deviation) increase of daylength was associated with a mean 2.8% drop (95% CI -0.042 to -0.014) of the receptor availability. CONCLUSIONS: Seasonally varying D2/3 receptor signaling may also underlie the seasonality of mood, feeding, and motivational processes. Our finding suggests that in future studies of brain dopamine signaling, especially in high-latitude regions, the effect of seasonality should be considered.
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RESEARCH QUESTION: Embryo blastomeres and the zona pellucida are occasionally damaged during vitrification; is this a result of crack-induced mechanical damage in the glass state, caused by external bending of the device? DESIGN: A stereomicroscope was used to observe external bending-induced cracks in a cryoprotectant. Thereafter, 309 human cleavage-stage embryos derived from abnormally fertilized eggs were used to assess embryo damage under two external bending conditions: forward bending and backward bending, with three bending degrees applied. Three distinct embryo positions were used to examine the correlation between bending and embryo damage. Damage was assessed by looking at blastomere lysis rates, and overall rates of damaged and surviving embryos. RESULTS: A series of parallel cracks were identified in the cryoprotectant used for external bending, which led to damage to the embryo blastomeres. Compared with forward bending and control, the embryos were found to be more easily damaged by backward bending, indicated by significantly higher blastomere lysis and embryo damage rates, and lower embryo survival rate of backward bending than forward bending (P < 0.001). The degree of embryo damage also increased as the degree of external forces increased. Embryo position correlated with degree of embryo damage. CONCLUSIONS: Cryoprotectant crack-induced damage was identified as the cause of embryo damage. Mechanical damage to the glass state occurs because of improper external bending of the cryodevice strip in liquid nitrogen during vitrification. To prevent damage, bending of the strip should be avoided and the embryos should be placed near the tip of the strip.
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Blastómeros , Criopreservación , Crioprotectores , Vitrificación , Humanos , Crioprotectores/farmacología , Femenino , Embrión de Mamíferos/efectos de los fármacosRESUMEN
BACKGROUND: Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown. METHODS: Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E. RESULTS: NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form. CONCLUSIONS: NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.
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Actinas , Meiosis , Oocitos , Proteína de Unión al GTP cdc42 , Animales , Oocitos/metabolismo , Ratones , Femenino , Actinas/metabolismo , Actinas/genética , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP cdc42/genética , Fosforilación , Huso Acromático/metabolismoRESUMEN
BACKGROUND: Drug shortage is a worldwide problem that seriously threatens public health. China released the most comprehensive list of key drug shortage monitoring varieties ever in 2022. We aim to analyze the attributes and characteristics of the medicines within the list to provide a reference for improving China's supply security of shortage drugs. METHODS: We used public data to extract information on drug types, dosage forms, indications, classification of clinical uses, whether they were included in medical catalogs such as the National Essential Drugs, and the number of drug and active pharmaceutical ingredient (API) manufacturers. A descriptive statistical analysis was used. RESULTS: Of the 980 drugs on the list, 99.59% were chemicals and 92.65% were injectables. Drugs for blood and hematopoietic organs, the cardiovascular system, and the digestive tract and metabolism ranked among the top three shortages. Verification of the medical catalogs showed that 90.41% of the drugs belonged to the national essential drugs, 95.10% were medicare drugs, 2.55% were volume-based procurement drugs, and 14.70% were for rare diseases, and 42.04% were for children. In terms of drug supply capacity, 21.33% of drug approvals are less than 10, and there were even 26 drugs for exclusive production, close to 90% of manufacturers need to purchase APIs from outside. Among the 256 APIs included in the list, 152 APIs had less than 10 manufacturers, and there were even 5 APIs produced by only one enterprise nationwide. CONCLUSIONS: The situation of drug shortages in China was severe and complex, with serious shortages of medicines adapted to basic medical and healthcare needs and clinically necessary medicines, and a need to improve the production capacity of drugs and the ability to supply APIs. We recommend strengthening drug monitoring and stockpiling and accelerating the approval of shortage drugs to improve drug supply security.
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Medicamentos Esenciales , China , Humanos , Estudios Transversales , Preparaciones Farmacéuticas/provisión & distribución , Medicamentos Esenciales/provisión & distribución , Industria FarmacéuticaRESUMEN
Uterine dysplasia is a common cause of infertility. Traditional Chinese medicine has unique advantages in the treatment of this disease. This paper introduces a case of infertility caused by uterine dysplasia treated by Professor MA Kun who adopted the therapy of tonifying kidney and activating blood, aiming to summarize the theoretical foundation and formula principles of Professor MA Kun in the clinical treatment of this disease. The kidney stores essence and governs reproduction. Kidney deficiency is the root cause of infertility. The deficiencies in kidney Qi, Yin, and Yang can result in blood stasis to obstruct the uterus, leading to insufficient source for essence and aggravating kidney deficiency. Kidney deficiency and blood stasis affect each other and form a vicious cycle, resulting in uterine dysplasia due to insufficient nutrition and difficult pregnancy. Therefore, Professor MA Kun believes that kidney deficiency and blood stasis is the key pathogenesis of infertility caused by uterine dysplasia and proposes the treatment principle of tonifying kidney and activating blood. Sufficient essence and Qi in the kidney can resolve stasis and generate blood, thus harmonizing Yin and Yang, which can reach thoroughfare and conception vessels to nourish the uterus and recover the normal physiological function of the uterus. In that case, normal pregnancy is possible. Professor MA Kun attaches importance to the therapeutic principle of supplementing Qi and nourishing blood. In addition, she advocates conforming to changes in the menstrual cycle to promote the development of the uterus and the implantation of fertilized eggs. She also integrates traditional Chinese medicine and western medicine to treat both symptoms and root causes. Professor MA Kun's experience has demonstrated definite clinical effect on this disease and can be taken as a reference.
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Medicamentos Herbarios Chinos , Infertilidad Femenina , Riñón , Femenino , Humanos , Medicamentos Herbarios Chinos/uso terapéutico , Infertilidad Femenina/etiología , Infertilidad Femenina/tratamiento farmacológico , Útero/anomalías , Adulto , Medicina Tradicional China , Embarazo , Enfermedades Renales/etiología , Enfermedades Renales/tratamiento farmacológico , Anomalías UrogenitalesRESUMEN
Uterine fibroids are a prevalent factor that impacts fertility in women of reproductive age. This study discusses the theoretical foundation and formula principles of Professor MA Kun's clinical treatment for infertility caused by uterine fibroids. The kidney stores essence and is responsible for reproduction, while blood serves as a vital material basis for women's physiological functions. Kidney deficiency is the fundamental pathogenesis of infertility, and imbalances in kidney Qi and essence or deficiencies in kidney Yin and Yang can result in blood stasis. Blood stasis plays a significant role throughout this condition by impeding the flow of blood, which is crucial for nourishing Qi. Therefore, both kidney deficiency and blood stasis are key factors contributing to infertility caused by uterine fibroids. Professor MA Kun treats infertility caused by uterine fibroids using an approach that involves tonifying the kidneys and activating blood circulation based on changes in Qi and blood during the menstrual cycle as well as follicular growth processes. By identifying stage-specific evidence, appropriate treatments can be applied accordingly. During menstruation when the uterus opens and menstrual blood flows out, promoting follicular development through nourishing kidney Yin and activating blood circulation becomes essential. In later stages of menstruation, additional measures are taken to remove blood stasis, alleviate symptoms, disperse knots, attack pathogens while simultaneously replenishing vital energy. During intermenstrual periods when Yin holds greater importance than Yang, tonifying the kidneys and activating blood circulation helps facilitate smooth discharge of eggs by promoting transformation between Yin and Yang energies. Premenstrual period to warm kidney Yang to promote pregnant egg implantation, and at the same time to dredge the liver and regulate Qi, Qi elimination stagnation, complementary in the line, with the symptoms of additional subtractions. Clinical effect is remarkable, for the reference of colleagues.
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Medicamentos Herbarios Chinos , Infertilidad Femenina , Riñón , Leiomioma , Humanos , Femenino , Riñón/fisiopatología , Infertilidad Femenina/etiología , Infertilidad Femenina/terapia , Infertilidad Femenina/fisiopatología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Drug shortage is a global problem, and the development of government-enterprise cooperative stockpiles of drugs in shortage, combining physical and production capacity, has become one of the most important means of coping with drug shortages. However, existing studies have tended to overlook the fact that shortages of Active Pharmaceutical Ingredients (APIs) have become an important constraint on production capacity stockpiling and that the lack of incentives and provisions for coordination of benefits have led to a double marginal effect of joint stockpiling by government and enterprises of drugs in shortage. Accordingly, this study introduced the option contract to the drug supply system composed of government and pharmaceutical enterprises and used the subsidy of API storage in lieu as an important initiative to incentivize the reserve of APIs, to construct a model of shortage drug reserve under the government's leadership. This study aims to improve the effect of government-enterprise joint stockpiling of drugs in shortage, which is of great theoretical and practical significance. According to the classification of production license types of pharmaceutical enterprises, this study established a three-level supply chain decentralized decision-making model consisting of the government, formulation enterprises, and API enterprises, and a two-level supply chain centralized decision-making model consisting of the government and API Formulation (API-F) integrated enterprises, respectively. By solving the inverse order derivation, the government-enterprise option cooperation conditions and optimal decision-making strategy were derived. The study results showed that: (i) The addition of enterprise API stockpiling mode can help the government conventional reserves, and enterprise production capacity reserves, broaden the way of drug reserves, and improve the effect of government-enterprise option cooperation; (ii) when the probability of drug shortages is high, the government should prefer the cooperation of API-F integrated enterprises, which is conducive to reducing intermediate links and government costs and improving the supply responsiveness to shortages of medicines; (iii) Setting appropriate government subsidies for API storage can incentivize enterprises to stockpile APIs and improve drug production capacity and physical supply response capability. This study took the problem of socialized stockpiling of drugs in shortage as an entry point and explored the problems and solution strategies in the government-enterprise cooperative stockpiling of drugs in shortage, which not only made some theoretical contributions to the application of options contract in the government-enterprise cooperative stockpiling of drugs in shortage but also provided new ideas and theoretical basis for the improvement of the stockpiling work of drugs in shortage.
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Industria Farmacéutica , Preparaciones Farmacéuticas/provisión & distribución , Preparaciones Farmacéuticas/economía , Industria Farmacéutica/economía , Humanos , Gobierno , Reserva EstratégicaRESUMEN
Objective: Since 2016, China has successively implemented Accelerated Drug Marketing Registration Procedures (ADMRPs) for drugs, including Breakthrough Therapy Drug (BTD), Conditional Approval (CA), and Priority Review and Approval (PRA), which have played an important role in promoting the development and review of clinically urgently needed drugs. In this study, we focused on the antineoplastic and immunomodulating agents approved for marketing through ADMRPs, to provide a reference for promoting the formation of a stable and mature regulatory system for the review and approval of antineoplastic drugs and immunomodulating agents in China. Methods: Reviewed the National Medical Products Administration (NMPA) drug review reports for the years 2016-2022 and screened the antineoplastic and immunomodulating agents approved through ADMRPs. Then, with the help of the NMPA website and the Yaozhi Database, two researchers independently queried and entered the detailed information of the selected drugs, and checked with each other. The attribute classification and main characteristics of the drugs were then analyzed with descriptive statistics to obtain the trend of drug types, drug review and approval status, and timeliness. Results: A total of 206 antineoplastic and immunomodulating agents were approved for marketing through five accelerated marketing registration procedures (or procedure combinations), with the average review time shortened by about 81 days. Among them, imported drugs accounted for a larger proportion, the most drugs for treating non-small cell lung cancer and lymphoma, and the largest number of PD-1/PDL-1 inhibitors, but pediatric drugs and rare disease drugs accounted for a smaller proportion. Conclusion: ADMRPs can promote the accessibility of antineoplastic and immunomodulating agents in China and safeguard the life and health rights of more patients. Nevertheless, it is necessary to pay attention to the expansion of the types of indications for medicines and to increase the development of drugs that are urgently needed by a small number of patients.
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In the past few decades, great progress has been made in prenatal diagnosis of congenital heart disease (CHD). Fetal echocardiography is recognized as the main prenatal screening and diagnostic tool that can accurately detect approximately 85 % of fetal cardiac abnormalities. Evaluation of the fetal heart remains a major challenge in prenatal ultrasound screening and diagnosis due to fetal position, involuntary movement, small and complex fetal cardiac anatomy, maternal abdominal wall conditions, and lack of expertise in fetal echocardiography by some physicians engaged in obstetric ultrasound. Artificial intelligence (AI) can automate and standardize the display of each diagnostic section of the fetal heart and thus contribute to accurate diagnosis, which significantly optimizes the clinical application of fetal echocardiography. In this review, we not only clarify the role of AI but also highlight its significance and future solutions in the field of fetal echocardiography.
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IL1RL2 has been reported to be highly expressed in a variety of tumor types whereas its role in bladder cancer (BLCA) remains unclear. The aim of the present study was to explore the prognostic value of Il1RL2 in BLCA and its relationship with clinical pathological features. The Cancer Genome Atlas (TCGA) database was used to assess the levels of IL1RL2 expression in BLCA tissues and cells, which were validated by reverse transcription-quantitative polymerase chain reaction and western blotting. Immunohistochemistry was employed to analyze expression of the IL1RL2 gene in 17 pairs of tumor and normal specimens, as well as 112 samples with different stages and grades of tumors. To investigate the biological functions of Il1RL2 in BLCA, co-expression networks and functional enrichment analyses were conducted. A protein-protein interaction network was constructed using interaction gene search tools. IL1RL2 was revealed to be clearly expressed in BLCA cells and tissues. The area under the curve for amplification of IL1RL2 distinguishing between tumor and normal tissues was 0.700 (95% CI: 0.579-0.821) in the TCGA database and 0.647 (95% CI: 0.497-0.797) in Miyun chart database, respectively. Furthermore, in our database, both univariate and multivariate analyses indicated that IL1RL2 expression was an independent risk factor for overall survival (OS). Kaplan-Meier survival analysis revealed an association between high IL1RL2 expression and low OS. Pathway enrichment analysis suggested that IL1RL2 is involved in the regulation of tumor progression through the MAPK signaling pathway. The expression level of IL1RL2 was associated with the stage, grade, lymph node album and prognosis of BLCA.
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Coronary slow flow (CSF) is characterized by slow progression of coronary angiography without epicardial stenosis. The aim of this study was to explore the potential biomarkers and regulatory mechanism for CSF. Peripheral blood mononuclear cells from 3 cases of CSF and 3 healthy controls were collected for high-throughput sequencing of mRNA and miRNA, respectively. The differentially expressed mRNAs (DE-mRNAs) and miRNAs (DE-miRNAs) was identified. A total of 117 DE-mRNAs and 32 DE-miRNAs were obtained and they were mainly enriched in immune and inflammatory responses. Twenty-six DE-mRNAs were the predicted target genes for miRNAs by RAID, and then the regulatory network of 15 miRNAs were constructed. In addition, through the PPI network, we identified the three genes (FPR1, FPR2 and CXCR4) with larger degrees as hub genes. Among them, FPR1 was regulated by hsa-miR-342-3p, hsa-let-7c-5p and hsa-miR-197-3p and participated in the immune response. Finally, we validated the differential expression of hub genes and key miRNAs between 20 CSF and 20 control. Moreover, we found that miR-342-3p has a targeted regulatory relationship with FPR1, and their expression is negatively correlated. Then we established a hypoxia/reoxygenation (H/R) HUVEC model and detected FPR1, cell proliferation and apoptosis. Transfection with miR-342-3p mimics can significantly promote the proliferation of HUVEC under H/R conditions. FPR1 were associated with CSF as a biomarker and may be regulated by miR-342-3p potential biomarkers.
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Leucocitos Mononucleares , MicroARNs , Humanos , Leucocitos Mononucleares/metabolismo , MicroARNs/metabolismo , Hipoxia , Expresión Génica , Biomarcadores , Redes Reguladoras de GenesRESUMEN
Ustiloxins is a mycotoxin produced by the metabolism of Rice false smut. Studies have shown that Ustiloxins may be toxic to animals, but there is still a lack of toxicological evidence. The liver, as the main organ for the biotransformation of foreign chemicals, may be the direct target organ of Ustiloxins toxicity. In this study, we found that cell viability decreased in a dose- and time-dependent manner when BNL CL.2 cells were treated with different concentrations of Ustiloxins (0, 5, 10, 20, 30, 40, 60, 80, 100, 150 and 200 µg/mL) for 24 and 48 h. In addition, scanning electron microscope observation showed that the cell membrane of the experimental group was damaged, with the appearance of apoptotic bodies. Moreover, the ROS and GSH levels were significantly increased in cells exposed to Ustiloxins. We analyzed the key action targets of Ustiloxins on hepatocyte injury using full-length transcriptomics. A total of 1099 differentially expressed genes were screened, of which 473 genes were up-regulated, and 626 genes were down-regulated. Besides, we also found that the expression of MCM7 and CDC45 in BNL CL.2 cells treated with Ustiloxins decreased, and the expression of CCl-2, CYP1b1, CYP4f13, and GSTM1 increased according to qRT-PCR. Ustiloxins might change CYP450 and GST-related genes, affect DNA replication and cell cycle, and lead to oxidative stress and liver cell injury.
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Oryza , Péptidos Cíclicos , Animales , Péptidos Cíclicos/toxicidad , Perfilación de la Expresión Génica , Hepatocitos , Hígado/químicaRESUMEN
Histone phosphorylation is instrumental in regulating diverse cellular processes across eukaryotes. Unraveling the kinases that target specific histone sites is key to deciphering the underlying mechanisms. Among the various sites on histone tails that can undergo phosphorylation, the kinase responsible for H3.3S31 phosphorylation remained elusive. Since both H3.3S31ph and H3T3ph occur specifically during mitosis, and Haspin is the known kinase for H3T3 phosphorylation, we investigated its potential role in H3.3S31 phosphorylation. We employed CRISPR/Cas9, RNA interference, and specific small molecule inhibitors to eliminate Haspin function in various cell types. Our data consistently revealed a link between Haspin and H3.3S31ph. Furthermore, in vitro kinase assays provided evidence supporting Haspin's contribution to H3.3S31ph. Loss- and gain-of-function experiments targeting Haspin and Aurora B further suggested a hierarchical relationship. Haspin acts as a downstream kinase of Aurora B, specifically orchestrating H3.3S31 phosphorylation in mESCs. This study unveils a novel role for Haspin as a kinase in regulating H3.3S31 phosphorylation during mitosis. This discovery holds promise for expanding our understanding of the functional significance of Haspin and H3.3S31ph in mammals.
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Aurora Quinasa B , Histonas , Péptidos y Proteínas de Señalización Intracelular , Células Madre Embrionarias de Ratones , Proteínas Serina-Treonina Quinasas , Animales , Humanos , Ratones , Aurora Quinasa B/metabolismo , Aurora Quinasa B/genética , Histonas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Embrionarias de Ratones/citología , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
BACKGROUND: Liver injury post allogeneic hematopoietic stem cell transplantation (Allo-HSCT), particularly first-time occurrences, is a prevalent and severe complication. METHODS: Clinical data from 262 patients treated at 3 medical centers in Shenzhen, China, between January 2018 and December 2021 were retrospectively collected. Risk factors and outcomes of initial liver injury post allo-HSCT were analyzed. RESULTS: Liver injury occurred in 70.8% of patients, with drug-induced liver injury (DILI) being the most common cause. Other causes included graft-versus-host disease (GVHD) and veno-occlusive disease (VOD). Pre-transplant HBsAg positivity was a significant risk factor. Differences in the timing and survival outcomes were observed among patients with different causes and types of liver injury. Patients with VOD or hepatic aGVHD had lower overall survival compared to those with DILI or hepatic cGVHD. Patients with isolated enzyme elevation had a more favorable prognosis than those with isolated bilirubin elevation or simultaneous enzyme and bilirubin elevation. CONCLUSION: Findings of our study serve as a crucial resource for clinicians, assisting in the challenging task of diagnosing and managing liver injuries after allo-HSCT, especially when it occurs for the first time, which may ultimately help to reduce early treatment-related mortality and enhance the long-term survival of transplant recipients.
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Glioma remains one of the most challenging primary brain malignancies to treat. Long noncoding RNAs (lncRNAs) and mRNAs (mRNAs) are implicated in regulating the malignant phenotypes of cancers including glioma. This study aimed to elucidate the functions and mechanisms of lncRNA LINC00265 and mRNA IFI30 in the pathogenesis of glioma. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed the upregulated expression of LINC00265 and IFI30 in glioma cells compared to normal human astrocytes. Western blot (WB) quantified the associated proteins. Glioma stemness and epithelial-to-mesenchymal transition (EMT) were assessed by aldehyde dehydrogenase 1 (ALDH1) activity, sphere formation, and WB. Mechanistic and rescue assays evaluated the LINC00265/miR-let-7d-5p/IFI30/ZNF384/IGF2BP2 axis. The results demonstrated that LINC00265 and IFI30 were highly expressed in glioma cells, promoting stemness and EMT. ZNF384 was identified as a transcription factor that upregulates IFI30. Moreover, LINC00265 elevated ZNF384 by sponging miR-let-7d-5p and recruiting IGF2BP2. In conclusion, LINC00265 and IFI30 act as oncogenes in glioma by driving stemness and EMT, underscoring their potential as therapeutic targets.
Asunto(s)
Neoplasias Encefálicas , Glioma , MicroARNs , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , ARN no Traducido/genéticaRESUMEN
Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.
RESUMEN
BACKGROUND: The diagnosis and evaluation of the severity of acute mountain sickness (AMS) continue to be problematic due to a lack of consensus on the inclusion of symptoms in a scoring system. Recent investigations highlight the significance of gastrointestinal symptoms in identifying this condition. However, the specific gastrointestinal symptoms associated with AMS have not been thoroughly elucidated in previous studies, and the underlying risk factors remain inadequately comprehended. METHODS: This study aimed to investigate the characteristics, trends, and risk factors related to gastrointestinal symptoms encountered during train travel to high altitude. A total of 69 passengers, specifically all with medical backgrounds, were surveyed 6 times over a period of 14 days. RESULTS: The daily incidence of abdominal discomfort was higher than non-gastrointestinal symptoms within 14 days. Gastrointestinal symptoms demonstrated a greater prevalence, longer duration, and increased risk compared to non-gastrointestinal symptoms, such as headaches. The symptoms of abdominal distension and bowel sound hyperaction were found to be prevalent and persistent among patients diagnosed with AMS, exhibiting a high incidence rate. Gender, age, body mass index (BMI), smoking habits, and alcohol consumption were identified as risk factors associated with the occurrence and duration of gastrointestinal symptoms. CONCLUSION: This study suggests that gastrointestinal symptoms are more common and persistent when traveling to the plateau by train. These symptoms should be taken into consideration in the further diagnosis and prevention of AMS. Therefore, this study provides a significant theoretical foundation for the prevention and treatment of AMS.