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Accurate quantification of flow dynamics during reservoir ecological scheduling hinders the maintenance of normal reproductive activities in downstream riverine fish. This study proposed a quantitative method for determining the flow rate changes in reservoir ecological scheduling. The approach utilized the daily flow rate and daily flow-rate increment to characterize the flow process. Adopting the perspective of shifting spawning grounds of adhesive egg-laying fish species in response to flow rate variations, we introduced the Spawning Ground Overlap Rate as an indicator and utilized it to determine flow rate changes. Focusing on the downstream area of the Yangqu Hydropower Station in the upper reaches of the Yellow River, we calculated the distribution of spawning grounds and the Spawning Ground Overlap Rate in the region. We set a threshold for the Spawning Ground Overlap Rate to restrict the flow rate changes. The results indicated that during the fish spawning period, the ecological flow range in the downstream area of the Yangqu Dam was 480-1200 m3/s. It was required to maintain a daily flow rate change of less than 49.45 m3/(s·d) and a maximum seven-day flow difference of less than 227.76 m3/s to maintain the optimal level of spawning ground overlap rate. Additionally, it was necessary to keep the daily flow rate change below 123.83 m3/(s·d) and the maximum seven-day flow difference below 368.84 m3/s to maintain the minimum spawning ground overlap rate. The findings provide foundational data for determining flow dynamics during the ecological scheduling of the spawning period for viscous-spawning fish.
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Ríos , Animales , Peces/fisiología , Reproducción , Ecosistema , Ecología , China , Movimientos del AguaRESUMEN
AIM: To synthesize qualitative research on perspectives and understandings of Intensive Care Unit (ICU) patients, family members, and staff regarding respect and dignity in ICU, in order to explore the connotations and meanings of respect and dignity in ICU. DESIGN: A qualitative meta-synthesis. METHODS: The Chinese and English databases were systematically searched, including PubMed, Web of Science, CINAHL, Embase, Cochrane Library, CNKI, Wangfang Data, VIP, and CBM from each database's inception to July 22, 2023. Studies were critically appraised using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Qualitative Research. Qualitative data were extracted, summarized, and meta-synthesized. (PROSPERO: CRD42023447218). RESULTS: A total of 9 studies from 6 countries were included in the meta-synthesis. Thirty-six main themes and 67 sub-themes were extracted, which were eventually integrated into 9 categories and 4 themes: (1) integrity of humanity; (2) autonomy; (3) equality; (4) environmental support. CONCLUSION: To maintain patient dignity, it is necessary to create an environment of respect within the ICU where healthcare professionals uphold the concept of preserving human integrity and respect patients' autonomy and equality. Healthcare professionals need to value the dignity of ICU patients and treat them as unique individuals during treatment and care. Hospital managers should also strive to create a respectful environment to provide environmental support for dignity care implementation.
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Unidades de Cuidados Intensivos , Investigación Cualitativa , Respeto , Humanos , Unidades de Cuidados Intensivos/organización & administración , PersoneidadRESUMEN
INTRODUCTION: Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with heart failure and stroke, leading sometimes to death. But the pathogenesis of AF remains unclear. Numerous studies have investigated whether the connexin 40 (Cx40) polymorphisms influences the risk of AF, but the results are controversial. METHODS: We searched English and Chinese databases and calculated the odds ratio (OR) and 95% confidence interval (CI) to examine the existence of genetic associations between the Cx40 polymorphisms and the risk of AF. All relevant studies were screened and meta-analyzed using Review Manager 5.0. RESULTS: A total of 12 studies, including 10 studies for -44 polymorphism (rs35594137) and 4 studies for -26 polymorphism (rs10465885), were identified for the meta-analysis. For -44 polymorphism, the results showed a significantly increased risk of AF in the five genetic models in the overall analysis. Furthermore, in subgroup analysis, increased AF risks were also observed in Asian and non-Asian populations. For -26 polymorphism, the overall OR revealed an increased risk of AF in dominant model. In subgroup analysis, increased AF risk was only found in recessive genetic model of the Asian population. CONCLUSIONS: The Cx40 polymorphisms were positively associated with AF in both populations, especially on -44 polymorphism.
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Fibrilación Atrial , Conexinas , Humanos , Fibrilación Atrial/complicaciones , Conexinas/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteína alfa-5 de Unión ComunicanteRESUMEN
Coronary ostial stenosis, treated by either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), is a rare but potentially life-threatening complication following surgical aortic valve replacement. However, in cases of complete occlusion of the coronary ostium (COCO), CABG is the typical treatment because guiding catheter engagement is extremely challenging. Herein, we presented a case of a patient with COCO who underwent successful PCI through a retrograde approach, and this case first demonstrates the feasibility of PCI for the treatment of COCO, which could help avoid the high risk of redo surgery.
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Estenosis de la Válvula Aórtica , Estenosis Coronaria , Prótesis Valvulares Cardíacas , Intervención Coronaria Percutánea , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/cirugía , Estenosis Coronaria/etiología , Estenosis Coronaria/cirugía , Prótesis Valvulares Cardíacas/efectos adversos , HumanosRESUMEN
Machine-vision-based defect detection, instead of manual visual inspection, is becoming increasingly popular. In practice, images of the upper surface of cableway load sealing steel wire ropes are seriously affected by complex environments, including factors such as lubricants, adhering dust, natural light, reflections from metal or oil stains, and lack of defect samples. This makes it difficult to directly use traditional threshold-segmentation-based or supervised machine-learning-based defect detection methods for wire rope strand segmentation and fracture defect detection. In this study, we proposed a segmentation-template-based rope strand segmentation method with high detection accuracy, insensitivity to light, and insensitivity to oil stain interference. The method used the structural characteristics of steel wire rope to create a steel wire rope segmentation template, the best coincidence position of the steel wire rope segmentation template on the real-time edge image was obtained through multiple translations, and the steel wire rope strands were segmented. Aiming at the problem of steel wire rope fracture defect detection, inspired by the idea of dynamic background modeling, a steel wire rope surface defect detection method based on a steel wire rope segmentation template and a timely spatial gray sample set was proposed. The spatiotemporal gray sample set of each pixel in the image was designed by using the gray similarity of the same position in the time domain and the gray similarity of pixel neighborhood in the space domain, the dynamic gray background of wire rope surface image was constructed to realize the detection of wire rope surface defects. The method proposed in this paper was tested on the image set of Z-type double-layer load sealing steel wire rope of mine ropeway, and compared with the classic dynamic background modeling methods such as VIBE, KNN, and MOG2. The results show that the purposed method is more accurate, more effective, and has strong adaptability to complex environments.
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Visual perception-based methods are a promising means of capturing the surface damage state of wire ropes and hence provide a potential way to monitor the condition of wire ropes. Previous methods mainly concentrated on the handcrafted feature-based flaw representation, and a classifier was constructed to realize fault recognition. However, appearances of outdoor wire ropes are seriously affected by noises like lubricating oil, dust, and light. In addition, in real applications, it is difficult to prepare a sufficient amount of flaw data to train a fault classifier. In the context of these issues, this study proposes a new flaw detection method based on the convolutional denoising autoencoder (CDAE) and Isolation Forest (iForest). CDAE is first trained by using an image reconstruction loss. Then, it is finetuned to minimize a cost function that penalizes the iForest-based flaw score difference between normal data and flaw data. Real hauling rope images of mine cableways were used to test the effectiveness and advantages of the newly developed method. Comparisons of various methods showed the CDAE-iForest method performed better in discriminative feature learning and flaw isolation with a small amount of flaw training data.
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Xenorhabdus spp., entomopathogenic bacteria symbiotically associated with the nematodes of the Steinernematid family, are known to produce several toxic proteins that interfere with the cellular immune responses of insects. In order to identify novel cytotoxins from Xenorhabdus spp., a fosmid library of X. stockiae HN_xs01 strain was constructed and the cytotoxicity of fosmid clones was tested against insect midgut CF-203 cells. An FS2 clone bearing the srfABC operon, originally identified in Salmonella enterica, exhibited excellent cytotoxicity against CF-203 cells. The srfABC operon alone exhibited cytotoxic effects and all three components of SrfABC toxin were essential for full cytotoxicity. Immunofluorescence studies showed that SrfABC toxin could depolymerize microtubules and disrupt mitochrondria. Flow cytometer analysis demonstrated that SrfABC toxin significantly induced G2/M phase arrest and apoptosis in CF-203 cells. Furthermore, SrfABC toxin exhibits highly injectable insecticidal activity against Helicoverpa armigera larvae. As is often found in host-associated microorganisms, SrfABC toxin is thought to play an important role in host colonization.
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Toxinas Bacterianas/farmacología , Mariposas Nocturnas/microbiología , Rhabditoidea/microbiología , Xenorhabdus , Animales , Toxinas Bacterianas/genética , Toxinas Bacterianas/toxicidad , Ciclo Celular/efectos de los fármacos , Línea Celular , Genoma Bacteriano , Biblioteca Genómica , Insectos/efectos de los fármacos , Insectos/microbiología , Insectos/parasitología , Insecticidas/farmacología , Mariposas Nocturnas/efectos de los fármacos , Mariposas Nocturnas/parasitología , Control Biológico de Vectores , Xenorhabdus/genética , Xenorhabdus/metabolismo , Xenorhabdus/patogenicidadRESUMEN
BACKGROUND: Glycogen Storage Disease Type III (GSD III) is a rare autosomal recessive metabolic disorder caused by AGL gene mutation. There is significant heterogeneity between the clinical manifestations and the gene mutation of AGL among different ethnic groups. However, GSD III is rarely reported in Chinese population. CASE PRESENTATION: In this study, we aimed to study the genetic and clinical characteristics of four patients with GSD IIIa from China, especially the neurological manifestations. Meanwhile, we conducted a literature review of GSD IIIa cases reported in Chinese population to investigate the relationship between genotype and phenotype. CONCLUSIONS: Three different AGL gene mutations were identified in our patients: c.206dupA, c.1735 + 1G > T and c.2590 C>T. Moreover, progressive myopathy accompanied by elevated creatine kinase level was the main manifestation of our patients in adolescents. Our results showed that AGL c.206dupA was a novel mutation and caused severe clinical manifestations. AGL c.1735 + 1G > T might be a recurrent mutation in the Chinese population. Genetic analysis of AGL gene mutation combined with muscle magnetic resonance imaging (MRI) might provide greater benefit to the patient in diagnosing GSD IIIa, rather than an invasive diagnostic procedure of biopsy.
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Creatina Quinasa/metabolismo , Sistema de la Enzima Desramificadora del Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno Tipo III/genética , Enfermedades Musculares/genética , Mutación , Preescolar , China , Femenino , Pruebas Genéticas , Enfermedad del Almacenamiento de Glucógeno Tipo III/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo III/metabolismo , Humanos , Lactante , Masculino , Enfermedades Musculares/etiología , Enfermedades Musculares/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Erythropoietin (EPO) has been reported to exert protective effects on a host of damaged tissues. However, the erythropoietic effect of this hormone can result in high risks of thrombosis, stroke, and hypertension, remarkably limiting the clinical use of EPO. Helix B surface peptide (HBSP) is a small peptide derived from the helix-B domain of EPO. Surprisingly, HBSP retains the tissue protective properties of EPO without altering the hematocrit. Thus, we evaluated the possible role of HBSP on diabetic cardiomyopathy. METHODS: Diabetes was induced in mice by intraperitoneal injections of streptozocin (STZ). Mice were randomly treated with normal saline or HBSP. Cardiac function, fibrosis, apoptosis, and myocardial mitochondrial morphology were examined. For in vitro experiments, H9C2 myoblast cells were randomly grouped as normal glucose (NG, 5 mM), NG+HBSP (100 nM), high glucose (HG, 33 mM), HG+HBSP (100 nM), HG+HBSP+3-methyladenine (3-MA, 10 mM), HG+rapamycin (Rapa, 100 nM), and HG+HBSP+Compound C (CC, 10 mM). Autophagosomes, LC3 dots, apoptosis and mitochondria membrane potential (MMP) of H9C2 cells were examined.The expressions of LC3, p62, p-AMPK (Thr172) and p-mTOR (Ser2448) were examined by Western blot. RESULTS: HBSP markedly improved cardiac function, attenuated cardiac interstitial fibrosis, inhibited myocardial apoptosis, and ameliorated mitochondrial ultrastructure in mice with diabetic cardiomyopathy. HG reduced autophagy in H9C2 cells. HBSP enhanced autophagy in HG-treated H9C2 cells. HBSP reduced the apoptosis index of HG-treated H9C2 cells. HBSP increased the MMP of HG-treated H9C2 cells. HBSP increased the levels of p-AMPK (Thr172), and reduced p-mTOR (Ser2448) in HG-treated H9C2 cells, and the increase of p-AMPK (Thr172) was accompanied by the stimulation of autophagy. Autophagy inhibitor 3-MA and AMPK inhibitor CC mitigated HBSP-induced beneficial effect, whereas autophagy inducer Rapa alleviated the HG-induced cell apoptosis. CONCLUSIONS: HBSP attenuates diabetic cardiomyopathy via autophagy mediated by AMPK-dependent pathway. HBSP may be a potential therapeutic intervention for diabetic cardiomyopathy.
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Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/efectos de los fármacos , Diabetes Mellitus Experimental/terapia , Cardiomiopatías Diabéticas/terapia , Eritropoyetina/química , Fragmentos de Péptidos/química , Animales , Apoptosis , Línea Celular Tumoral , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Ecocardiografía , Hematócrito , Interleucina-6/metabolismo , Masculino , Potenciales de la Membrana , Ratones , Ratones Endogámicos C57BL , Mitocondrias/patología , Miocardio/patología , Ratas , Estreptozocina , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Diabetic cardiomyopathy (DCM) is often associated with suppressed cardiac autophagy, mitochondrial structural and functional impairment. Sirtuin-3 (Sirt3) has been reported to play a crucial role in mitochondrial homeostasis and confers a protective role against the onset and development of DCM although the precise mechanism(s) remains elusive. Here we hypothesized that Sirt3 exerts cardioprotection against DCM by activating Parkin-mediated mitophagy, en route to preserved mitochondrial homeostasis and suppressed cardiomyocyte apoptosis. Adult male wild-type (WT) and Sirt3 knockout (Sirt3KO) mice were treated with streptozotocin (STZ) or vehicle for 3months prior to assessment of echocardiographic property, interstitial fibrosis, cardiomyocyte apoptosis, mitochondrial morphology, cardiac autophagy and cell signaling molecules. Our findings revealed that STZ-induced diabetes mellitus prompted cardiac dysfunction, interstitial fibrosis, cardiomyocyte apoptosis and mitochondrial injury, accompanied with suppressed autophagy and mitophagy, the effects of which were aggravated by Sirt3KO. To the contrary, Sirt3 overexpression in vitro activated autophagy and mitophagy, inhibited mitochondrial injury and cardiomyocyte apoptosis, the effects of which were attenuated by autophagy inhibition using 3-MA. Moreover, deacetylation of Foxo3A and expression of Parkin were decreased by Sirt3KO, while these effects were facilitated by Sirt3OE in diabetic and high glucose settings. Taken together, our data suggested that suppressed Sirt3-Foxo3A-Parkin signaling mediated downregulation of mitophagy may play a vital role in the development of diabetic cardiomyopathy. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure edited by Dr. Jun Ren & Yingmei Zhang.
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Cardiomiopatías Diabéticas/metabolismo , Mitocondrias Cardíacas/metabolismo , Mitofagia , Miocitos Cardíacos/metabolismo , Transducción de Señal , Sirtuina 3/deficiencia , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Apoptosis , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/patología , Miocitos Cardíacos/patología , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Emerging evidence favors the notion that macrophage autophagy plays a prominent role in the pathogenesis of vulnerable plaque, suggesting the therapeutic potential of targeting autophagy in atherosclerosis. Here ApoE(-/-) mice were crossed with Mst1 knockout or Mst1 Tg mice to generate ApoE(-/-):Mst1(-/-) and ApoE(-/-):Mst1Tg mice. All animals were fed high-fat-diet for 4months to induce arterial atherosclerosis. Murine macrophage RAW264.7 cells were subjected to ox-LDL (50µg/mL) in an effort to examine the cellular mechanisms. A significant increase in the levels of Mst1 and p-Mst1 was observed in the aorta of ApoE(-/-) mice. Mst1 knockout significantly reduced atherosclerotic area, decreased lipid core area and macrophage accumulation as compared with ApoE(-/-) mice. Along the same line, Mst1 overexpression increased plaque area, lipid core and macrophage accumulation as compared with ApoE(-/-) mice. Mst1 deficiency significantly increased levels of Beclin1 and LC3II, while decreased that of p62 in aortic atherosclerosis. Moreover, in vitro data indicated that Mst1 knockdown prompted more typical autophagosomes upon ox-LDL challenge. Mst1 knockdown also enhanced autophagic flux as evidenced by GFP-mRFP-LC3 staining, increased LC3-II expression and decreased p62 expression in the presence of bafilomycin A1. Mst1 knockdown decreased, while Mst1 overexpression increased macrophage apoptosis upon ox-LDL exposure. In conclusion, Mst1 deficiency diminishes atherosclerosis and stabilizes atherosclerotic plaques in ApoE(-/-) mice. Mst1 may participate in atherosclerosis progression through inhibition of macrophage autophagy and promotion of macrophage apoptosis.
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Apoptosis/genética , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Autofagia/genética , Factor de Crecimiento de Hepatocito/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Proteínas Proto-Oncogénicas/genética , Animales , Apolipoproteínas E/deficiencia , Aterosclerosis/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Genotipo , Factor de Crecimiento de Hepatocito/deficiencia , Factor de Crecimiento de Hepatocito/metabolismo , Lipoproteínas LDL/administración & dosificación , Lipoproteínas LDL/metabolismo , Ratones , Ratones Noqueados , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
Invasive yeast infections cause significant morbidity and mortality. Surveillance for the infection is necessary to detect trends in species distribution and antifungal resistance. We performed this retrospective study of yeast infection at Jinling Hospital, Nanjing in China, from year of 2010 to 2012. A total of 341 yeast isolates were obtained from patients with invasive infections in the period. Among these isolates, Candida spp. comprised of the highest percentage of yeast strains (91.8 %), followed by Cryptococcus neoformans (5.9 %) and other non-Candida yeast strains (2.3 %). Bloodstream isolates made up 41.3 % of yeast strains and the isolates from CVC made up 17.3 %. Among Candida spp., C. albicans was the most common species identified from non-blood clinical specimens (42.9 %), but appeared in only 20.8 % of blood isolates (P < 0.001). C. tropicalis was the most prevalent Candida species in the blood samples (28.5 %). Candida spp. was mainly isolated from specimens of the ICU patients, while C. neoformans was mainly isolated from specimens in medical wards. Resistance to FLC occurred in 3.7 % of C. albicans, 9.9 % of C. tropicalis, 74.0 % of C. glabrata, and 4.4 % of C. parapsilosis. Most (>92 %) isolates of C. albicans, C. tropicalis, C. parapsilosis, and C. neoformans strains were susceptible to VRC; However, 26.7 % of isolates of C. glabrata were VRC resistant.
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Antifúngicos/farmacología , Candida/clasificación , Candida/efectos de los fármacos , Cryptococcus/clasificación , Cryptococcus/efectos de los fármacos , Fungemia/epidemiología , Fungemia/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Candida/aislamiento & purificación , Niño , Preescolar , China/epidemiología , Cryptococcus/aislamiento & purificación , Monitoreo Epidemiológico , Femenino , Hospitales , Humanos , Lactante , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
The development of hydroelectric projects has adversely affected the reproductive activities of downstream fish species. To facilitate the natural reproduction of fish and restore spawning grounds post-dam construction, it is imperative to explore the ecological factors crucial for their reproduction. Currently, various research methods with different advantages and limitations are employed for this purpose. Using identified spawning locations and periods as clues, we quantitatively investigate the flow velocity, water depth, water temperature, and riverbed substrate required for spawning. The results are validated using habitat simulation methods, aiming to establish a more scientific approach to explore ecological factors affecting fish reproduction. This study provides a more scientific, systematic, and detailed report on the ecological factors required for the spawning of Gymnocypris eckloni: flow velocity ranging from 0.19 to 0.97 m/s, water depth from 0.28 to 1.12 m, water temperature between 11.4 and 15.2°C, and predominantly gravel substrate. The reliability of the results was verified in another spawning ground, with good verification results. This research provides crucial data for the bio-mimetic reproductive technology of Gymnocypris eckloni and the restoration of spawning grounds for natural fish reproduction post-dam construction. It addresses the lack of suitable ecological factor data for protective fish species in the upper reaches of the Yellow River. The method exhibits strong scientific, accurate, and implementable characteristics.
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AIMS: To explore the clinico-sero-pathological characteristics and risk prediction model of idiopathic inflammatory myopathy (IIM) patients with different muscular perifascicular (PF) changes. METHODS: IIM patients in our center were enrolled and the clinico-sero-pathological data were retrospectively analyzed. A decision tree model was established through machine learning. RESULTS: There were 231 IIM patients enrolled, including 53 with perifascicular atrophy (PFA), 39 with perifascicular necrosis (PFN), and 26 with isolated perifascicular enhancement of MHC-I/MHC-II (PF-MHCn). Clinically, PFA patients exhibited skin rashes and dermatomyositis-specific antibodies (DM-MSAs, 74.5%) except for anti-Mi2. PFN patients showed the most severe muscle weakness, highest creatine kinase (CK), anti-Mi2 (56.8%), and anti-Jo-1 (24.3%) antibodies. PF-MHCn patients demonstrated negative MSAs (48.0%) and elevated CK. Histopathologically, MAC predominantly deposited on PF capillaries in PFA but on non-necrotic myofiber in PFN (43.4% and 36.8%, p < 0.001). MxA expression was least in PF-MHCn (36.0% vs. 83.0% vs. 63.2%, p < 0.001). The decision tree model could effectively predict different subgroups, especially PFA and PFN. CONCLUSIONS: Three types of PF change of IIMs representing distinct clinico-serological characteristics and pathomechanism. Undiscovered MSAs should be explored especially in PF-MHCn patients. The three pathological features could be accurately predicted through the decision tree model.
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Miositis , Humanos , Miositis/patología , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Anciano , Autoanticuerpos/sangre , Necrosis , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Aprendizaje Automático , Árboles de DecisiónRESUMEN
BACKGROUND: Wenqingyin (WQY), an ancient Chinese medicinal agent, has been extensively used in treating infectious ailments throughout history. However, the anti-sepsis mechanism remains unknown. PURPOSE: This study investigated the diverse mechanisms of WQY in mitigating sepsis-induced acute lung injury (ALI). Additionally, the effects of WQY were validated using biological experiments. METHODS: This study combined UHPLC-Orbitrap-HRMS analysis and network pharmacology to predict the potential anti-sepsis mechanism of WQY. Sepsis-induced ALI models were established in vivo via intraperitoneal lipopolysaccharide (LPS) administration and in vitro by LPS-stimulated RAW 264.7 macrophages. Various techniques, including hematoxylin-eosin staining, TUNEL, qPCR, and ELISA, were used to assess lung damage and quantify inflammatory cytokines. Inflammatory cell infiltration was visualized through immunohistochemistry. Hub targets and signaling pathways were identified using Western blotting, immunohistochemistry, and immunofluorescence staining. RESULTS: Seventy-five active components and 237 associated targets were acquired, with 145 of these targets overlapping with processes related to sepsis. Based on the comprehensive protein-protein interaction network analysis, JUN, AKT1, TP53, IL-6, HSP90AA1, CASP3, VEGFA, IL-1ß, RELA, and EGFR may be targets of WQY for sepsis. Analysis of the Kyoto Gene and Genome Encyclopedia revealed that WQY is implicated in the advanced glycation end products/receptor for advanced glycation end products (AGE/RAGE) signaling pathway. In vivo, WQY alleviated sepsis-induced ALI, suppressing proinflammatory cytokines and inhibiting macrophage/neutrophil infiltration. In vitro, WQY reduced TNF-α, IL-6, and IL-1ß in LPS-induced RAW 264.7 macrophages. Furthermore, we verified that WQY protected against sepsis-induced ALI by regulating the RAGE pathway for the first time. Baicalin, coptisine, and paeoniflorin may be the effective components of WQY that inhibit RAGE. CONCLUSION: The primary mechanism of WQY in combating sepsis-induced ALI involves controlling RAGE levels and the PI3K/AKT pathway, suppressing inflammation, and mitigating lung damage. This study establishes a scientific foundation for understanding the mechanism of WQY and its clinical use in treating sepsis.
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Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Lipopolisacáridos , Receptor para Productos Finales de Glicación Avanzada , Sepsis , Transducción de Señal , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Ratones , Células RAW 264.7 , Medicamentos Herbarios Chinos/farmacología , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Citocinas/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Farmacología en Red , Sustancias Protectoras/farmacología , Productos Finales de Glicación Avanzada/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ferroptosis, a recently identified non-apoptotic form of cell death reliant on iron, is distinguished by an escalation in lipid reactive oxygen species (ROS) that are iron-dependent. This phenomenon has a strong correlation with irregularities in iron metabolism and lipid peroxidation. Salvia miltiorrhiza Bunge (DS), a medicinal herb frequently utilized in China, is highly esteemed for its therapeutic effectiveness in enhancing blood circulation and ameliorating blood stasis, particularly during the treatment of cardiovascular diseases (CVDs). Numerous pharmacological studies have identified that DS manifests antioxidative stress effects as well as inhibits lipid peroxidation. However, ambiguity persists regarding the potential of DS to impede ferroptosis in cardiomyocytes and subsequently improve myocardial damage post-myocardial infarction (MI). AIM OF THE STUDY: The present work focused on investigating whether DS could be used to prevent the ferroptosis of cardiomyocytes and improve post-MI myocardial damage. MATERIALS AND METHODS: In vivo experiments: Through ligation of the left anterior descending coronary artery, we constructed both a wild-type (WT) and NF-E2 p45-related factor 2 knockout (Nrf2-/-) mouse model of MI. Effects of DS and ferrostatin-1 (Fer-1) on post-MI cardiomyocyte ferroptosis were examined through detecting ferroptosis and myocardial damage-related indicators as well as Nrf2 signaling-associated protein levels. In vitro experiments: Erastin was used for stimulating H9C2 cardiomyocytes to construct an in vitro ferroptosis cardiomyocyte model. Effects of DS and Fer-1 on cardiomyocyte ferroptosis were determined based on ferroptosis-related indicators and Nrf2 signaling-associated protein levels. Additionally, inhibitor and activator of Nrf2 were used for confirming the impact of Nrf2 signaling on DS's effect on cardiomyocyte ferroptosis. RESULTS: In vivo: In comparison to the model group, DS suppressed ferroptosis in cardiomyocytes post-MI and ameliorated myocardial damage by inducing Nrf2 signaling-related proteins (Nrf2, xCT, GPX4), diminishing tissue ferrous iron and malondialdehyde (MDA) content. Additionally, it enhanced glutathione (GSH) levels and total superoxide dismutase (SOD) activity, effects that are aligned with those of Fer-1. Moreover, the effect of DS on alleviating cardiomyocyte ferroptosis after MI could be partly inhibited through Nrf2 knockdown. In vitro: Compared with the erastin group, DS inhibited cardiomyocyte ferroptosis by promoting the expression of Nrf2 signaling-related proteins, reducing ferrous iron, ROS, and MDA levels, but increasing GSH content and SOD activity, consistent with the effect of Fer-1. Additionally, Nrf2 inhibition increased erastin-mediated ferroptosis of cardiomyocytes through decreasing Nrf2 signaling-related protein expressions. Co-treatment with DS and Nrf2 activator failed to further enhance the anti-ferroptosis effect of DS. CONCLUSION: MI is accompanied by cardiomyocyte ferroptosis, whose underlying mechanism is probably associated with Nrf2 signaling inhibition. DS possibly suppresses ferroptosis of cardiomyocytes and improves myocardial damage after MI through activating Nrf2 signaling.
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Ferroptosis , Infarto del Miocardio , Miocitos Cardíacos , Salvia miltiorrhiza , Transducción de Señal , Animales , Masculino , Ratones , Ratas , Línea Celular , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Salvia miltiorrhiza/química , Transducción de Señal/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: It has been reported that apoptosis and oxidative stress are related to cyclophosphamide (CYC)-induced premature ovarian failure (POF). Therefore, anti-apoptotic and anti-oxidative stress treatments exhibit therapeutic efficacy in CYC-induced POF. Danggui Shaoyao San (DSS), which has been extensively used to treat gynecologic diseases, is found to inhibit apoptosis and reduce oxidative stress. However, the roles of DSS in regulating apoptosis and oxidative stress during CYC-induced POF, and its associated mechanisms are still unknown. AIM OF THE STUDY: This work aimed to investigate the roles and mechanisms of DSS in inhibiting apoptosis and oxidative stress in CYC-induced POF. MATERIALS AND METHODS: CYC (75 mg/kg) was intraperitoneally injected in mice to construct the POF mouse model for in vivo study. Thereafter, alterations of body weight, ovary morphology and estrous cycle were monitored to assess the ovarian protective properties of DSS. Serum LH and E2 levels were analyzed by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was employed for examining ovarian pathological morphology and quantifying follicles in various stages. Meanwhile, TUNEL staining and apoptosis-related proteins were adopted for evaluating apoptosis. Oxidative stress was measured by the levels of ROS, MDA, and 4-HNE. Western blot (WB) assay was performed to detect proteins related to the SIRT1/p53 pathway. KGN cells were used for in vitro experiment. TBHP stimulation was carried out for establishing the oxidative stress-induced apoptosis cell model. Furthermore, MTT assay was employed for evaluating the protection of DSS from TBHP-induced oxidative stress. The anti-apoptotic ability of DSS was evaluated by hoechst/PI staining, JC-1 staining, and apoptosis-related proteins. Additionally, the anti-oxidative stress ability of DSS was measured by detecting the levels of ROS, MDA, and 4-HNE. Proteins related to SIRT1/p53 signaling pathway were also measured using WB and immunofluorescence (IF) staining. Besides, SIRT1 expression was suppressed by EX527 to further investigate the role of SIRT1 in the effects of DSS against apoptosis and oxidative stress. RESULTS: In the in vivo experiment, DSS dose-dependently exerted its anti-apoptotic, anti-oxidative stress, and ovarian protective effects. In addition, apoptosis, apoptosis-related protein and oxidative stress levels were inhibited by DSS treatment. DSS treatment up-regulated SIRT1 and down-regulated p53 expression. From in vitro experiment, it was found that DSS treatment protected KGN cells from TBHP-induced oxidative stress injury. Besides, DSS administration suppressed the apoptosis ratio, apoptosis-related protein levels, mitochondrial membrane potential damage, and oxidative stress. SIRT1 suppression by EX527 abolished the anti-apoptotic, anti-oxidative stress, and ovarian protective effects, as discovered from in vivo and in vitro experiments. CONCLUSIONS: DSS exerts the anti-apoptotic, anti-oxidative stress, and ovarian protective effects in POF mice, and suppresses the apoptosis and oxidative stress of KGN cells through activating SIRT1 and suppressing p53 pathway.
Asunto(s)
Menopausia Prematura , Insuficiencia Ovárica Primaria , Humanos , Femenino , Ratones , Animales , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Insuficiencia Ovárica Primaria/prevención & control , Proteína p53 Supresora de Tumor/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/metabolismo , Estrés Oxidativo , Apoptosis , Ciclofosfamida/toxicidad , Transducción de SeñalRESUMEN
BACKGROUND: Wenqingyin (WQY) is a classic traditional Chinese medicine formula used to treat various inflammatory diseases. However, its protective activity against ferroptosis in the pathogenesis of sepsis-induced liver injury and underlying mechanisms remain unclear. PURPOSE: This study aimed to determine the therapeutic efficacy and potential mechanism of action of WQY in sepsis-induced liver injury both in vivo and in vitro. METHODS: In vivo: Lipopolysaccharide was intraperitoneally injected into nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (Nrf2-/-) and wild-type mice to construct a septic liver injury mouse model. Experimental mice were intraperitoneally injected with ferroptosis-1 and intragastrically administered WQY. In vitro: LO2 hepatocytes were stimulated with erastin to activate ferroptosis and later treated with varying concentrations of WQY and an Nrf2 inhibitor (ML385). Pathological damage was evaluated following hematoxylin and eosin staining. Lipid peroxidation levels were assessed using malondialdehyde, superoxide dismutase, and glutathione, as well as reactive oxygen species fluorescent probes. JC-1 staining was performed to evaluate the mitochondrial membrane potential damage. Quantitative reverse transcription polymerase chain reaction and western blot assay were performed to detect the related gene and protein levels. The levels of inflammatory factors were measured using Enzyme-Linked Immunosorbent Assay kits. RESULTS: In vivo, sepsis-induced liver injury activated ferroptosis in mouse liver tissue. Fer-1 and WQY attenuated septic liver injury, which was associated with increased Nrf2 expression. Deletion of the Nrf2 gene led to aggravation of septic liver injury. The effect of WQY on the attenuation of septic liver injury was partially abolished by the knockdown of Nrf2. In vitro, erastin-induced ferroptosis resulted in decreased hepatocyte viability, lipid peroxidation, and mitochondrial membrane potential damage. WQY protected hepatocytes from erastin-induced ferroptosis by activating Nrf2. The attenuation effect of ferroptosis in hepatocytes by WQY was partially abolished by the inhibition of Nrf2. CONCLUSION: Ferroptosis has a critical role in the development of sepsis-mediated liver injury. Inhibition of ferroptosis is a possible novel treatment strategy for alleviating septic liver injury. WQY attenuates sepsis-mediated liver injury by suppressing ferroptosis in hepatocytes, which is related to its ability to activate Nrf2.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Ferroptosis , Sepsis , Animales , Ratones , Factor 2 Relacionado con NF-E2 , Transducción de SeñalRESUMEN
OBJECTIVES: Ferroptosis, a new regulated cell death pathway, plays a crucial part in the development of cardiovascular disease. However, the precise underlying mechanism remains unclear. Therefore, this study aimed to elucidate this. METHODS: Herein, an erastin-induced H9C2 cell ferroptosis in vitro model and a myocardial infarction murine model, which was created by ligating the left anterior descending coronary artery, were established. Ferroptosis-related indicators, myocardial injury-related indicators, and Nrf2 signaling-related proteins expression were analyzed to explore the potential mechanism underlying cardiomyocyte ferroptosis-mediated cardiovascular disease development. RESULTS: We demonstrated that Nrf2 downregulation in myocardial tissue, accompanied by ferroptotic events and changes in xCT and GPX4 expressions, induced cardiomyocyte ferroptosis and myocardial injury after myocardial infarction. These events, including ferroptosis and changes in Nrf2, xCT, and GPX4 expressions, were improved by ferrostatin-1 in vivo and in vitro. Besides, Nrf2 deficiency or inhibition aggravated myocardial infarction-induced cardiomyocyte ferroptosis by decreasing xCT and GPX4 expressions in vivo and in vitro. Moreover, ferrostatin-1 directly targeted Nrf2, as evidenced by surface plasmon resonance analysis. CONCLUSIONS: These results indicated that myocardial infarction is accompanied by cardiomyocyte ferroptosis and that Nrf2 signaling plays a crucial part in regulating cardiomyocyte ferroptosis after myocardial infarction.
Asunto(s)
Ferroptosis , Infarto del Miocardio , Animales , Ratones , Miocitos Cardíacos , Factor 2 Relacionado con NF-E2 , Infarto del Miocardio/tratamiento farmacológicoRESUMEN
Background: Myocardial fibrosis post-myocardial infarction (MI) can induce maladaptive cardiac remodeling as well as heart failure. Although 20(S)-ginsenoside Rg3 (Rg3) has been applied to cardiovascular diseases, its efficacy and specific molecular mechanism in myocardial fibrosis are largely unknown. Herein, we aimed to explore whether TGFBR1 signaling was involved in Rg3's anti-fibrotic effect post-MI. Methods: Left anterior descending (LAD) coronary artery ligation-induced MI mice and TGF-ß1-stimulated primary cardiac fibroblasts (CFs) were adopted. Echocardiography, hematoxlin-eosin and Masson staining, Western-blot and immunohistochemistry, CCK8 and Edu were used to study the effects of Rg3 on myocardial fibrosis and TGFBR1 signaling. The combination mechanism of Rg3 and TGFBR1 was explored by surface plasmon resonance imaging (SPRi). Moreover, myocardial Tgfbr1-deficient mice and TGFBR1 adenovirus were adopted to confirm the pharmacological mechanism of Rg3. Results: In vivo experiments, Rg3 ameliorated myocardial fibrosis and hypertrophy and enhanced cardiac function. Rg3-TGFBR1 had the 1.78 × 10-7 M equilibrium dissociation constant based on SPRi analysis, and Rg3 inhibited the activation of TGFBR1/Smads signaling dose-dependently. Cardiac-specific Tgfbr1 knockdown abolished Rg3's protection against myocardial fibrosis post-MI. In addition, Rg3 down-regulated the TGF-ß1-mediated CFs growth together with collagen production in vitro through TGFBR1 signaling. Moreover, TGFBR1 adenovirus partially blocked the inhibitory effect of Rg3. Conclusion: Rg3 improves myocardial fibrosis and cardiac function through suppressing CFs proliferation along with collagen deposition by inactivation of TGFBR1 pathway.