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Nitrogen compounds in current seawater treatment processes typically are converted to nitrate, threatening seawater quality and marine ecology. Electrochemical denitrification is a promising technique, but its efficiency is severely limited by the presence of excess chloride ions. In this work, a flow-through cell went through an on-demand chlorine-mediated electrochemical-chemical tandem reaction process was designed for efficient seawater denitrification. Equipped with ultrathin cobalt-based nanosheets as the cathode catalyst and commercial IrO2-RuO2/Ti as the anode, the newly designed flow-through cell achieved nitrate removal efficiency that was about 50 times greater than the batch cell and nearly 100 % N2 selectivity. Moreover, nitrite and ammonia can also be removed with over 93 % efficiency in total nitrogen (TN) removal. Furthermore, the concentration of active chlorine in the effluent could be adjusted within two orders of magnitude, enabling on-demand release of active chlorine. Finally, this flow-through cell reduced the TN of actual mariculture tailwater (40.1 mg N L-1 nitrate) to only 5.7 mg N L-1, meeting the discharge standard for aquaculture tailwater of Fujian, China. This work demonstrates the paradigm of deep denitrification from ultra-concentrated chlorine ion wastewater using an on-demand active chlorine-mediated electrochemical-chemical tandem reaction process.
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AIMS: Coagulase (Coa), a crucial virulence factor of Staphylococcus aureus (S. aureus), is considered an vital target for anti-virulence strategies. The research aimed to discover a natural compound capable of inhibiting S. aureus infection by targeting the virulence factor Coa. METHODS AND RESULTS: The study showed that sinensetin at a concentration of 128 µg mL-1 effectively inhibited both Coa-induced coagulation and biofilm formation in S. aureus. However, western blot results indicated that sinensetin did not impact the expression of Coa protein, suggesting that sinensetin may directly target Coa to counteract the virulence of S. aureus. Thermal shift assay results demonstrated that sinensetin enhanced the thermal stability of Coa, supporting the theory of direct binding. Molecular docking and point mutation experiments identified two key binding sites for sinensetin to Coa as R73A-Coa and R204A-Coa. In vivo studies on mice revealed that sinensetin not only reduced lung tissue damage caused by S. aureus infection, but also decreased inflammatory factors in the lung lavage fluid. Furthermore, combining sinensetin with oxacillin improved the survival rates of the Galleria mellonella and mice. CONCLUSIONS: Sinensetin is a promising natural compound that acts as a direct inhibitor of Coa against S. aureus infections.
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Translation of mRNA to protein is tightly regulated by tRNAs, which are subject to various chemical modifications that maintain the structure, stability and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite of incompetent proliferation and osteogenic commitment. Further exploration revealed that impaired Rho GTPase signaling upregulated branched-chain amino acid transaminase 1 (BCAT1) level that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation either by targeting ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulating cellular metabolism, and indicates that suspension of translation initiation as quality control mechanism in response to tRNA dysregulation.
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Aging is an irresistible natural law of the progressive decline of body molecules, organs, and overall function with the passage of time, resulting in eventual death. World Health Organization data show that aging is correlated with a wide range of common chronic diseases in the elderly, and is an essential driver of many diseases. Panax Ginseng C.A Meyer is an ancient herbal medicine, which has an effect of "long service, light weight, and longevity" recorded in the ancient Chinese medicine book "Compendium of Materia Medica." Ginsenoside Rg2, the main active ingredient of ginseng, also exerts a marked effect on the treatment of liver injury. However, it remains unclear whether Rg2 has the potential to ameliorate aging-induced liver injury. Hence, exploring the hepatoprotective properties of Rg2 and its possible molecular mechanism by Senescence Accelerate Mouse Prone 8 (SAMP8) and gut microbiota. Our study demonstrated that Rg2 can inhibit pyroptosis and apoptosis through caspase 8, and regulate the gut-liver axis to alleviate liver inflammation by changing the composition of gut microbiota, thus improving aging-induced liver injury. These findings provide theoretical support for the pharmacological effects of ginsenosides in delaying aging-induced liver injury.
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Proposing and utilizing machine learning descriptors for chemical property prediction and material screening have become a cutting-edge field in artificial intelligence-enabled chemical research. However, a single descriptor typically captures only partial features of a chemical object, resulting in an information deficiency and limiting generalizability. Obtaining a comprehensive set of descriptors is essential but challenging, especially when accessing some microlevel structural and electronic features due to technological limitations. Herein, we exploit multimodal chemical descriptors to construct an encoder-decoder machine learning framework that enables the cross-modal prediction of spectral and structural descriptors. By pretraining the model to endow it with chemical insights, the multimodal data fusion is implemented in a descriptor-encoded hidden layer. The model's capabilities are validated in the system of CO/NO adsorption on Au/Ag surfaces, demonstrating successful reciprocal prediction of infrared spectra, Raman spectra, and internal coordinates. This work provides a proof-of-concept for the feasibility of cross-modal predictions between different chemical features and will significantly reduce the machine learning model's dependence on complete physicochemical parameters and improve its multitarget prediction capabilities.
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Multi-resistant Staphylococcus aureus (S. aureus) infection is a significant global health concern owing to its high mortality and morbidity rates. Coagulase (Coa), a key enzyme that activates prothrombin to initiate host coagulation, has emerged as a promising target for anti-infective therapeutic approaches. This study identified sinigrin as a potent Coa inhibitor that significantly inhibited S. aureus-induced coagulation at concentration as low as 32 mg/L. Additionally, at a higher concentration of 128 mg/L, sinigrin disrupted the self-protection mechanism of S. aureus. Thermal shift and fluorescence-quenching assays confirmed the direct binding of sinigrin to the Coa protein. Molecular docking analysis predicted specific binding sites for sinigrin in the Coa molecule, and point mutation experiments highlighted the importance of Arg-187 and Asp-222 as critical binding sites for both Coa and sinigrin. In vivo studies demonstrated that the combination of sinigrin with oxacillin exhibited greater antibacterial efficacy than oxacillin alone in the treatment of S. aureus-induced pneumonia in mice. Furthermore, sinigrin was shown to reduce bacterial counts and inflammatory cytokine levels in the lung tissues of S. aureus-infected mice. In summary, sinigrin was shown to directly target Coa, resulting in the attenuation of S. aureus virulence, which suggests the potential of sinigrin as an adjuvant for future antimicrobial therapies.
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Antibacterianos , Coagulasa , Simulación del Acoplamiento Molecular , Infecciones Estafilocócicas , Staphylococcus aureus , Coagulasa/metabolismo , Animales , Ratones , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/enzimología , Virulencia/efectos de los fármacos , Antibacterianos/farmacología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Modelos Animales de Enfermedad , Citocinas/metabolismo , Oxacilina/farmacología , Sitios de Unión , Coagulación Sanguínea/efectos de los fármacos , Pulmón/microbiología , Pulmón/patología , Femenino , Ratones Endogámicos BALB CRESUMEN
Cartilage maintains the structure and function of joints, with disturbances leading to potential osteoarthritis. N6-methyladenosine (m6A), the most widespread post-transcriptional modification in eukaryotes, plays a crucial role in regulating biological processes. While current research has indicated that m6A affects the progression of osteoarthritis, its function in the development and homeostasis of articular cartilage remains unclear. Here we report that Mettl3 deficiency in chondrocytes leads to mandibular condylar cartilage morphological alterations, early temporomandibular joint osteoarthritis, and diminished adaptive response to abnormal mechanical stimuli. Mechanistically, METTL3 modulates Lats1 mRNA methylation and facilitates its degradation in an m6A-YTHDF2-dependent manner, which subsequently influences the degradation and nuclear translocation of YAP1. Intervention with the Hippo pathway inhibitor XMU-MP-1 alleviates condylar abnormality caused by Mettl3 knockout. Our findings demonstrate the role of METTL3 in cartilage development and homeostasis, offering insights into potential treatment strategies for osteoarthritis.
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Adenosina , Condrocitos , Homeostasis , Metiltransferasas , Proteínas Serina-Treonina Quinasas , Estabilidad del ARN , Proteínas de Unión al ARN , Metiltransferasas/metabolismo , Metiltransferasas/genética , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ratones , Condrocitos/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas Señalizadoras YAP/metabolismo , Ratones Noqueados , Osteoartritis/metabolismo , Osteoartritis/genética , Osteoartritis/patología , ARN Mensajero/metabolismo , ARN Mensajero/genética , Cartílago Articular/metabolismo , Cartílago Articular/patología , Cartílago/metabolismo , Ratones Endogámicos C57BL , Condrogénesis/genética , Metilación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Humanos , Masculino , Cóndilo Mandibular/metabolismoRESUMEN
RSA-1 is a polysaccharide obtained from Raphani semen with a relatively clear structure and anti-colon cancer activity. In this study, high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) spectroscopy were applied to characterise the complex chain structure of RSA-1. Subsequently, the inhibitory effect on colon cancer growth through apoptosis induction in colon cancer cells was explored. The findings indicate that the main chain of RSA-1 consists of â3)-ß-D-Galp-(1 â and 3,6)-ß-D-Galp-(1 â substituted at C-6 with branched α-L-Araf side chains. RSA-1 disrupts the Bax/Bcl-2 ratio and thus inhibits the viability of colon cancer cells in vitro. Furthermore, it inhibits colon cancer migration by attenuating epithelial-mesenchymal transition. Notably, RSA-1 exhibited negligible impact on the growth of human intestinal epithelial cells within a relevant concentration range. This study establishes a theoretical foundation and provides technical support for the prospective development and application of RSA-1 as a dual-purpose anti-colon cancer drug and functional food.
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Neoplasias del Colon , Galactanos , Humanos , Galactanos/química , Galactanos/farmacología , Galactanos/aislamiento & purificación , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacosRESUMEN
The overactivation of ß-adrenergic receptors (ß-ARs) can result in acute myocardial ischemic injury, culminating in myocardial necrosis. Berberine (BBR) has exhibited promising potential for prevention and treatment in various heart diseases. However, its specific role in mitigating myocardial injury induced by acute ß-AR overactivation remains unexplored. This study aimed to investigate the effects and underlying mechanisms of BBR pretreatment in a rat model of acute ß-AR overactivation induced by a single dose of the nonselective ß-adrenergic agonist isoprenaline (ISO). Rats were pretreated with saline or BBR (100 mg/kg/day) via gavage for 14 consecutive days, followed by a subcutaneous injection of ISO or saline on the 14th day. The findings indicated that BBR pretreatment significantly attenuated myocardial injury in ISO-stimulated rats, as evidenced by reduced pathological inflammatory infiltration, necrosis, and serum markers of myocardial damage. Additionally, BBR decreased oxidative stress and inflammation in the system and heart. Furthermore, BBR pretreatment enhanced myocardial ATP levels, improved mitochondrial dysfunction through increased Drp1 phosphorylation, and augmented myocardial autophagy. In a CoCl2-induced H9c2 cell hypoxic injury model, BBR pretreatment mitigated cellular injury, apoptosis, and oxidative stress while upregulating Drp1 and autophagy-associated proteins. Mechanistically, BBR pretreatment activated AKT, AMPK, and LKB1 both in vivo and in vitro, implicating the involvement of the AKT and LKB1/AMPK signaling pathways in its cardioprotective effects. Our study demonstrated the protective effects of BBR against myocardial injury induced by acute ß-AR overactivation in rats, highlighting the potential of BBR as a preventive agent for myocardial injury associated with ß-adrenergic overactivation.
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In recent years, there has been a growing concern regarding health issues arising from exposure to nanoplastics (Nps) in the natural environment. The Nps bioaccumulate within the body via the circulatory system and accumulate in the liver, resulting in damage. Previous studies have demonstrated that maltol, derived from red ginseng (Panax ginseng C.A. Meyer) as a Maillard product, exhibits hepatoprotective effects by alleviating liver damage caused by carbon tetrachloride or cisplatin. In order to explore the specific mechanism of maltol in improving hepatotoxicity induced by Nps, mice exposed to 100 mg/kg Nps were given maltol at doses of 50 and 100 mg/kg, respectively. The results showed that Nps induced an increase in the levels of liver apoptotic factors BAX and cytochrome c, a decrease in the levels of the autophagy key gene LC3 II/I, and an increase in P62. It also caused oxidative stress by affecting the Nrf2/HO-1 pathway, and a decrease in GPX4 protein expression suggested the occurrence of ferroptosis. However, treatment with maltol significantly improved these changes. In addition, maltol (2, 4, and 8 µM) also protected human normal liver L02 cells from Np (400 µg/mL)-induced damage. Our data suggest that maltol could ameliorate Np-induced L02 cytotoxicity by reducing autophagy-dependent oxidative stress, exhibiting similar protective effects in vitro as in vivo. This study helps shed light on the specific molecular mechanism of Np-induced hepatotoxicity. For the first time, we studied the protective effect of maltol on Np-induced liver injury from multiple perspectives, expanding the possibility of treatment for diseases caused by environmental pollutants.
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Autofagia , Enfermedad Hepática Inducida por Sustancias y Drogas , Hígado , Pironas , Animales , Ratones , Autofagia/efectos de los fármacos , Pironas/farmacología , Humanos , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Panax/química , Nanopartículas/química , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Línea CelularRESUMEN
Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular diseases (CVDs) that has become a global public health problem. Puerarin (PUE), the principal active compound of Pueraria lobata, has the effects of regulating glucose and lipid metabolism and protecting against cardiovascular damage. This study aimed to investigate whether dietary supplementation with PUE could ameliorate MetS and its associated cardiovascular damage. Rats were randomly divided into three groups: the normal diet group (NC), the high-fat/high-sucrose diet group (HFHS), and the HFHS plus PUE diet group (HFHS-PUE). The results showed that PUE-supplemented rats exhibited enhanced glucose tolerance, improved lipid parameters, and reduced blood pressure compared to those on the HFHS diet alone. Additionally, PUE reversed the HFHS-induced elevations in the atherogenic index (AI) and the activities of serum lactate dehydrogenase (LDH) and creatine kinase (CK). Ultrasonic evaluations indicated that PUE significantly ameliorated cardiac dysfunction and arterial stiffness. Histopathological assessments further confirmed that PUE significantly mitigated cardiac remodeling, arterial remodeling, and neuronal damage in the brain. Moreover, PUE lowered systemic inflammatory indices including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII). In conclusion, dietary supplementation with PUE effectively moderated metabolic disorders, attenuated systemic inflammation, and minimized cardiovascular damage in rats with MetS induced by an HFHS diet. These results provide novel insights into the potential benefits of dietary PUE supplementation for the prevention and management of MetS and its related CVDs.
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Enfermedades Cardiovasculares , Dieta Alta en Grasa , Isoflavonas , Síndrome Metabólico , Animales , Síndrome Metabólico/etiología , Síndrome Metabólico/tratamiento farmacológico , Isoflavonas/farmacología , Dieta Alta en Grasa/efectos adversos , Masculino , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/etiología , Ratas , Suplementos Dietéticos , Ratas Sprague-Dawley , Presión Sanguínea/efectos de los fármacos , Glucemia/metabolismo , Sacarosa en la Dieta/efectos adversos , Rigidez Vascular/efectos de los fármacos , Modelos Animales de Enfermedad , Lípidos/sangre , Pueraria/químicaRESUMEN
The incidence of contrast-induced acute kidney injury (CI-AKI) has escalated to become the third most prevalent cause of hospital-acquired AKI, with a lack of efficacious interventions. Berberine (BBR) possesses diverse pharmacological effects and exhibits renoprotective properties; however, limited knowledge exists regarding its impact on CI-AKI. Therefore, our study aimed to investigate the protective effects and underlying mechanisms of BBR on CI-AKI in a mice model, focusing on the nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3) inflammasome and mitophagy. The CI-AKI mice model was established by administering NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg), indomethacin (10 mg/kg), and iohexol (11 g/kg) following water deprivation. A pretreatment of 100 mg/kg of BBR was orally administered to the mice for two weeks. Renal injury markers, damage-associated molecular patterns (DAMPs), renal histopathology, mitochondrial morphology, autophagosomes, and potential mechanisms were investigated. BBR effectively reduced levels of renal injury biomarkers such as serum cystatin C, urea nitrogen, and creatinine, downregulated the protein level of kidney injury molecule 1 (KIM1), and mitigated renal histomorphological damage. Moreover, BBR reduced DAMPs, including high mobility group box-1 (HMGB1), heat shock protein 70 (HSP70), and uric acid (UA). It also alleviated oxidative stress and inflammatory factors such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß). Furthermore, the activation of NLRP3 inflammasome was attenuated in the BBR pretreatment group, as evidenced by both mRNA and protein levels. Electron microscopy and western blotting examination revealed that BBR mitigated mitochondrial damage and enhanced mitophagy. Additionally, BBR increased the P-AMPK/AMPK ratio. These findings indicated that BBR exerted a protective effect against CI-AKI by suppressing NLRP3 inflammasome activation and modulating mitophagy, providing a potential therapeutic strategy for its prevention.
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Lesión Renal Aguda , Berberina , Medios de Contraste , Modelos Animales de Enfermedad , Inflamasomas , Mitofagia , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Masculino , Ratones , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Berberina/farmacología , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Ratones Endogámicos C57BL , Mitofagia/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
Purpose: The prevalence of obesity and myopia in young people is increasing worldwide; however, the association between body mass index (BMI) and myopia remains controversial. This study aimed to assess the association between BMI and myopia in Chinese schoolchildren. Patients and Methods: In this study, the open data for analysis were obtained from DATADRYAD website (www.datadryad.org). A total of 3658 children were enrolled in this study. Logistic regression model was used to analyze the relationship between BMI and myopia. Results: Compared with individuals with lower BMI Q1 (less than 25 kg/m2), the adjusted odds ratios (ORs) for BMI and myopia were 2.15 (95% confidence interval [CI]: 1.62-2.86) in Q2 (25.0-29.9 kg/m2) and 2.39 (95% CI: 1.37-4.18) in Q3 (30.0 kg/m2 or more). Moreover, the association between BMI and myopia exhibited an inverted L-shaped curve (nonlinear; p < 0.001). When the BMI was <25 kg/m2, an increased BMI was significantly associated with a higher risk of myopia (OR = 1.244 [95% CI: 1.211-1.277], p < 0.001). However, when the BMI was ≥25 kg/m2, the association lost its significance (OR = 1.063 [95% Cl: 0.964-1.171], p = 0.219). Conclusion: This study found an inverted L-shaped association between BMI and myopia in Chinese schoolchildren. A higher BMI was associated with a higher risk of myopia reaching 25 kg/m2, after which an increase in BMI was no longer associated with an increased risk of myopia.
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A perennial challenge in harnessing the rich biological activity of medicinal and edible plants is the accurate identification and sensitive detection of their active compounds. In this study, an innovative, ultra-sensitive detection platform for plant chemical profiling is created using surface-enhanced Raman spectroscopy (SERS) technology. The platform uses silver nanoparticles as the enhancing substrate, excess sodium borohydride prevents substrate oxidation, and methanol enables the tested molecules to be better adsorbed onto the silver nanoparticles. Subsequently, nanoparticle aggregation to form stable "hot spots" is induced by Ca2+, and the Raman signal of the target molecule is strongly enhanced. At the same time, deuterated methanol was used as the internal standard for quantitative determination. The method has excellent reproducibility, RSD ≤ 1.79%, and the enhancement factor of this method for the detection of active ingredients in the medicinal plant Coptis chinensis was 1.24 × 109, with detection limits as low as 3 fM. The platform successfully compared the alkaloid distribution in different parts of Coptis chinensis: root > leaf > stem, and the difference in content between different batches of Coptis chinensis decoction was successfully evaluated. The analytical technology adopted by the platform can speed up the determination of Coptis chinensis and reduce the cost of analysis, not only making better use of these valuable resources but also promoting development and innovation in the food and pharmaceutical industries. This study provides a new method for the development, evaluation, and comprehensive utilization of both medicinal and edible plants. It is expected that this method will be extended to the modern rapid detection of other medicinal and edible plants and will provide technical support for the vigorous development of the medicinal and edible plants industry.
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Nanopartículas del Metal , Plantas Comestibles , Plantas Medicinales , Plata , Espectrometría Raman , Espectrometría Raman/métodos , Nanopartículas del Metal/química , Plantas Medicinales/química , Plata/química , Plantas Comestibles/química , Límite de Detección , Fitoquímicos/análisis , Fitoquímicos/química , Reproducibilidad de los Resultados , Alcaloides/análisisRESUMEN
Leptospirosis, a globally significant zoonotic disease caused by pathogenic Leptospira, continues to threaten the health and public safety of both humans and animals. Current clinical treatment of leptospirosis mainly relies on antibiotics but their efficacy in severe cases is controversial. Passive immunization has a protective effect in the treatment of infectious diseases. In addition, chicken egg yolk antibody (IgY) has gained increasing attention as a safe passive immunization agent. This study aimed to investigate whether hens produce specific IgY after immunization with inactivated Leptospira and the protective effect of specific IgY against leptospirosis. First, it was demonstrated that specific IgY could be extracted from the eggs of hens vaccinated with inactivated Leptospira and that specific IgY can specifically recognize and bind homotypic Leptospira with a high titre, as shown by MAT and ELISA. Next, we tested the therapeutic effects of IgY in early and late leptospirosis using a hamster model. The results showed that early specific IgY treatment increased the survival rate of hamsters to 100%, alleviated pathological damage to the liver, kidney, and lung, reduced leptospiral burden, and restored haematological indices as well as functional indicators of the liver and kidney. The therapeutic effect of early specific IgY was comparable to that of doxycycline. Late IgY treatment also enhanced the survival rate of hamsters and improved the symptoms of leptospirosis similar to early IgY treatment. However, the therapeutic effect of late IgY treatment was better when combined with doxycycline. Furthermore, no Leptospira colonization was observed in the kidneys, livers, or lungs of the surviving hamsters treated with specific IgY. Mechanistically, IgY was found to inhibit the growth and adhesion to cells of Leptospira. In conclusion, passive immunotherapy with specific IgY can be considered an effective treatment for leptospirosis, and may replace antibiotics regarding its therapeutic effects.
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Anticuerpos Antibacterianos , Inmunización Pasiva , Inmunoglobulinas , Leptospira , Leptospirosis , Animales , Cricetinae , Femenino , Anticuerpos Antibacterianos/inmunología , Pollos/inmunología , Modelos Animales de Enfermedad , Doxiciclina/uso terapéutico , Doxiciclina/administración & dosificación , Doxiciclina/farmacología , Yema de Huevo/inmunología , Inmunización Pasiva/métodos , Inmunoglobulinas/inmunología , Inmunoglobulinas/administración & dosificación , Riñón/patología , Riñón/inmunología , Riñón/microbiología , Leptospira/inmunología , Leptospirosis/inmunología , Leptospirosis/prevención & control , Leptospirosis/terapia , Hígado/inmunología , Hígado/patología , Hígado/microbiología , Mesocricetus , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/administración & dosificaciónRESUMEN
The current study aimed to assess the effectiveness of pharmacological intervention with Platycodin D (PD), a critically active compound isolated from the roots of Platycodon grandiflorum, in mitigating cardiotoxicity in a murine model of type 2 diabetes-induced cardiac injury and in H9c2 cells in vitro. Following oral administration for 4 weeks, PD (2.5 mg/kg) significantly suppressed the elevation of fasting blood glucose (FBG) levels, improved dyslipidemia, and effectively inhibited the rise of the cardiac injury markers creatine kinase isoenzyme MB (CK-MB) and cardiac troponin T (cTnT). PD treatment could ameliorate energy metabolism disorders induced by impaired glucose uptake by activating AMPK protein expression in the DCM mouse model, thereby promoting the GLUT4 transporter and further activating autophagy-related proteins. Furthermore, in vitro experiments demonstrated that PD exerted a concentration-dependent increase in cell viability while also inhibiting palmitic acid and glucose (HG-PA)-stimulated H9c2 cytotoxicity and activating AMPK protein expression. Notably, the AMPK activator AICAR (1 mM) was observed to upregulate the expression of AMPK in H9c2 cells after high-glucose and -fat exposure. Meanwhile, we used AMPK inhibitor Compound C (20 µM) to investigate the effect of PD activation of AMPK on cells. In addition, the molecular docking approach was employed to dock PD with AMPK, revealing a binding energy of -8.2 kcal/mol and indicating a tight interaction between the components and the target. PD could reduce the expression of autophagy-related protein p62, reduce the accumulation of autophagy products, promote the flow of autophagy, and improve myocardial cell injury. In conclusion, it has been demonstrated that PD effectively inhibits cardiac injury-induced type 2 diabetes in mice and enhances energy metabolism in HG-PA-stimulated H9c2 cells by activating the AMPK signaling pathway. These findings collectively unveil the potential cardioprotective effects of PD via modulation of the AMPK signaling pathway.
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Proteínas Quinasas Activadas por AMP , Diabetes Mellitus Tipo 2 , Saponinas , Transducción de Señal , Triterpenos , Animales , Humanos , Masculino , Ratones , Ratas , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Línea Celular , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/metabolismo , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Platycodon/química , Saponinas/química , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Objective: To investigate the relevant risk factors of proliferative diabetic retinopathy (PDR) in patients with Type-2 diabetes mellitus (T2DM) and their correlations with the central macular thickness (CMT). Methods: This is a retrospective study. The clinical data of 300 patients with T2DM were collected and divided into a PDR group (observation group) and non-PDR group (control group) according to the occurrence of PDR in Aier Eye Hospital (Taiyuan) from February 2019 to February 2022. The relevant risk factors were screened out through the t test and the χ2 test, and analyzed by logistic regression. Results: Logistic regression analysis showed that systolic blood pressure, diastolic blood pressure, course of diabetes, fasting blood glucose (FBG), two hours postprandial blood glucose (two hours PBG) and urinary albumin were independent risk factors for T2DM complicated with PDR. ROC curve revealed that systolic blood pressure, course of diabetes and urinary albumin had the highest diagnostic efficiency. Correlation analysis demonstrated that CMT was positively correlated with systolic blood pressure, course of diabetes, HbA1c level and urinary albumin level. Conclusion: For patients with T2DM, blood pressure, course of diabetes, FBG, 2hPBG and urinary albumin are independent risk factors for PDR, and increased systolic blood pressure, course of diabetes, HbA1c level and urinary albumin level will increase CMT. Combining the above indexes to predict the occurrence of PDR has a synergistic effect, and the increase in systolic blood pressure, course of diabetes, HbA1c level and urinary albumin level will increase the CMT of the patients.
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BACKGROUND: Myocardial ischemia is a prevalent cardiovascular disorder associated with significant morbidity and mortality. While prompt restoration of blood flow is essential for improving patient outcomes, the subsequent reperfusion process can result in myocardial ischemia-reperfusion injury (MIRI). Mitophagy, a specialized autophagic mechanism, has consistently been implicated in various cardiovascular disorders. However, the specific connection between ischemia-reperfusion and mitophagy remains elusive. This study aims to elucidate and validate central mitophagy-related genes associated with MIRI through comprehensive bioinformatics analysis. METHODS: We acquired the microarray expression profile dataset (GSE108940) from the Gene Expression Omnibus (GEO) and identified differentially expressed genes (DEGs) using GEO2R. Subsequently, these DEGs were cross-referenced with the mitophagy database, and differential nucleotide sequence analysis was performed through enrichment analysis. Protein-protein interaction (PPI) network analysis was employed to identify hub genes, followed by clustering of these hub genes using cytoHubba and MCODE within Cytoscape software. Gene set enrichment analysis (GSEA) was conducted on central genes. Additionally, Western blotting, immunofluorescence, and quantitative polymerase chain reaction (qPCR) analyses were conducted to validate the expression patterns of pivotal genes in MIRI rat model and H9C2 cardiomyocytes. RESULTS: A total of 2719 DEGs and 61 mitophagy-DEGs were identified, followed by enrichment analyses and the construction of a PPI network. HSP90AA1, RPS27A, EEF2, EIF4A1, EIF2S1, HIF-1α, and BNIP3 emerged as the seven hub genes identified by cytoHubba and MCODE of Cytoscape software. Functional clustering analysis of HIF-1α and BNIP3 yielded a score of 9.647, as determined by Cytoscape (MCODE). In our MIRI rat model, Western blot and immunofluorescence analyses confirmed a significant elevation in the expression of HIF-1α and BNIP3, accompanied by a notable increase in the ratio of LC3II to LC3I. Subsequently, qPCR confirmed a significant upregulation of HIF-1α, BNIP3, and LC3 mRNA in the MIRI group. Activation of the HIF-1α/BNIP3 pathway mediates the regulation of the degree of Mitophagy, thereby effectively reducing apoptosis in rat H9C2 cardiomyocytes. CONCLUSIONS: This study has identified seven central genes among mitophagy-related DEGs that may play a pivotal role in MIRI, suggesting a correlation between the HIF-1α/BNIP3 pathway of mitophagy and the pathogenesis of MIRI. The findings highlight the potential importance of mitophagy in MIRI and provide valuable insights into underlying mechanisms and potential therapeutic targets for further exploration in future studies.
Asunto(s)
Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Humanos , Ratas , Animales , Daño por Reperfusión Miocárdica/metabolismo , Mitofagia/genética , Mapas de Interacción de Proteínas/genética , Biología ComputacionalRESUMEN
Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide, characterized by high malignancy and rapid progression. Most cases are diagnosed at intermediate to advanced stages. Current treatment methods have limited efficacy, resulting in high recurrence rates and poor prognosis. Radical hepatectomy remains the primary treatment for HCC, complemented by radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Despite significant improvement in patient prognosis with radical hepatectomy, the five-year survival rate post-surgery remains low; thus necessitating exploration of more effective therapeutic approaches. Ferroptosis is a recently discovered form of cell death that can modulate the occurrence and development of HCC through various mechanisms. This article aims to elucidate the mechanism of ferroptosis and its impact on HCC development to provide novel insights for diagnosis and treatment.