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Recurrent epidemics of coronaviruses have posed significant threats to human life and health. The mortality rate of patients infected with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is 35 %. The main protease (Mpro) plays a crucial role in the MERS-CoV life cycle, and Mpro exhibited a high degree of conservation among different coronaviruses. Therefore inhibition of Mpro has become an effective strategy for the development of broad-spectrum anti-coronaviral drugs. The inhibition of SARS-CoV-2 Mpro by the anti-tumor drug carmofur has been revealed, but structural studies of carmofur in complex with Mpro from other types of coronavirus have not been reported. Hence, we revealed the structure of the MERS-CoV Mpro-carmofur complex, analysed the structural basis for the binding of carmofur to MERS-CoV Mpro in detail, and compared the binding patterns of carmofur to Mpros of two different coronaviruses, MERS-CoV and SARS-CoV-2. Considering the importance of Mpros for coronavirus therapy, structural understanding of Mpro inhibition by carmofur could contribute to the design and development of novel antiviral drugs with safe and broad-spectrum efficacy.
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High-fat diet-induced metabolic syndrome (MetS) is closely associated with cardiac dysfunction. Recent research studies have indicated a potential association between MetS and ferroptosis. Furthermore, metformin can alleviate MetS-induced cardiac ferroptosis. Metformin is a classic biguanide anti-diabetic drug that has protective effects on cardiovascular diseases, which extend beyond its indirect glycemic control. This study aimed to assess whether MetS mediates cardiac ferroptosis, thereby causing oxidative stress and mitochondrial dysfunction. The results revealed that metformin can mitigate cardiac reactive oxygen species and mitochondrial damage, thereby preserving cardiac function. Mechanistic analysis revealed that metformin upregulates the expression of cardiac Nrf2. Moreover, Nrf2 downregulation compromises the cardio-protective effects of metformin. In summary, this study indicated that MetS promotes cardiac ferroptosis, and metformin plays a preventive and therapeutic role, partially through modulation of Nrf2 expression.
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Verticillium dahliae causes Verticillium wilt in more than 200 plant species worldwide. As a soilborne fungus, it forms melanized microsclerotia and colonizes the xylem of host plants. Our previous study revealed a subfamily of C2H2-homeobox transcription factors in V. dahliae, but their biological roles remain unknown. In this study, we systematically characterized the functions of seven C2H2-homeobox transcription factors in V. dahliae. Deletion of VdChtf3 and VdChtf6 significantly decreased the production of melanized microsclerotia, and knockout of VdChtf1 and VdChtf4 enhanced virulence. Loss of VdChtf2 and VdChtf6 increased conidium production, whereas loss of VdChtf5 and VdChtf7 did not affect growth, conidiation, microsclerotial formation, or virulence. Further research showed that VdChtf3 activated the expression of genes encoding pectic enzymes to participate in microsclerotial formation. In addition, VdChtf4 reduced the expression of VdSOD1 to disturb the scavenging of superoxide radicals but induced the expression of genes related to cell wall synthesis to maintain cell wall integrity. These findings highlight the diverse roles of different members of the C2H2-homeobox gene family in V. dahliae. IMPORTANCE: Verticillium dahliae is a soilborne fungus that causes plant wilt and can infect a variety of economic crops and woody trees. The molecular basis of microsclerotial formation and infection by this fungus remains to be further studied. In this study, we analyzed the functions of seven C2H2-homobox transcription factors. Notably, VdChtf3 and VdChtf4 exhibited the most severe defects, affecting phenotypes associated with critical developmental stages in the V. dahliae disease cycle. Our results indicate that VdChtf3 is a potential specific regulator of microsclerotial formation, modulating the expression of pectinase-encoding genes. This finding could contribute to a better understanding of microsclerotial development in V. dahliae. Moreover, VdChtf4 was associated with cell wall integrity, reactive oxygen species (ROS) stress resistance, and increased virulence. These discoveries shed light on the biological significance of C2H2-homeobox transcription factors in V. dahliae's adaptation to the environment and infection of host plants.
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Interstitial nephritis is the primary cause of mortality in IBV-infected chickens. Our previous research has demonstrated that Radix Isatidis polysaccharide (RIP) could alleviate this form of interstitial nephritis. To explore the mechanism, SPF chickens and chicken embryonic kidney cells (CEKs) were pre-treated with RIP and subsequently infected with QX-genotype IBV strain. Kidneys were sampled for transcriptomic and metabolomic analyses, and the cecum contents were collected for 16S rRNA gene sequencing. Results showed that pre-treatment with RIP led to a 50 % morbidity reduction in infected-chickens, along with decreased tissue lesion and viral load in the kidneys. Multi-omics analysis indicated three possible pathways (including antioxidant, anti-inflammatory and anti-apoptosis) which associated with RIP's efficacy against interstitial nephritis. Following further validation both in vivo and in vitro, the results showed that pre-treatment with RIP could activate the antioxidant transcription factor Nrf2, stimulate antioxidant enzyme expression, and consequently inhibit oxidative stress. Pre-treatment with RIP could also significantly reduce the expression of NLRP3 inflammasome and apoptosis-associated proteins (including Bax, Caspase-3, and Caspase-9). Additionally, RIP was also observed to promote the growth of beneficial bacteria in the intestine. Overall, pretreatment with RIP can alleviate QX-genotype IBV-induced interstitial nephritis via the Nrf2/NLRP3/Caspase-3 signaling pathway. This study lays the groundwork for the potential use of RIP in controlling avian infectious bronchitis (IB).
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Changes in mechanosensitive ion channels following radiation have seldom been linked to therapeutic sensitivity or specific factors involved in antitumor immunity. Here, in this study, we found that the mechanical force sensor, Piezo2, was significantly upregulated in tumor cells after radiation, and Piezo2 knockout in tumor cells enhanced tumor growth suppression by radiotherapy. Specifically, loss of Piezo2 in tumor cells induced their IL-15 expression via unleashing JAK2/STAT1/IRF-1 axis after radiation. This increase in IL-15 activates IL-15Rα on tumor-infiltrating CD8+ T cells, thereby leading to their augmented effector and stem cell-like properties, along with reduced terminal exhausted feature. Importantly, Piezo2 expression was negatively correlated with CD8 infiltration, as well as with radiosensitivity of patients with rectum adenocarcinoma receiving radiotherapy treatment. Together, our findings reveal that tumor cell-intrinsic Piezo2 induces radioresistance by dampening the IRF-1/IL-15 axis, thus leading to impaired CD8+ T cell-dependent antitumor responses, providing insights into the further development of combination strategies to treat radioresistant cancers.
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Linfocitos T CD8-positivos , Interleucina-15 , Canales Iónicos , Tolerancia a Radiación , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Animales , Humanos , Canales Iónicos/metabolismo , Canales Iónicos/genética , Tolerancia a Radiación/genética , Ratones , Interleucina-15/metabolismo , Interleucina-15/genética , Línea Celular Tumoral , Janus Quinasa 2/metabolismo , Janus Quinasa 2/genética , Factor 1 Regulador del Interferón/metabolismo , Factor 1 Regulador del Interferón/genética , Ratones Endogámicos C57BL , Femenino , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Masculino , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Transducción de SeñalRESUMEN
Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent malignancies with a 5-year survival rate of only 15% in patients with advanced diseases. Tumor protein 63 (TP63), a master transcription factor (TF) in ESCC, cooperates with other TFs to regulate enhancers and/or promoters of target oncogenes, which in turn promotes tumorigenesis. TAR-DNA-binding protein-43 (TDP-43) is an RNA/DNA binding protein with elevated expression in several neoplasms. However, it remains unclear how TDP-43 contributes to ESCC progression. In this study, TDP-43 is identified as a novel oncogene with markedly upregulated expression in ESCC tissues through profiling expression levels of one hundred and fifty canonical RNA binding protein (RBP) genes in multiple ESCC patient cohorts. Importantly, TDP-43 boosted TP63 expression via post-transcriptionally stabilizing TP63 mRNAs as a RBP and promoting TP63 transcription as a TF binding to the TP63 promoter in ESCC cells. In contrast, the master TF TP63 also bound to the TDP-43 promoter, accelerated TDP-43 transcription, and caused a noticeable increase in TDP-43 expression in ESCC cells. The findings highlight TDP-43 as a viable therapeutic target for ESCC and uncover a hitherto unrecognized TDP-43/TP63 circuit in cancer.
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Background: The Juan-Bi decoction (JBD) is a classic traditional Chinese medicines (TCMs) prescription for the treatment of rheumatoid arthritis (RA). However, the active compounds of the JBD in RA treatment remain unclear. Aim: The aim of this study is to screen effective compounds in the JBD for RA treatment using systems pharmacology and experimental approaches. Method: Botanical drugs and compounds in the JBD were acquired from multiple public TCM databases. All compounds were initially screened using absorption, distribution, metabolism, excretion, and toxicity (ADMET) and physicochemical properties, and then a target prediction was performed. RA pathological genes were acquired from the DisGeNet database. Potential active compounds were screened by constructing a compound-target-pathogenic gene (C-T-P) network and calculating the cumulative interaction intensity of the compounds on pathogenic genes. The effectiveness of the compounds was verified using lipopolysaccharide (LPS)-induced RAW.264.7 cells and collagen-induced arthritis (CIA) mouse models. Results: We screened 15 potentially active compounds in the JBD for RA treatment. These compounds primarily act on multiple metabolic pathways, immune pathways, and signaling transduction pathways. Furthermore, in vivo and in vitro experiments showed that bornyl acetate (BAC) alleviated joint damage, and inflammatory cells infiltrated and facilitated a smooth cartilage surface via the suppression of the steroid hormone biosynthesis. Conclusion: We screened potential compounds in the JBD for the treatment of RA using systems pharmacology approaches. In particular, BAC had an anti-rheumatic effect, and future studies are required to elucidate the underlying mechanisms.
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The main protease (M pro) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M pro. Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M pro and seven M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M pros. In addition, the crystal structures of SARS-CoV-2 M pro, SARS-CoV M pro, MERS-CoV M pro, and seven SARS-CoV-2 M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M pros. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M pro inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.
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Lung cancer subtyping, particularly differentiating adenocarcinoma (ADC) from squamous cell carcinoma (SCC), is paramount for clinicians to develop effective treatment strategies. In this study, we aimed: (i) to discover volatile organic compound (VOC) biomarkers for precise diagnosis of ADC and SCC, (ii) to investigated the impact of risk factors on ADC and SCC prediction, and (iii) to explore the metabolic pathways of VOC biomarkers. Exhaled breath samples from patients with ADC (n= 149) and SCC (n= 94) were analyzed by gas chromatography-mass spectrometry. Both multivariate and univariate statistical analysis method were employed to identify VOC biomarkers. Support vector machine (SVM) prediction models were developed and validated based on these VOC biomarkers. The impact of risk factors on ADC and SCC prediction was investigated. A panel of 13 VOCs was found to differ significantly between ADC and SCC. Utilizing the SVM algorithm, the VOC biomarkers achieved a specificity of 90.48%, a sensitivity of 83.50%, and an area under the curve (AUC) value of 0.958 on the training set. On the validation set, these VOC biomarkers attained a predictive power of 85.71% for sensitivity and 73.08% for specificity, along with an AUC value of 0.875. Clinical risk factors exhibit certain predictive power on ADC and SCC prediction. Integrating these risk factors into the prediction model based on VOC biomarkers can enhance its predictive accuracy. This work indicates that exhaled breath holds the potential to precisely detect ADCs and SCCs. Considering clinical risk factors is essential when differentiating between these two subtypes.
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Pruebas Respiratorias , Carcinoma de Células Escamosas , Espiración , Cromatografía de Gases y Espectrometría de Masas , Neoplasias Pulmonares , Compuestos Orgánicos Volátiles , Humanos , Compuestos Orgánicos Volátiles/análisis , Pruebas Respiratorias/métodos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Anciano , Biomarcadores de Tumor/análisis , Adenocarcinoma del Pulmón/diagnóstico , Máquina de Vectores de Soporte , Diagnóstico DiferencialRESUMEN
Rhei Radix et Rhizoma and Magnoliae Officinalis Cortex have been used together to treat constipation in the clinical practices for more than 2000 years. Nonetheless, their compatibility mechanism is still unclear. In this study, the amelioration of Rhei Radix et Rhizoma combined with Magnoliae Officinalis Cortex on constipation was systematically and comprehensively evaluated. The results showed that their compatibility could markedly shorten gastrointestinal transport time, increase fecal water content and frequency of defecation, improve gastrointestinal hormone disorders and protect colon tissue of constipation rats compared with the single drug. Furthermore, according to 16S rRNA sequencing in conjunction with UPLC-Q-TOF/MS, the combination of two herbal medications could greatly raise the number of salutary bacteria (Lachnospiraceae, Romboutsia and Subdoligranulum) while decreasing the abundance of pathogenic bacteria (Erysipelatoclostridiaceae). And two herb drugs could markedly improve the disorder of fecal metabolic profiles. A total of 7 different metabolites associated with constipation were remarkably shifted by the compatibility of two herbs, which were mainly related to arachidonic acid metabolism, alpha-linolenic acid metabolism, unsaturated fatty acid biosynthesis and other metabolic ways. Thus, the regulation of intestinal microbiome and its metabolism could be a potential target for Rhei Radix et Rhizoma and Magnoliae Officinalis Cortex herb pair to treat constipation. Furthermore, the multi-omics approach utilized in this study, which integrated the microbiome and metabolome, had potential for investigating the mechanism of traditional Chinese medicines.
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Estreñimiento , Medicamentos Herbarios Chinos , Heces , Microbioma Gastrointestinal , Magnolia , Ratas Sprague-Dawley , Rheum , Ratas , Animales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Magnolia/química , Microbioma Gastrointestinal/efectos de los fármacos , Estreñimiento/tratamiento farmacológico , Estreñimiento/metabolismo , Masculino , Rheum/química , Heces/microbiología , Heces/química , Cromatografía Líquida de Alta Presión , Metabolómica , Rizoma/química , Metaboloma/efectos de los fármacos , MultiómicaRESUMEN
Enhancing infrared images is essential for detecting wind turbine blades using infrared technology. This paper introduces an Infrared Image Enhancement Method based on Adaptive Iterative Cutoff Threshold Difference Multi-Scale Top-Hat Transformation (AICT-DMTH) to address the challenge of low image clarity in infrared detection. The method involves performing a black-white difference top-hat transformation by utilizing structural elements of varying scales for dilation and erosion. Additionally, an iterative threshold method is applied to extract more detailed image features, followed by setting a cutoff constant to determine the final scale of the structural element. The effectiveness of the proposed method is evaluated both qualitatively and quantitatively, with infrared images from laboratory and wind farm settings enhanced and compared against existing methods. The experimental results indicate that the proposed method significantly improves the clarity of infrared images, demonstrating robustness in enhancing images from various environments.
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Transition metal disulfide compounds (TMDCs) emerges as the promising candidate for new-generation flexible (opto-)electronic device fabrication. However, the harsh growth condition of TMDCs results in the necessity of using hard dielectric substrates, and thus the additional transfer process is essential but still challenging. Here, an efficient strategy for preparation and easy separation-transfer of high-uniform and quality-enhanced MoS2 via the precursor pre-annealing on the designed graphene inserting layer is demonstrated. Based on the novel strategy, it achieves the intact separation and transfer of a 2-inch MoS2 array onto the flexible resin. It reveals that the graphene inserting layer not only enhances MoS2 quality but also decreases interfacial adhesion for easy separation-transfer, which achieves a high yield of ≈99.83%. The theoretical calculations show that the chemical bonding formation at the growth interface has been eliminated by graphene. The separable graphene serves as a photocarrier transportation channel, making a largely enhanced responsivity up to 6.86 mA W-1, and the photodetector array also qualifies for imaging featured with high contrast. The flexible device exhibits high bending stability, which preserves almost 100% of initial performance after 5000 cycles. The proposed novel TMDCs growth and separation-transfer strategy lightens their significance for advances in curved and wearable (opto-)electronic applications.
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The swift emergence and propagation of multidrug-resistant (MDR) bacterial pathogens constitute a tremendous global health crisis. Among these pathogens, the challenge of antibiotic resistance in Gram-negative bacteria is particularly pressing due to their distinctive structure, such as highly impermeable outer membrane, overexpressed efflux pumps, and mutations. Several strategies have been documented to combat MDR Gram-negative bacteria, including the structural modification of existing antibiotics, the development of antimicrobial adjuvants, and research on novel targets that MDR bacteria are sensitive to. Drugs functioning as adjuvants to mitigate resistance to existing antibiotics may play a pivotal role in future antibacterial therapy strategies. In this review, we provide a brief overview of potential antibacterial adjuvants against Gram-negative bacteria and their mechanisms of action, and discuss the application prospects and potential for bacterial resistance to these adjuvants, along with strategies to reduce this risk.
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Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas , Bacterias Gramnegativas/efectos de los fármacos , Antibacterianos/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Adyuvantes Farmacéuticos/farmacología , Adyuvantes Farmacéuticos/uso terapéuticoRESUMEN
Main proteases (Mpros) are a class of conserved cysteine hydrolases among coronaviruses and play a crucial role in viral replication. Therefore, Mpros are ideal targets for the development of pan-coronavirus drugs. X77, previously developed against SARS-CoV Mpro, was repurposed as a non-covalent tight binder inhibitor against SARS-CoV-2 Mpro during COVID-19 pandemic. Many novel inhibitors with favorable efficacy have been discovered using X77 as a reference, suggesting that X77 could be a valuable scaffold for drug design. However, the broad-spectrum performance of X77 and underlying mechanism remain less understood. Here, we reported the crystal structures of Mpros from SARS-CoV-2, SARS-CoV, and MERS-CoV, and several Mpro mutants from SARS-CoV-2 variants bound to X77. A detailed analysis of these structures revealed key structural determinants essential for interaction and elucidated the binding modes of X77 with different coronaviral Mpros. The potencies of X77 against these investigated Mpros were further evaluated through molecular dynamic simulation and binding free energy calculation. These data provide molecular insights into broad-spectrum inhibition against coronaviral Mpros by X77 and the similarities and differences of X77 when bound to various Mpros, which will promote X77-based design of novel antivirals with broad-spectrum efficacy against different coronaviruses and SARS-CoV-2 variants.
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Proteasas 3C de Coronavirus , Simulación de Dinámica Molecular , SARS-CoV-2 , SARS-CoV-2/enzimología , SARS-CoV-2/efectos de los fármacos , Cristalografía por Rayos X , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Antivirales/química , Antivirales/farmacología , Humanos , Unión Proteica , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , COVID-19/virología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , Betacoronavirus/enzimología , Betacoronavirus/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/enzimología , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Sitios de Unión , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/tratamiento farmacológico , Pandemias , Neumonía Viral/virología , Neumonía Viral/tratamiento farmacológicoRESUMEN
Earthworms are pivotal in soil ecosystems due to their crucial role in shaping soil characteristics through casts and burrow walls. Previous research has predominantly focused on the direct impact of soil pollution on live earthworms, overlooking the subsequent effects on earthworm-mediated soil, such as casts and burrow walls. Using 2D-terraria as incubation containers and the geophagous earthworm species Metaphire guillelmi, this study assessed the change in various properties of earthworm-mediated soil in both uncontaminated soils and Cd- and Pye-contaminated soils. Overall, both Cd and Pye overall improved the ammonium nitrogen (NH4+-N), Olsen's phosphorus (Olsen-P) levels, and invertase and catalase activities while decreasing catalase activities in earthworm-mediated soil. They also fluctuating affected the pH, soil organic matter (SOM) content, soil urease, alkaline phosphatase activities, and microbial functional genes in the cast and burrow walls. These results indicated that earthworms remained crucial "ecosystem engineers" even in polluted soil. Additionally, differences were observed in the responses of properties between casts and burrow walls, showing unequal contributions of transit-through-gut and burrowing processes to soil modification. Specifically, transit-through-gut was found to have a more significant influence on soil NH4+-N and Olsen-P content compared to burrowing behavior. Regarding the pattern of microbial functional genes in earthworm-associated compartments, results revealed that they differed significantly in casts from those in bulk soil and burrow walls under unpolluted conditions, with pollution-enhancing disparities among compartments. Furthermore, NH4+-N and Olsen-P content, urease, and catalase activities in burrow walls and/or casts were identified as potential biomarkers for soil pollution, exhibiting a clear dose-effect relationship. Developing such biomarkers could address ethical concerns related to conventional earthworm biomarkers that require sacrificing earthworms. This study provides insights into the consequences of soil pollution on earthworm-mediated soil components, highlighting the importance of considering the indirect effects of contaminants on soil ecosystems.
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Cadmio , Oligoquetos , Pirenos , Contaminantes del Suelo , Suelo , Oligoquetos/fisiología , Animales , Contaminantes del Suelo/análisis , Suelo/química , Cadmio/análisis , Fósforo/análisisRESUMEN
Acute kidney injury (AKI) is common and an independent risk factor for mortality in patients with paraquat (PQ) poisoning. Currently, no specific antidote is available. Synaptotagmin-1 (SYT1) has been identified as a key protein that facilitates PQ efflux in PQ-resistant A549 cells, thereby preventing PQ-induced lung injury. However, the protective effect of STY1 on PQ-induced AKI remains to be elucidated. This study exposed human kidney 2 (HK-2) cells overexpressing SYT1 to PQ. These cells exhibited significantly lower levels of growth inhibition, reactive oxygen species production, early apoptosis, and PQ accumulation compared to the parent HK-2 cells. Transcriptomic screening and Western blot analysis revealed that SYT1 overexpression significantly promoted the expression of glucose transporter 2 (GLUT2). Inhibition of GLUT2 completely abolished the protective effects of SYT1 overexpression in HK-2 cells and restored intracellular PQ concentrations. Further immunoprecipitation-shotgun and RNA interference experiments revealed that SYT1 binds to and stabilizes the protein SERPINE1 mRNA-binding protein 1 (SERBP1), enhancing the stability of GLUT2 mRNA and its protein levels. In summary, SYT1 antagonizes PQ intracellular accumulation and prevents nephrocyte toxicity by up-regulating SERBP1/GLUT2 expression. This study identifies a potential target for the treatment of PQ-induced AKI.
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Transportador de Glucosa de Tipo 2 , Paraquat , Sinaptotagmina I , Regulación hacia Arriba , Humanos , Paraquat/toxicidad , Sinaptotagmina I/metabolismo , Sinaptotagmina I/genética , Regulación hacia Arriba/efectos de los fármacos , Línea Celular , Transportador de Glucosa de Tipo 2/metabolismo , Transportador de Glucosa de Tipo 2/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patologíaRESUMEN
Coregonus ussuriensis Berg, distributed widely in cold waters above 45° N latitude, is a savored freshwater whitefish that has been included in the list of endangered animals as a consequence of overfishing. Lack of genomic information seriously hampers evolutionary and genetic research on C. ussuriensis warranting the need to assemble a high-quality reference genome to promote its genetic breeding. We assembled and constructed a reference chromosome-level C. ussuriensis genome (sequence length, 2.51 Gb; contig N50 length, 4.27 Mb) using PacBio sequencing and Hi-C assembly technology, 3,109 contigs were assembled into scaffolds, resulting in a genome assembly with 40 chromosomes and a scaffold N50 length of 62.20 Mb. In addition, 43,320 protein-coding genes were annotated. The peak Ks position in the species comparison reflects the whole-genome replication event of C. ussuriensis. This chromosome-level genome provides reference data for further studies on the molecular breeding of C. ussuriensis.
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Cromosomas , Genoma , Animales , Cromosomas/genética , Evolución MolecularRESUMEN
Pogostemon cablin (PC) is a traditional Chinese medicine (TCM) and food as well as an important essential oil plant in China. PC essential oil exerts pharmacological effects such as anti-inflammatory, anti-oxidant, anti-platelet, anti-thrombotic, and anti-depressant. This study established a reliable and sensitive gas chromatography-mass spectrometry (GC-MS) method for the simultaneous determination of the pharmacokinetics of patchouli alcohol, ß-elemene, ß-caryophyllene, caryophyllene oxide, and farnesol in the plasma of rats after oral administration of PC essential oil extract. Using ethyl acetate to prepare the plasma samples, and p-menthone was used as the internal standard (IS). An HP5-MS column (0.25 µm × 0.25 mm × 30 m) was used for chromatographic separation, and detection was performed in selected ion monitoring (SIM) mode. The accuracies of intra-day and inter-day for all analytes displayed a range of -6.7 %-9.2 %, with precision below 12.5 %. Extraction recoveries for analytes ranged from 74.0 to 106.4 % and matrix effects ranged from 92.4 to 106.9 %. Stability results have demonstrated that the relative standard deviations (RSD) of analytes were below 12.1 %. Therefore, the developed GC-MS method successfully evaluated the pharmacokinetics of five volatile components in PC essential oil extract administered orally to rats.
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A novel polysaccharide, Inonotus obliquus polysaccharide (IOP), was extracted using a microwave extraction method and subsequently subjected to modifications through sulfation, carboxymethylation, phosphorylation, and acetylation. Its physical and chemical properties were analyzed using various chemical techniques, including high-pressure liquid chromatography, ultraviolet light, Fourier-transform infrared spectroscopy, X-ray diffraction, Congo red test, and scanning electron microscopy. The antioxidant capacity was assessed using DPPH, ABTS, and hydroxyl radical assays, as well as by measuring the reducing power. Additionally, hypoglycemic activity was evaluated through α-glucosidase and α-amylase assays. The results indicated that the chemical modifications effectively altered the physical and chemical properties, as well as the biological activities of IOP. Compared to the unmodified IOP, the derivatives exhibited reduced sugar content, uronic acid content, and molecular weight, while demonstrating varying levels of antioxidant and hypoglycemic capabilities. Notably, the carboxymethylated IOP (IOP-C) displayed lower molecular weight, higher ABTS free radical scavenging rate, greater reducing ability, and increased α-amylase inhibition rate. Therefore, IOP-C shows promise as a potential edible antioxidant and hypoglycemic agent.
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Human coronaviruses are a group of pathogens that primarily cause respiratory and intestinal diseases. Infection can easily cause respiratory symptoms, as well as a variety of serious complications. There are several types of human coronaviruses, such as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, and SARS-CoV-2. The prevalence of COVID-19 has led to a growing focus on drug research against human coronaviruses. The main protease (Mpro) from human coronaviruses is a relatively conserved that controls viral replication. X77 was discovered to have extremely high inhibitory activity against SARS-CoV-2 Mpro through the use of computer-simulated docking. In this paper, we have resolved the crystal structure of the HCoV-NL63 Mpro complexed with X77 and analyzed their interaction in detail. This data provides essential information for solving their binding modes and their structural determinants. Then, we compared the binding modes of X77 with SARS-CoV-2 Mpro and HCoV-NL63 Mpro in detail. This study illustrates the structural basis of HCoV-NL63 Mpro binding to the inhibitor X77. The structural insights derived from this study will inform the development of new drugs with broad-spectrum resistance to human coronaviruses.