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The aim of this work was to investigate the therapeutic effect of modified Shisiwei Jianzhong Decoction (SJD) on aplastic anemia (AA) and its potential pharmacological mechanism from the perspective of mitophagy. A comprehensive approach combining network pharmacology, mendelian randomization, molecular docking and animal experiments was applied to evaluate the properties of SJD against AA. By integrating multiple databases, it was determined that SJD exerted its therapeutic effect on AA by targeting three key targets [mammalian target of rapamycin (MTOR), poly(ADP-ribose) polymerase 1 (PARP1) and Sirtuin 1 (SIRT1)] through four core compounds (quercetin, resveratrol, genistein and curcumin). Mendelian randomization analysis identified MTOR as a risk factor for AA occurrence while PARP1 was a protective factor. Results of animal experiments showed that SJD improved peripheral blood counts and promoted the proliferation of hematopoietic stem cells. Mechanistically, SJD, especially at high dose, played a therapeutic role in AA by activating mitophagy-related proteins PTEN induced kinase 1 (PINK1)/Parkin and inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase (AKT)/MTOR pathway. This study revealed for the first time the core chemical composition of SJD and its pharmacological effects against AA, which can restore hematopoietic function by activating mitophagy. The results provide inspiration for the clinical application of traditional Chinese medicine in AA treatment.
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Histone deacetylase inhibitors (HDACis) show beneficial effects on different hematological malignancy subtypes. However, their impacts on treating solid tumors are still limited due to diverse resistance mechanisms. Recent studies have found that the feedback activation of BRD4-LIFR-JAK1-STAT3 pathway after HDACi incubation is a vital mechanism inducing resistance of specific solid tumor cells to HDACis. This review summarizes the recent development of multi-target HDACis that can concurrently block BRD4-LIFR-JAK1-STAT3 pathway. Moreover, our findings hope to shed novel lights on developing novel multi-target HDACis with reduced BRD4-LIFR-JAK1-STAT3-mediated drug resistance in some tumors.
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Inhibidores de Histona Desacetilasas , Janus Quinasa 1 , Neoplasias , Factor de Transcripción STAT3 , Transducción de Señal , Factores de Transcripción , Humanos , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Proteínas que Contienen BromodominioRESUMEN
Alfin-like (AL) is a small plant-specific gene family characterized by a PHD-finger-like structural domain at the C-terminus and a DUF3594 structural domain at the N-terminus, and these genes play prominent roles in plant development and abiotic stress response. In this study, we conducted genome-wide identification and analyzed the AL protein family in Gossypium hirsutum cv. NDM8 to assess their response to various abiotic stresses for the first time. A total of 26 AL genes were identified in NDM8 and classified into four groups based on a phylogenetic tree. Moreover, cis-acting element analysis revealed that multiple phytohormone response and abiotic stress response elements were highly prevalent in AL gene promoters. Further, we discovered that the GhAL19 gene could negatively regulate drought and salt stresses via physiological and biochemical changes, gene expression, and the VIGS assay. The study found there was a significant increase in POD and SOD activity, as well as a significant change in MDA in VIGS-NaCl and VIGS-PEG plants. Transcriptome analysis demonstrated that the expression levels of the ABA biosynthesis gene (GhNCED1), signaling genes (GhABI1, GhABI2, and GhABI5), responsive genes (GhCOR47, GhRD22, and GhERFs), and the stress-related marker gene GhLEA14 were regulated in VIGS lines under drought and NaCl treatment. In summary, GhAL19 as an AL TF may negatively regulate tolerance to drought and salt by regulating the antioxidant capacity and ABA-mediated pathway.
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Purpose: Diabetes and its complications cause a heavy burden of disease worldwide. In recent years, Mendelian randomization (MR) has been widely used to discover the pathogenesis and epidemiology of diseases, as well as to discover new therapeutic targets. Therefore, based on systematic "druggable" genomics, we aim to identify new therapeutic targets for diabetes and analyze its pathophysiological mechanisms to promote its new therapeutic strategies. Material and method: We used double sample MR to integrate the identified druggable genomics to evaluate the causal effect of quantitative trait loci (eQTLs) expressed by druggable genes in blood on type 1 and 2 diabetes (T1DM and T2DM). Repeat the study using different data sources on diabetes and its complications to verify the identified genes. Not only that, we also use Bayesian co-localization analysis to evaluate the posterior probabilities of different causal variations, shared causal variations, and co-localization probabilities to examine the possibility of genetic confounding. Finally, using diabetes markers with available genome-wide association studies data, we evaluated the causal relationship between established diabetes markers to explore possible mechanisms. Result: Overall, a total of 4,477 unique druggable genes have been gathered. After filtering using methods such as Bonferroni significance (P<1.90e-05), the MR Steiger directionality test, Bayesian co-localization analysis, and validation with different datasets, Finally, 7 potential druggable genes that may affect the results of T1DM and 7 potential druggable genes that may affect the results of T2DM were identified. Reverse MR suggests that C4B may play a bidirectional role in the pathogenesis of T1DM, and none of the other 13 target genes have a reverse causal relationship. And the 7 target genes in T2DM may each affect the biomarkers of T2DM to mediate the pathogenesis of T2DM. Conclusion: This study provides genetic evidence supporting the potential therapeutic benefits of targeting seven druggable genes, namely MAP3K13, KCNJ11, REG4, KIF11, CCNE2, PEAK1, and NRBP1, for T2DM treatment. Similarly, targeting seven druggable genes, namely ERBB3, C4B, CD69, PTPN22, IL27, ATP2A1, and LT-ß, has The potential therapeutic benefits of T1DM treatment. This will provide new ideas for the treatment of diabetes and also help to determine the priority of drug development for diabetes.
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Diabetes Mellitus Tipo 2 , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Sitios de Carácter Cuantitativo , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Predisposición Genética a la Enfermedad , Teorema de Bayes , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Genómica/métodos , Hipoglucemiantes/uso terapéutico , Polimorfismo de Nucleótido SimpleRESUMEN
For every epidemic outbreak, the prevention and treatments in resource-limited areas are always out of reach. Critical to this is that high accuracy, stability, and more comprehensive analytical techniques always rely on expensive and bulky instruments and large laboratories. Here, a fully integrated and high-throughput microfluidic system is proposed for ultra-multiple point-of-care immunoassay, termed Dac system. Specifically, the Dac system only requires a handheld portable device to automatically recycle repetitive multi-step reactions including on-demand liquid releasing, dispensing, metering, collecting, oscillatory mixing, and discharging. The Dac system performs high-precision enzyme-linked immunosorbent assays for up to 17 samples or targets simultaneously on a single chip. Furthermore, reagent consumption is only 2% compared to conventional ELISA, and microbubble-accelerated reactions shorten the assay time by more than half. As a proof of concept, the multiplexed detections are achieved by detecting at least four infection targets for two samples simultaneously on a singular chip. Furthermore, the barcode-based multi-target results can rapidly distinguish between five similar cases, allowing for accurate therapeutic interventions. Compared to bulky clinical instruments, the accuracy of clinical inflammation classification is 92.38% (n = 105), with a quantitative correlation coefficient of R2 = 0.9838, while the clinical specificity is 100% and the sensitivity is 98.93%.
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Background: Probiotic supplementation has a positive effect on endurance exercise performance and body composition in athletes, but the underlying mechanisms remain unclear. Gut microbiota can provide measurable markers of immune function in athletes, and microbial composition analysis may be sensitive enough to detect stress and metabolic disorders caused by exercise. Methods: Nineteen healthy active amateur marathon runners (15 male and 4 female) with a mean age of 29.11 years volunteered to participate in this double-blind controlled study. Based on the performance of the Cooper 12-min running test (CRT), the participants were allocated into two groups to receive either a probiotic formulation comprising lactobacillus acidophilus and bifidobacterium longum (n = 10) or placebo containing maltodextrin (n = 9) for five weeks. Consistency of diet and exercise was ensured throughout the experimental period. Before and after the intervention, all participants were assessed for CRT, emotional stability and gastrointestinal symptoms, gut microbiota composition, body composition and magnetic resonance imaging (MRI) indicators of skeletal muscle microcirculation. Results: Compared to before the intervention, the probiotics group showed an increase in CRT score (2.88 ± 0.57 vs 3.01 ± 0.60 km, Pï¼0.05), significant improvement in GSRS and GIQLI (9.20 ± 4.64 vs 7.40 ± 3.24, 118.90 ± 12.30 vs 127.50 ± 9.85, Pï¼0.05), while these indicators remained unchanged in the control group, with a significant time-group interaction effect on gastrointestinal symptoms. Additionally, some MRI metabolic cycling indicators of the thigh skeletal muscle also changed in the probiotics group (Pï¼0.05). Regarding microbiota abundance, the probiotics group exhibited a significant increase in the abundance of beneficial bacteria and a significant decrease in the abundance of harmful bacteria post-intervention (Pï¼0.05). Conclusion: As a sports nutritional supplement, probiotics have the potential to improve athletic performance by optimizing the balance of gut microbiota, alleviating gastrointestinal symptoms.
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Point of care testing (POCT) of nucleic acids holds significant importance in the realm of infectious disease prevention and control, as well as the advancement of personalized precision medicine. Nevertheless, conventional nucleic acid testing methods continue to face challenges such as prolonged detection times and dependence on extensive specialized equipment and personnel, rendering them unsuitable for point of care applications. Here, we proposed an innovative active centrifugal microfluidic system (ACMS) for automatic nucleic acid extraction, encompassing modules for active valve control and magnetic control. An on-chip centrifugal puncture valve (PV) was devised based on the elastic tolerance differences between silicone membranes and tinfoils to release pre-embedded liquid reagents on demand. Furthermore, we have utilized the returnable valve (RV) technology to accurately control the retention and release of liquids, leveraging the high elastic tolerance of the silicone membrane. By incorporating an online controllable magnetic valve, we have achieved controlled and rapid aggregation and dispersion of magnetic beads. The final chip encapsulates multiple reagents and magnetic beads necessary for nucleic acid extraction. Upon sample addition and loading into the instrument, automated on-chip sample loading and nucleic acid extraction, purification, and collection can be accomplished within 30 minutes, halving the overall operation time and even increasing the efficiency of pseudovirus extraction by three orders of magnitude. Consequently, real-time fluorescence quantitative PCR amplification has successfully detected multiple targets of the SARS-CoV-2 virus (with an impressive detection limit as low as 10 copies per µL), along with targeted sequencing analysis yielding a conformity rate of 99%.
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Centrifugación , Dispositivos Laboratorio en un Chip , Centrifugación/instrumentación , Humanos , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/genética , Técnicas Analíticas Microfluídicas/instrumentación , Diseño de Equipo , Ácidos Nucleicos/aislamiento & purificación , Ácidos Nucleicos/análisis , ARN Viral/aislamiento & purificación , ARN Viral/análisis , COVID-19/diagnóstico , COVID-19/virologíaRESUMEN
The NAPRT-induced increase in NAD+ levels was proposed as a mechanism contributing to hepatocellular carcinoma (HCC) resistance to NAMPT inhibitors. Thus, concurrently targeting NAMPT and NAPRT could be considered to overcome drug resistance. A BRD4 inhibitor downregulates the expression of NAPRT in HCC, and the combination of NAMPT inhibitors with BRD4 inhibitors simultaneously blocks NAD+ generation via salvage and the PH synthesis pathway. Moreover, the combination of the two agents significantly downregulated the expression of tumor-promoting genes and strongly promoted apoptosis. The present work identified various NAMPT/BRD4 dual inhibitors based on the multitargeted drug rationale. Among them, compound A2, which demonstrated the strongest effect, exhibited potent inhibition of NAMPT and BRD4 (IC50 = 35 and 58 nM, respectively). It significantly suppressed the growth and migration of HCC cells and facilitated their apoptosis. Furthermore, compound A2 also manifested a robust anticancer effect in HCCLM3 xenograft mouse models, with no apparent toxic effects. Our findings in this study provide an effective approach to target NAD+ metabolism for HCC treatment.
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Antineoplásicos , Apoptosis , Carcinoma Hepatocelular , Proteínas de Ciclo Celular , Proliferación Celular , Citocinas , Neoplasias Hepáticas , Nicotinamida Fosforribosiltransferasa , Factores de Transcripción , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Nicotinamida Fosforribosiltransferasa/metabolismo , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Ratones , Apoptosis/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Citocinas/metabolismo , Citocinas/antagonistas & inhibidores , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Ratones Desnudos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Proteínas que Contienen BromodominioRESUMEN
Fiber quality is a major breeding goal in cotton, but phenotypically direct selection is often hindered. In this study, we identified fiber quality and yield related loci using GWAS based on 2.97 million SNPs obtained from 10.65× resequencing data of 1081 accessions. The results showed that 585 novel fiber loci, including two novel stable SNP peaks associated with fiber length on chromosomes At12 and Dt05 and one novel genome regions linked with fiber strength on chromosome Dt12 were identified. Furthermore, by means of gene expression analysis, GhM_A12G0090, GhM_D05G1692, GhM_D12G3135 were identified and GhM_D11G2208 function was identified in Arabidopsis. Additionally, 14 consistent and stable superior haplotypes were identified, and 25 accessions were detected as possessing these 14 superior haplotype in breeding. This study providing fundamental insight relevant to identification of genes associated with fiber quality and yield will enhance future efforts toward improvement of upland cotton.
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Gossypium , Haplotipos , Fitomejoramiento , Polimorfismo de Nucleótido Simple , Gossypium/genética , Genoma de Planta , Fibra de Algodón , Estudio de Asociación del Genoma Completo , Sitios de Carácter CuantitativoRESUMEN
Immunoassays serve as powerful diagnostic tools for early disease screening, process monitoring, and precision treatment. However, the current methods are limited by high costs, prolonged processing times (>2 h), and operational complexities that hinder their widespread application in point-of-care testing. Here, we propose a novel centrifugo-pneumatic reciprocating flowing coupled with spatial confinement strategy, termed PRCM, for ultrafast multiplexed immunoassay of pathogens on a centrifugal microfluidic platform. Each chip consists of four replicated units; each unit allows simultaneous detection of three targets, thereby facilitating high-throughput parallel analysis of multiple targets. The PRCM platform enables sequential execution of critical steps such as solution mixing, reaction, and drainage by coordinating inherent parameters, including motor rotation speed, rotation direction, and acceleration/deceleration. By integrating centrifugal-mediated pneumatic reciprocating flow with spatial confinement strategies, we significantly reduce the duration of immune binding from 30 to 5 min, enabling completion of the entire testing process within 20 min. As proof of concept, we conducted a simultaneous comparative test on- and off-the-microfluidics using 12 negative and positive clinical samples. The outcomes yielded 100% accuracy in detecting the presence or absence of the SARS-CoV-2 virus, thus highlighting the potential of our PRCM system for multiplexed point-of-care immunoassays.
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COVID-19 , Centrifugación , SARS-CoV-2 , Inmunoensayo/métodos , Inmunoensayo/instrumentación , SARS-CoV-2/aislamiento & purificación , Centrifugación/instrumentación , COVID-19/diagnóstico , COVID-19/virología , Humanos , Técnicas Analíticas Microfluídicas/instrumentación , Dispositivos Laboratorio en un ChipRESUMEN
The expression of Bacillus thuringiensis (Bt) toxins in transgenic cotton confers resistance to insect pests. However, it has been demonstrated that its effectiveness varies among cotton cultivars and different tissues. In this study, we evaluated the expression of Bt protein in 28 cotton cultivars and selected 7 cultivars that differed in Bt protein expression for transcriptome analysis. Based on their Bt protein expression levels, the selected cultivars were categorized into three groups: H (high Bt protein expression), M (moderate expression), and L (low expression). In total, 342, 318, and 965 differentially expressed genes were detected in the H vs. L, M vs. L, and H vs. M comparison groups, respectively. And three modules significantly associated with Bt protein expression were identified by weighted gene co-expression network analysis. Three hub genes were selected to verify their relationships with Bt protein expression using virus-induced gene silencing (VIGS). Silencing GhM_D11G1176, encoding an MYC transcription factor, was confirmed to significantly decrease the expression of Bt protein. The present findings contribute to an improved understanding of the mechanisms that influence Bt protein expression in transgenic cotton.
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Bacillus thuringiensis , Regulación de la Expresión Génica de las Plantas , Gossypium , Plantas Modificadas Genéticamente , Bacillus thuringiensis/genética , Toxinas de Bacillus thuringiensis/genética , Proteínas Bacterianas/genética , Endotoxinas/genética , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Gossypium/genética , Gossypium/parasitología , Gossypium/metabolismo , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente/genética , TranscriptomaRESUMEN
In the present study, we successfully developed an efficient thiocyanation of carbonyl compounds by using low-toxicity and inexpensive ammonium thiocyanate as the thiocyanate source under visible light in air (O2) at room temperature. This unified strategy is very facile for thiocyanation of various carbonyl compound derivatives (ß-keto esters, ß-keto amides, pyrazo-5-ones, isoxazol-5-ones, etc.). More importantly, the reaction proceeded smoothly without the addition of a photocatalyst and strong oxidant, ultimately minimizing the production of chemical waste. Furthermore, this green and sustainable synthetic chemistry can be used in the late-stage functionalization (LSF) of biorelevant compounds, which offers unique opportunities to achieve smooth and clean thiocyanation of drugs under mild reaction conditions.
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Current research on the effects of glyceryl trinitrate (GTN) on the lowering of elevated blood pressure (BP) among patients with acute intracerebral hemorrhage (AIH) has not been highly emphasized. The aim of this meta-analysis is to examine the effects of GTN in patients with acute stroke. The lowering of BP was the primary outcome measure in patients treated with GTN compared to no-GTN treatment. A meta-analysis was performed to evaluate the efficacy of GTN in lowering BPs and analyze the outcomes of GTN treatment. Appropriate articles were searched using PubMed, Taylor & Francis Online, Cochrane, Scopus, ScienceDirect, Wiley Online Library, and Springer, with the use of appropriate keywords as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Out of 13 articles eligible for this study, 7 studies qualified for the meta-analysis by meeting the inclusion criteria. The PRISMA guidelines and the recommendations of Cochrane Collaboration were followed when conducting this meta-analysis. After subgroup analysis, differences between patients treated with GTN and without GTN were analyzed. The lowering of BP resulted in improved functional outcomes in patients treated with GTN. This meta-analysis showed differences between the 2 groups, with a risk ratio (RR) of 1.01 (95% confidence interval (95% CI): 0.92-10.07, p = 0.30, I2 = 18%). There was a significant improvement in outcome measures in patients treated with GTN by lowering elevated BP after acute stroke.
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Hemorragia Cerebral , Nitroglicerina , Accidente Cerebrovascular , Humanos , Hemorragia Cerebral/tratamiento farmacológico , Hipertensión , Nitroglicerina/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Respiratory tract infections are associated with the most common diseases transmitted among people and remain a huge threat to global public health. Rapid and sensitive diagnosis of causative agents is critical for timely treatment and disease control. Here, we developed a novel method based on recombinase polymerase amplification (RPA) combined with CRISPR-Cas12a to detect three viral pathogens, including SARS-CoV-2, influenza A, and influenza B, which cause similar symptom complexes of flu cold in the respiratory tract. The detection method can be completed within 1 h, which is faster than other standard detection methods, and the limit of detection is approximately 102 copies/µL. Additionally, this detection system is highly specific and there is no cross-reactivity with other common respiratory tract pathogens. Based on this assay, we further developed a more simplified RPA/CRISPR-Cas12a system combined with lateral flow assay on a manual microfluidic chip, which can simultaneously detect these three viruses. This low-cost detection system is rapid and sensitive, which could be applied in the field and resource-limited areas without bulky and expensive instruments, providing powerful tools for the point-of-care diagnostic.
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COVID-19 , Gripe Humana , Orthomyxoviridae , Humanos , Recombinasas , SARS-CoV-2 , Sistemas CRISPR-Cas , Nucleotidiltransferasas , Técnicas de Amplificación de Ácido NucleicoRESUMEN
Weeds seriously affect the yield and quality of crops. Because manual weeding is time-consuming and laborious, the use of herbicides becomes an effective way to solve the harm caused by weeds in fields. Both 5-enolpyruvyl shikimate-3-phosphate synthetase (EPSPS) and acetyltransferase genes (bialaphos resistance, BAR) are widely used to improve crop resistance to herbicides. However, cotton, as the most important natural fiber crop, is not tolerant to herbicides in China, and the EPSPS and BAR family genes have not yet been characterized in cotton. Therefore, we explore the genes of these two families to provide candidate genes for the study of herbicide resistance mechanisms. In this study, 8, 8, 4, and 5 EPSPS genes and 6, 6, 5, and 5 BAR genes were identified in allotetraploid Gossypium hirsutum and Gossypium barbadense, diploid Gossypium arboreum and Gossypium raimondii, respectively. Members of the EPSPS and BAR families were classified into three subgroups based on the distribution of phylogenetic trees, conserved motifs, and gene structures. In addition, the promoter sequences of EPSPS and BAR family members included growth and development, stress, and hormone-related cis-elements. Based on the expression analysis, the family members showed tissue-specific expression and differed significantly in response to abiotic stresses. Finally, qRT-PCR analysis revealed that the expression levels of GhEPSPS3, GhEPSPS4, and GhBAR1 were significantly upregulated after exogenous spraying of herbicides. Overall, we characterized the EPSPS and BAR gene families of cotton at the genome-wide level, which will provide a basis for further studying the functions of EPSPS and BAR genes during growth and development and herbicide stress.
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Cotton fiber quality-related traits, such as fiber length, fiber strength, and fiber elongation, are affected by complex mechanisms controlled by multiple genes. Determining the QTN-by-QTN interactions (QQIs) associated with fiber quality-related traits is therefore essential for accelerating the genetic enhancement of cotton breeding. In this study, a natural population of 1,245 upland cotton varieties with 1,122,352 SNPs was used for detecting the main-effect QTNs and QQIs using the 3V multi-locus random-SNP-effect mixed linear model (3VmrMLM) method. A total of 171 significant main-effect QTNs and 42 QQIs were detected, of which 22 were both main-effect QTNs and QQIs. Of the detected 42 QQIs, a total of 13 significant loci and 5 candidate genes were reported in previous studies. Among the three interaction types, the AD interaction type has a preference for the trait of FE. Additionally, the QQIs have a substantial impact on the enhancement predictability for fiber quality-related traits. The study of QQIs is crucial for elucidating the genetic mechanism of cotton fiber quality and enhancing breeding efficiency.
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INTRODUCTION: Neonatal hypoxic-ischemic brain damage (HIBD) is a serious inflammatory injury. At present, the standard treatment for this disease is hypothermia therapy, and the effect of drug intervention is still limited. L-F001 is a compound of fasudil and lipoic acid. Previous in vitro experiments have confirmed that L-F001 has anti-inflammatory neuroprotective functions. However, its therapeutic effect on neonates with HIBD remains unknown. This study was aimed at exploring the therapeutic effect of L-F001 on HIBD rats. METHODS: The newborn rats were divided into three groups: Sham operation group, HIBD group, and HIBD + L-F001 group. HE staining, Nissil staining, the immunofluorescence of iNOS and COX-2, ELISA (IL-1ß, IL-6, TNF-α, and IL-10), and western blotting analyses were performed to determine the therapeutic effect of L-F001. Finally, we evaluated the growth and development of each group by measuring body weight. RESULTS: The hippocampal structure of HIBD rats was disordered, and the Nissil body was small and shallow. The expressions of iNOS and COX-2 in HIBD rats were increased, whereas the expressions of IL-1ß, IL-6, and TNF-α in plasma were upregulated, and the expression of IL-10 was decreased. L-F001 could improve the tissue structure and reduce the expression of iNOS and COX-2 in HIBD rats. Meanwhile, L-F001 could also reduce the expression of pro-inflammatory cytokines and restore the content of anti-inflammatory cytokines in plasma. We further found that the TLR4 pathway was activated after hypoxic-ischemia in neonatal rats. L-F001 could inhibit the activation of TLR4 pathway. Finally, we found that after L-F001 treatment, the body weight of HIBD rats increased significantly compared with the untreated group. CONCLUSIONS: L-F001 antagonizes the inflammatory response after hypoxic-ischemia by inhibiting the activation of the TLR4 signaling pathway, thus playing a neuroprotective role. L-F001 may be a potential therapeutic agent for neonatal HIBD.
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Hipoxia-Isquemia Encefálica , Ácido Tióctico , Ratas , Animales , Animales Recién Nacidos , Ratas Sprague-Dawley , Interleucina-10/metabolismo , Receptor Toll-Like 4/metabolismo , Factor 88 de Diferenciación Mieloide , Ácido Tióctico/farmacología , Ácido Tióctico/metabolismo , Interleucina-6 , Factor de Necrosis Tumoral alfa/metabolismo , Ciclooxigenasa 2/metabolismo , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Transducción de Señal , Isquemia , Hipocampo/metabolismo , Citocinas/metabolismo , Antiinflamatorios/farmacología , Peso CorporalRESUMEN
There remains an unmet need for a fully integrated microfluidic platform that can automatically perform multistep and multireagent immunoassays. Here, we proposed a novel online dual-active valve-based centrifugal microfluidic chip, termed DAVM, for fully automatic point-of-care immunoassay. Practically, the puncture valve, one of the dual active valves, is capable of achieving precise, on-demand, sequential release of prestored reagents, while the other valve-reversible active valve enables controlled retention and drainage of the reaction solutions. Thereby, our technology mitigates the challenges of hydrophilic/hydrophobic modifications and unstable valve control performance commonly observed in passive valve controls. As a proof of concept, the indirect enzymatic immunoblotting technique was employed on DAVM for fully automated immunological analysis of eight targets, yielding outcomes within an hour. Furthermore, we conducted a comparative analysis of 28 clinical samples with autoimmune diseases. According to 224 clinical data, the sample testing concordance rate between DAVM and the traditional instrument was 82%, with a target compliance rate of 97%. Therefore, our DAVM system has powerful potential for fully automated immunoassays.
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Técnicas Analíticas Microfluídicas , Microfluídica , Sistemas de Atención de Punto , Dispositivos Laboratorio en un Chip , Inmunoensayo/métodos , ImmunoblottingRESUMEN
Background: With the development of thrombopoietin receptor agonists, the prognosis of immune thrombocytopenia (ITP) in patients in whom there was a poor response to first-line treatment has greatly improved. However, there are still some patients who are refractory to eltrombopag. Objectives: To explore the efficacy and safety of eltrombopag combined with low-dose cyclosporine in the management of patients with refractory ITP. Methods: A total of 21 participants with ITP who failed to respond to multiple lines of therapy (including a daily dose of 75 mg of eltrombopag for at least 30 days) treated at The First Affiliated Hospital of Zhejiang Chinese Medical University between January 2018 and August 2022 were included. All enrolled patients subsequently received 50 mg of eltrombopag daily and low-dose cyclosporine (3 mg/kg/d, with an initial target concentration of 75-120 ng/mL). The efficacy and safety of the combined therapies were evaluated. Results: A total of 76.2% (16/21) of the patients responded to the combination of cyclosporine and eltrombopag, with a median time to response of 14.5 (range, 5-37) days. A complete response (platelet count ≥ 100 × 109/L) was observed in 81.3% (13/16) of the patients, among whom 1 patient experienced relapse due to self-reduction in eltrombopag. During a median follow-up of 180 days, there were no relapses, and 70% (7/10) of the patients successfully stopped or decreased concomitant ITP medications. One patient had both a catheter-related deep vein thrombosis and a venous cerebral thrombotic event later; no other severe drug-related adverse events were observed. Conclusion: Combining low-dose cyclosporine with eltrombopag may be an effective alternative for multirefractory ITP that is nonresponsive to eltrombopag alone.
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Crops must efficiently allocate their limited energy resources to survival, growth and reproduction, including balancing growth and defense. Thus, investigating the underlying molecular mechanism of crop under stress is crucial for breeding. Chloroplasts immunity is an important facet involving in plant resistance and growth, however, whether and how crop immunity modulated by chloroplast is influenced by epigenetic regulation remains unclear. Here, the cotton lysine 2-hydroxyisobutyrylation (Khib) and succinylation (Ksuc) modifications are firstly identified and characterized, and discover that the chloroplast proteins are hit most. Both modifications are strongly associated with plant resistance to Verticillium dahliae, reflected by Khib specifically modulating PR and salicylic acid (SA) signal pathway and the identified GhHDA15 and GhSRT1 negatively regulating Verticillium wilt (VW) resistance via removing Khib and Ksuc. Further investigation uncovers that photosystem repair protein GhPSB27 situates in the core hub of both Khib- and Ksuc-modified proteins network. The acylated GhPSB27 regulated by GhHDA15 and GhSRT1 can raise the D1 protein content, further enhancing plant biomass- and seed-yield and disease resistance via increasing photosynthesis and by-products of chloroplast-derived reactive oxygen species (cROS). Therefore, this study reveals a mechanism balancing high disease resistance and high yield through epigenetic regulation of chloroplast protein, providing a novel strategy to crop improvements.