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1.
Cell Mol Life Sci ; 81(1): 64, 2024 Jan 28.
Article in English | MEDLINE | ID: mdl-38280930

ABSTRACT

Silenced protein tyrosine phosphatase receptor type R (PTPRR) participates in mitogen-activated protein kinase (MAPK) signaling cascades during the genesis and development of tumors. Rat sarcoma virus (Ras) genes are frequently mutated in lung adenocarcinoma, thereby resulting in hyperactivation of downstream MAPK signaling. However, the molecular mechanism manipulating the regulation and function of PTPRR in RAS-mutant lung adenocarcinoma is not known. Patient records collected from the Cancer Genome Atlas and Gene Expression Omnibus showed that silenced PTPRR was positively correlated with the prognosis. Exogenous expression of PTPRR suppressed the proliferation and migration of lung cancer cells. PTPRR expression and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibition acted synergistically to control ERK1/2 phosphorylation in RAS-driven lung cancer cells. Chromatin immunoprecipitation assay revealed that HDAC inhibition induced enriched histone acetylation in the promoter region of PTPRR and recovered PTPRR transcription. The combination of the HDAC inhibitor SAHA and SHP2 inhibitor SHP099 suppressed the progression of lung cancer markedly in vitro and in vivo. Therefore, we revealed the epigenetic silencing mechanism of PTPRR and demonstrated that combination therapy targeting HDAC and SHP2 might represent a novel strategy to treat RAS-mutant lung cancer.


Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Histones/metabolism , Acetylation , Adenocarcinoma of Lung/genetics , Lung Neoplasms/pathology , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Cell Line, Tumor , Receptor-Like Protein Tyrosine Phosphatases, Class 7/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 7/metabolism
2.
Plant J ; 116(3): 690-705, 2023 11.
Article in English | MEDLINE | ID: mdl-37494542

ABSTRACT

Spartina alterniflora is a halophyte that can survive in high-salinity environments, and it is phylogenetically close to important cereal crops, such as maize and rice. It is of scientific interest to understand why S. alterniflora can live under such extremely stressful conditions. The molecular mechanism underlying its high-saline tolerance is still largely unknown. Here we investigated the possibility that high-affinity K+ transporters (HKTs), which function in salt tolerance and maintenance of ion homeostasis in plants, are responsible for salt tolerance in S. alterniflora. To overcome the imprecision and unstable of the gene screening method caused by the conventional sequence alignment, we used a deep learning method, DeepGOPlus, to automatically extract sequence and protein characteristics from our newly assemble S. alterniflora genome to identify SaHKTs. Results showed that a total of 16 HKT genes were identified. The number of S. alterniflora HKTs (SaHKTs) is larger than that in all other investigated plant species except wheat. Phylogenetically related SaHKT members had similar gene structures, conserved protein domains and cis-elements. Expression profiling showed that most SaHKT genes are expressed in specific tissues and are differentially expressed under salt stress. Yeast complementation expression analysis showed that type I members SaHKT1;2, SaHKT1;3 and SaHKT1;8 and type II members SaHKT2;1, SaHKT2;3 and SaHKT2;4 had low-affinity K+ uptake ability and that type II members showed stronger K+ affinity than rice and Arabidopsis HKTs, as well as most SaHKTs showed preference for Na+ transport. We believe the deep learning-based methods are powerful approaches to uncovering new functional genes, and the SaHKT genes identified are important resources for breeding new varieties of salt-tolerant crops.


Subject(s)
Deep Learning , Oryza , Genes, Plant , Plant Breeding , Poaceae/genetics , Poaceae/metabolism , Oryza/genetics , Oryza/metabolism
3.
BMC Plant Biol ; 24(1): 319, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38654176

ABSTRACT

Stripe rust of wheat, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most important diseases of wheat worldwide. Identification of new and elite Pst-resistance loci or genes has the potential to enhance overall resistance to this pathogen. Here, we conducted an integrated genome-wide association study (GWAS) and transcriptomic analysis to screen for loci associated with resistance to stripe rust in 335 accessions from Yunnan, including 311 landraces and 24 cultivars. Based on the environmental phenotype, we identified 113 protein kinases significantly associated with Pst resistance using mixed linear model (MLM) and generalized linear model (GLM) models. Transcriptomic analysis revealed that 52 of 113 protein kinases identified by GWAS were up and down regulated in response to Pst infection. Among these genes, a total of 15 receptor kinase genes were identified associated with Pst resistance. 11 candidate genes were newly discovered in Yunnan wheat germplasm. Our results revealed that resistance alleles to stripe rust were accumulated in Yunnan wheat germplasm, implying direct or indirect selection for improving stripe rust resistance in elite wheat breeding programs.


Subject(s)
Disease Resistance , Genome-Wide Association Study , Plant Diseases , Puccinia , Triticum , Triticum/genetics , Triticum/microbiology , Plant Diseases/microbiology , Plant Diseases/genetics , Disease Resistance/genetics , China , Puccinia/physiology , Gene Expression Profiling , Basidiomycota/physiology , Genes, Plant , Protein Kinases/genetics , Transcriptome , Plant Proteins/genetics , Plant Proteins/metabolism
4.
Plant Biotechnol J ; 22(1): 98-115, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37688588

ABSTRACT

As a multifunctional hormone-like molecule, melatonin exhibits a pleiotropic role in plant salt stress tolerance. While actin cytoskeleton is essential to plant tolerance to salt stress, it is unclear if and how actin cytoskeleton participates in the melatonin-mediated alleviation of plant salt stress. Here, we report that melatonin alleviates salt stress damage in pigeon pea by activating a kinase-like protein, which interacts with an actin-depolymerizing factor. Cajanus cajan Actin-Depolymerizing Factor 9 (CcADF9) has the function of severing actin filaments and is highly expressed under salt stress. The CcADF9 overexpression lines (CcADF9-OE) showed a reduction of transgenic root length and an increased sensitivity to salt stress. By using CcADF9 as a bait to screen an Y2H library, we identified actin depolymerizing factor-related phosphokinase 1 (ARP1), a novel protein kinase that interacts with CcADF9. CcARP1, induced by melatonin, promotes salt resistance of pigeon pea through phosphorylating CcADF9, inhibiting its severing activity. The CcARP1 overexpression lines (CcARP1-OE) displayed an increased transgenic root length and resistance to salt stress, whereas CcARP1 RNA interference lines (CcARP1-RNAi) presented the opposite phenotype. Altogether, our findings reveal that melatonin-induced CcARP1 maintains F-actin dynamics balance by phosphorylating CcADF9, thereby promoting root growth and enhancing salt tolerance.


Subject(s)
Cajanus , Melatonin , Melatonin/pharmacology , Melatonin/metabolism , Actins/metabolism , Cajanus/genetics , Destrin/metabolism , Salt Tolerance/genetics , Phosphorylation , Actin Cytoskeleton/metabolism
5.
Plant Biotechnol J ; 22(1): 181-199, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37776153

ABSTRACT

Aluminium (Al) toxicity decreases crop production in acid soils in general, but many crops have evolved complex mechanisms to resist it. However, our current understanding of how plants cope with Al stress and perform Al resistance is still at the initial stage. In this study, the citrate transporter CcMATE35 was identified to be involved in Al stress response. The release of citrate was increased substantially in CcMATE35 over-expression (OE) lines under Al stress, indicating enhanced Al resistance. It was demonstrated that transcription factor CcNFYB3 regulated the expression of CcMATE35, promoting the release of citrate from roots to increase Al resistance in pigeon pea. We also found that a Long noncoding RNA Targeting Citrate Synthase (CcLTCS) is involved in Al resistance in pigeon pea. Compared with controls, overexpression of CcLTCS elevated the expression level of the Citrate Synthase gene (CcCS), leading to increases in root citrate level and citrate release, which forms another module to regulate Al resistance in pigeon pea. Simultaneous overexpression of CcNFYB3 and CcLTCS further increased Al resistance. Taken together, these findings suggest that the two modules, CcNFYB3-CcMATE35 and CcLTCS-CcCS, jointly regulate the efflux and synthesis of citrate and may play an important role in enhancing the resistance of pigeon pea under Al stress.


Subject(s)
Cajanus , RNA, Long Noncoding , Citric Acid/metabolism , Cajanus/genetics , Aluminum/toxicity , Aluminum/metabolism , Citrate (si)-Synthase , Citrates/metabolism
6.
Plant Biotechnol J ; 22(9): 2558-2574, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38685729

ABSTRACT

Spartina alterniflora is an exo-recretohalophyte Poaceae species that is able to grow well in seashore, but the genomic basis underlying its adaptation to salt tolerance remains unknown. Here, we report a high-quality, chromosome-level genome assembly of S. alterniflora constructed through PacBio HiFi sequencing, combined with high-throughput chromosome conformation capture (Hi-C) technology and Illumina-based transcriptomic analyses. The final 1.58 Gb genome assembly has a contig N50 size of 46.74 Mb. Phylogenetic analysis suggests that S. alterniflora diverged from Zoysia japonica approximately 21.72 million years ago (MYA). Moreover, whole-genome duplication (WGD) events in S. alterniflora appear to have expanded gene families and transcription factors relevant to salt tolerance and adaptation to saline environments. Comparative genomics analyses identified numerous species-specific genes, significantly expanded genes and positively selected genes that are enriched for 'ion transport' and 'response to salt stress'. RNA-seq analysis identified several ion transporter genes including the high-affinity K+ transporters (HKTs), SaHKT1;2, SaHKT1;3 and SaHKT1;8, and high copy number of Salt Overly Sensitive (SOS) up-regulated under high salt conditions, and the overexpression of SaHKT2;4 in Arabidopsis thaliana conferred salt tolerance to the plant, suggesting specialized roles for S. alterniflora to adapt to saline environments. Integrated metabolomics and transcriptomics analyses revealed that salt stress activate glutathione metabolism, with differential expressions of several genes such as γ-ECS, GSH-S, GPX, GST and PCS in the glutathione metabolism. This study suggests several adaptive mechanisms that could contribute our understanding of evolutional basis of the halophyte.


Subject(s)
Genome, Plant , Phylogeny , Poaceae , Salt Tolerance , Salt Tolerance/genetics , Genome, Plant/genetics , Poaceae/genetics , Poaceae/metabolism , Salt-Tolerant Plants/genetics , Salt-Tolerant Plants/metabolism , Gene Expression Regulation, Plant
7.
FASEB J ; 37(10): e23167, 2023 10.
Article in English | MEDLINE | ID: mdl-37651093

ABSTRACT

Auditory frequency coding is place-specific, which depends on the mechanical coupling of the basilar membrane-outer hair cell (OHC)-tectorial membrane network. Prestin-based OHC electromotility improves cochlear frequency selectivity and sensitivity. Cochlear amplification determines the frequency coding wherein discrete sound frequencies find a 'best' place along the cochlear length. Loss of OHC is the leading cause of age-related hearing loss (ARHL) and is the most common cause of sensorineural hearing loss and compromised speech perception. Lipid interaction with Prestin impacts OHC function. It has been established that high-fat diet (HFD) is associated with ARHL. To determine whether genetic background and metabolism preserve cochlear frequency place coding, we examined the effect of HFD in C57BL/6J (B6) and CBA/CaJ (CBA) on ARHL.We found a significant rescuing effect on ARHL in aged B6 HFD cohort. Prestin levels and cell sizes were better maintained in the experimental B6-HFD group. We also found that distortion product otoacoustic emission (DPOAE) group delay measurement was preserved, which suggested stable frequency place coding. In contrast, the response to HFD in the CBA cohort was modest with no appreciable benefit to hearing threshold. Notably, group delay was shortened with age along with the control. In addition, the frequency dependent OHC nonlinear capacitance gradient was most pronounced at young age but decreased with age. Cochlear RNA-seq analysis revealed differential TRPV1 expression and lipid homeostasis. Activation of TRPV1 and downregulation of arachidonic acid led to downregulation of inflammatory response in B6 HFD, which protects the cochlea from ARHL. The genetic background and metabolic state-derived changes in OHC morphology and function collectively contribute to a redefined cochlear frequency place coding and improved age-related pitch perception.


Subject(s)
Cochlea , Diet, High-Fat , Humans , Aged , Diet, High-Fat/adverse effects , Arachidonic Acid , Cell Size , Down-Regulation
8.
Physiol Plant ; 176(2): e14241, 2024.
Article in English | MEDLINE | ID: mdl-38454807

ABSTRACT

Vein severing in plants caused by leaf damage is common in fields where crops are cultivated. It is hypothesized that leaves with complex reticulate venation can withstand hydraulic disturbances caused by vein severing, thereby preserving leaf carbon assimilation. However, limited research focuses on vein damage of leaves with parallel venation. We studied how vein-severing affected the photosynthetic traits of rice (Oryza sativa) leaves in seconds, minutes and days, under varying water-demand conditions and differing extents of water supply disruption. Rice leaves completely lost their photosynthetic capacity within 2.5 minutes after excision. Severing the midrib resulted in reduced light-saturated photosynthetic rate (A), stomatal conductance (gsw ) and transpiration rate (E) by 2.6, 6.8 and 5.9%, respectively, already after thirty minutes. We further investigated the photosynthetic trait responses to various extents of leaf width severing, while keeping the midrib functional. Surprisingly, A, gsw and E in the downstream area of the severed leaves largely remained stable, showing minimal variation across different leaf width severing ratios. These traits declined only slightly even under increased ambient light intensity and leaf-to-air vapor pressure deficit. This sustained photosynthesis post-severing is attributed to the efficient lateral water transport. Long-term leaf damage slightly but not significantly, impacted the downstream photosynthetic traits within five days post-severing. However, a more pronounced reduction in gas exchange during leaf senescence was observed nine days after severing. These findings suggested that rice leaves can tolerate hydraulic disturbances from vein severing and maintain functionality under various conditions, which is crucial for crop yield stability. However, long-term consequences require further investigation.


Subject(s)
Oryza , Oryza/physiology , Plant Leaves/physiology , Water/physiology , Plants , Photosynthesis
9.
Physiol Plant ; 176(5): e14529, 2024.
Article in English | MEDLINE | ID: mdl-39319936

ABSTRACT

The olive tree is an important oil woody plant with high economic value, yet it is vulnerable to the attack of numerous fungi. The successful control of olive fungal diseases requires a comprehensive understanding of the disease resistance mechanisms in plants. Here, we isolated Alternaria alternata from the diseased leaves of olive plants, and screened a resistant ("Leccino") and susceptible ("Manzanilla de Sevilla") cultivar from eight olive cultivars to explore their resistance mechanisms. Transcriptomic and metabolomic analyses identified the flavonoid biosynthesis as a key defense pathway against A. alternata. Five important transcription factors associated with flavonoid biosynthesis were also determined. The overexpression of OeWRKY40 significantly enhanced the disease resistance of the susceptible cultivar and upregulated the expression of genes involved in flavonoid biosynthesis and the accumulation of related metabolites. LUC assays further proved that OeWRKY40 can activate the expression of OeC4H. These results help to better clarify the molecular mechanisms of flavonoid biosynthesis against A. alternata. Our study provides key information for further exploration of the molecular pathways of olive plants and their resistance to fungi, an important factor for molecular breeding and utilization of resistant cultivars.


Subject(s)
Alternaria , Disease Resistance , Flavonoids , Metabolome , Olea , Plant Diseases , Transcriptome , Alternaria/physiology , Alternaria/pathogenicity , Olea/microbiology , Olea/genetics , Olea/metabolism , Flavonoids/metabolism , Flavonoids/biosynthesis , Transcriptome/genetics , Metabolome/genetics , Plant Diseases/microbiology , Plant Diseases/genetics , Plant Diseases/immunology , Disease Resistance/genetics , Gene Expression Regulation, Plant , Plant Proteins/genetics , Plant Proteins/metabolism , Plant Leaves/microbiology , Plant Leaves/genetics , Plant Leaves/metabolism
10.
Bioorg Chem ; 152: 107742, 2024 Nov.
Article in English | MEDLINE | ID: mdl-39186916

ABSTRACT

Human serum albumin (HSA) serves as a crucial indicator for therapeutic monitoring and biomedical diagnosis. In this study, a near infrared (NIR) fluorescent probe, termed BTPA, characterized a donor-π-acceptor (D-π-A) structure based on bridged triphenylamine (TPA) was developed. BTPA exhibited outstanding sensitivity and selectivity towards HSA among various analysts, with a remarkable 50-fold fluorescence enhancement with a significant Stokes shift (∼190 nm) and a wide linear detection range of 0-20 µM of HSA. Especially, BTPA displayed selectivity for discrimination of HSA from BSA. Job's Plot analysis suggested a 1:1 stoichiometry for the formation of the BTPA-HSA complex. Displacement assays and molecular docking demonstrated that BTPA binds to subdomain IB of HSA which could effectively avoid interference from most drugs. Besides, BTPA have good biocompatibility and could detect of exogenous HSA with a relatively low fluorescence background. For practical applications, BTPA was tested for detecting HSA levels in human urine without any pretreatment, showing detection capability in the range of 0-10 µM with a fast response (<30 s), a limit of detection (LOD) of 0.12 µM and good recoveries (81.7-92.9 %), highlighting the high performance of bridged triphenylamine-based probe BTPA.


Subject(s)
Fluorescent Dyes , Serum Albumin, Human , Humans , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Serum Albumin, Human/urine , Molecular Structure , Molecular Docking Simulation , Aniline Compounds/chemistry , Aniline Compounds/chemical synthesis , Spectrometry, Fluorescence
11.
Nutr Metab Cardiovasc Dis ; 34(5): 1314-1324, 2024 May.
Article in English | MEDLINE | ID: mdl-38220507

ABSTRACT

BACKGROUND AND AIMS: To estimate the number of patients who required a referral to hepatologists following the 2016 EASL-EASD-EASO guideline and a second-line vibration controlled transient elastography (VCTE) examination following the 2021 EASL guideline according to obesity, glycated hemoglobin (HbA1c), blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) control status in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A total of 2515 T2DM patients who were hospitalized were cross-sectionally assessed. When we applied the 2016 EASL-EASD-EASO guideline, 26.8 %-46.4 % (depending on the scores used for diagnosing fibrosis) of T2DM patients needed a referral to hepatologists. When we applied the 2021 EASL guideline, a VCTE examination was required in 10.9 %-35 % (depending on the scores used for diagnosing fibrosis) of T2DM patients. The referral rates and the VCTE requirement were even higher in patients who were obese and/or had poor HbA1c, BP, and/or LDL-C control. CONCLUSIONS: Application of the screening guidelines would lead to a referral to hepatologists or a second-line VCTE examination requirement for a substantial number of T2DM patients, regardless of obesity and metabolic goal attainment status.


Subject(s)
Diabetes Mellitus, Type 2 , Gastroenterologists , Humans , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Glycated Hemoglobin , Cholesterol, LDL , Obesity , Fibrosis , Referral and Consultation
12.
J Ultrasound Med ; 43(9): 1611-1625, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38808580

ABSTRACT

OBJECTIVE: This study seeks to construct a machine learning model that merges clinical characteristics with ultrasound radiomic analysis-encompassing both the intratumoral and peritumoral-to predict the status of axillary lymph nodes in patients with early-stage breast cancer. METHODS: The study employed retrospective methods, collecting clinical information, ultrasound data, and postoperative pathological results from 321 breast cancer patients (including 224 in the training group and 97 in the validation group). Through correlation analysis, univariate analysis, and Lasso regression analysis, independent risk factors related to axillary lymph node metastasis in breast cancer were identified from conventional ultrasound and immunohistochemical indicators, and a clinical feature model was constructed. Additionally, features were extracted from ultrasound images of the intratumoral and its 1-5 mm peritumoral to establish a radiomics feature formula. Furthermore, by combining clinical features and ultrasound radiomics features, six machine learning models (Logistic Regression, Decision Tree, Support Vector Machine, Extreme Gradient Boosting, Random Forest, and K-Nearest Neighbors) were compared for diagnostic efficacy, and constructing a joint prediction model based on the optimal ML algorithm. The use of Shapley Additive Explanations (SHAP) enhanced the visualization and interpretability of the model during the diagnostic process. RESULTS: Among the 321 breast cancer patients, 121 had axillary lymph node metastasis, and 200 did not. The clinical feature model had an AUC of 0.779 and 0.777 in the training and validation groups, respectively. Radiomics model analysis showed that the model including the Intratumor +3 mm peritumor area had the best diagnostic performance, with AUCs of 0.847 and 0.844 in the training and validation groups, respectively. The joint prediction model based on the XGBoost algorithm reached AUCs of 0.917 and 0.905 in the training and validation groups, respectively. SHAP analysis indicated that the Rad Score had the highest weight in the prediction model, playing a significant role in predicting axillary lymph node metastasis in breast cancer. CONCLUSION: The predictive model, which integrates clinical features and radiomic characteristics using the XGBoost algorithm, demonstrates significant diagnostic value for axillary lymph node metastasis in breast cancer. This model can provide significant references for preoperative surgical strategy selection and prognosis evaluation for breast cancer patients, helping to reduce postoperative complications and improve long-term survival rates. Additionally, the utilization of SHAP enhancing the global and local interpretability of the model.


Subject(s)
Axilla , Breast Neoplasms , Lymph Nodes , Lymphatic Metastasis , Machine Learning , Humans , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Lymphatic Metastasis/diagnostic imaging , Female , Middle Aged , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Retrospective Studies , Adult , Predictive Value of Tests , Aged , Ultrasonography, Mammary/methods , Radiomics
13.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Article in English | MEDLINE | ID: mdl-34050020

ABSTRACT

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43, mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.


Subject(s)
Codon, Nonsense , Connexins/metabolism , Genes, Dominant , Hearing Loss, Central/genetics , Membrane Proteins/genetics , Animals , Cochlear Implantation , Female , Hearing Loss, Central/metabolism , Hearing Loss, Central/physiopathology , Hearing Loss, Central/surgery , Humans , Male , Mice , Mice, Inbred C57BL , Pedigree , Speech Perception
14.
Chem Biodivers ; : e202401801, 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-39211952

ABSTRACT

Three undescribed pregnane steroids, 12ß-O-4-hydroxybenzoyl tenacigenin D (1), 12ß-O-4-hydroxybenzoyl tenacigenin A (2), and 11α-nicotinoyl-17ß-marsdenin (3), along with two known analogues (4 and 5), were isolated from the roots of Marsdenia tenacissima. Their structures were elucidated using one- and two-dimensional NMR, high-resolution electron ionization-mass spectrometry, single-crystal X-ray diffraction data, and experimental and density-functional-theory-calculated electronic circular dichroism measurements. All isolated compounds were evaluated for their cytotoxic activities against human lung cancer cells (A549), ovarian carcinoma cells (SKOV-3), gastric cancer cells (MGC 803) and breast cancer cells (MCF-7). Notably, 3 exhibited significant cytotoxic activity against both A549 (median inhibitory concentration (IC50) = 16.79 µM) and SKOV-3 (IC50 = 12.30 µM) cells while exhibiting moderate cytotoxicity on MGC803 and MCF-7 cells.

15.
J Neuroinflammation ; 20(1): 161, 2023 Jul 08.
Article in English | MEDLINE | ID: mdl-37422673

ABSTRACT

Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.


Subject(s)
Epilepsy, Temporal Lobe , Serpins , Animals , Mice , Astrocytes/metabolism , Epilepsy, Temporal Lobe/chemically induced , Epilepsy, Temporal Lobe/metabolism , Hippocampus/metabolism , Kainic Acid/toxicity , Neuroinflammatory Diseases , NF-kappa B/metabolism , Ryanodine Receptor Calcium Release Channel/metabolism , Seizures/chemically induced , Seizures/metabolism , Signal Transduction , Serpins/metabolism
16.
Eur Radiol ; 33(12): 8869-8878, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37389609

ABSTRACT

OBJECTIVES: This study aims to develop a deep learning algorithm, Pneumonia-Plus, based on computed tomography (CT) images for accurate classification of bacterial, fungal, and viral pneumonia. METHODS: A total of 2763 participants with chest CT images and definite pathogen diagnosis were included to train and validate an algorithm. Pneumonia-Plus was prospectively tested on a nonoverlapping dataset of 173 patients. The algorithm's performance in classifying three types of pneumonia was compared to that of three radiologists using the McNemar test to verify its clinical usefulness. RESULTS: Among the 173 patients, area under the curve (AUC) values for viral, fungal, and bacterial pneumonia were 0.816, 0.715, and 0.934, respectively. Viral pneumonia was accurately classified with sensitivity, specificity, and accuracy of 0.847, 0.919, and 0.873. Three radiologists also showed good consistency with Pneumonia-Plus. The AUC values of bacterial, fungal, and viral pneumonia were 0.480, 0.541, and 0.580 (radiologist 1: 3-year experience); 0.637, 0.693, and 0.730 (radiologist 2: 7-year experience); and 0.734, 0.757, and 0.847 (radiologist 3: 12-year experience), respectively. The McNemar test results for sensitivity showed that the diagnostic performance of the algorithm was significantly better than that of radiologist 1 and radiologist 2 (p < 0.05) in differentiating bacterial and viral pneumonia. Radiologist 3 had a higher diagnostic accuracy than the algorithm. CONCLUSIONS: The Pneumonia-Plus algorithm is used to differentiate between bacterial, fungal, and viral pneumonia, which has reached the level of an attending radiologist and reduce the risk of misdiagnosis. The Pneumonia-Plus is important for appropriate treatment and avoiding the use of unnecessary antibiotics, and provide timely information to guide clinical decision-making and improve patient outcomes. CLINICAL RELEVANCE STATEMENT: Pneumonia-Plus algorithm could assist in the accurate classification of pneumonia based on CT images, which has great clinical value in avoiding the use of unnecessary antibiotics, and providing timely information to guide clinical decision-making and improve patient outcomes. KEY POINTS: • The Pneumonia-Plus algorithm trained from data collected from multiple centers can accurately identify bacterial, fungal, and viral pneumonia. • The Pneumonia-Plus algorithm was found to have better sensitivity in classifying viral and bacterial pneumonia in comparison to radiologist 1 (5-year experience) and radiologist 2 (7-year experience). • The Pneumonia-Plus algorithm is used to differentiate between bacterial, fungal, and viral pneumonia, which has reached the level of an attending radiologist.


Subject(s)
Deep Learning , Pneumonia, Bacterial , Pneumonia, Viral , Humans , Pneumonia, Viral/diagnostic imaging , Tomography, X-Ray Computed/methods , Anti-Bacterial Agents , Pneumonia, Bacterial/diagnostic imaging , Retrospective Studies
17.
Fish Shellfish Immunol ; 142: 109151, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37838210

ABSTRACT

The Macrobrachium rosenbergii industry is threatened by various Aeromonas, resulting in high mortality of adult prawns. However, there are few studies on the immune response of M. rosenbergii infected with Aeromonas dhakensis. In this study, we observed the hepatopancreas and gills histopathologically, performed a comparative transcriptome analysis of the hepatopancreas, and analyzed the candidate gene expression of immune-related genes in the hemolymph, hepatopancreas, and gills of M. rosenbergii that had been infected with A. dhakensis. Histopathology revealed the hepatopancreas was successively inflamed, followed by cellular vacuolation, lumen deformation, and finally tissue erosion; partial and severe inflammation of the gills occurred successively, and eventually the gill tissue atrophy and the gill filaments detached from the gill arch. Transcriptome analysis showed that a total of 77,742 unigenes and 8664 differentially expressed genes (DEGs), and the immune-related DEGs were mainly enriched in lysosome and phagosome pathways. In addition, 4 immune-related candidate genes (RhoA, CASP9, PKC, and DSCIGN) based on KEGG and PPI analysis were monitored at 6, 12, and 24h post injection (hpi) in hepatopancreas, hemolymph and gills. Their spatio-temporal expression results indicated that A. dhakensis have activated the immune system of M. rosenbergii. The present study may provide new information on the complex immune mechanism of M. rosenbergii.


Subject(s)
Aeromonas , Palaemonidae , Animals , Gene Expression Profiling , Transcriptome , Aeromonas/genetics , Immunity
18.
Environ Sci Technol ; 57(8): 3206-3217, 2023 02 28.
Article in English | MEDLINE | ID: mdl-36730723

ABSTRACT

Nanoplastics (NPs), as emerging contaminants, have attracted increasing attention for their effects on human exposure and potential health risks. The protein corona formed on the surface of NPs affects the biological activity and fate of the NPs in vivo. However, how environmental aging, an inevitable process once NPs enter the environment, affects the formation of protein corona on NPs is still unclear. This study investigated the changes in the compositions of protein corona formed on photo-aged polystyrene (PS) NPs in human bronchoalveolar lavage fluid (BALF), corresponding to the inhalation exposure pathway. The results demonstrated that both the species and abundance of proteins in the BALF protein corona on the surface of PS NPs were altered by aging. In addition, the aged PS NPs are more hydrophilic and less electronegative than the pristine PS NPs; hence, there is an increased sorption of more negatively charged hydrophilic proteins. Moreover, aging-induced alterations in BALF protein corona enhanced the uptake of aged PS NPs by lung macrophages J774A.1 through phagocytosis and clathrin-mediated endocytosis. These findings highlight the importance of environmental aging processes in the biosafety assessment of nanoplastics.


Subject(s)
Nanoparticles , Protein Corona , Humans , Aged , Protein Corona/metabolism , Microplastics , Macrophages/metabolism , Biological Transport , Polystyrenes
19.
Bioorg Chem ; 140: 106814, 2023 11.
Article in English | MEDLINE | ID: mdl-37657197

ABSTRACT

Phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer and has become a key target for cancer drug development. Based on a 4-methyl quinazoline scaffold, we designed and synthesized a novel series of bivalent PI3K inhibitors with different linker lengths and types. Bivalent PI3K inhibitor 27 demonstrates improved PI3K potency and antiproliferative cell activity, relative to the corresponding monovalent inhibitor 11. Compound 27 also significantly blocks the PI3K signal pathway, induces cell cycle arrest in G1 phase, and inhibits colony formation and cell migration. Furthermore, compound 27 shows dose-dependent anticancer efficacies in a HGC-27 xenograft mice model. Overall, this work provides a possible strategy to discover novel PI3K inhibitors for the treatment of cancers.


Subject(s)
Neoplasms , Phosphatidylinositol 3-Kinases , Humans , Animals , Mice , Neoplasms/drug therapy , Phosphatidylinositol 3-Kinase , Cell Movement , Disease Models, Animal , Phosphoinositide-3 Kinase Inhibitors/pharmacology
20.
Med Sci Monit ; 29: e939695, 2023 Oct 25.
Article in English | MEDLINE | ID: mdl-37876155

ABSTRACT

BACKGROUND Neurological bowel dysfunction (NBD) due to spinal cord injuries (SCIs) is common and significantly impacts patients' quality of life. This study evaluated the efficacy of quantitative assessment-based nursing interventions on bowel function recovery, quality of life, and caregivers' satisfaction with SCI patients with NBD. MATERIAL AND METHODS The study included 418 SCI patients with NBD. Patients were categorized into 3 cohorts: quantitative assessment-based nursing intervention (QN, n=114), conventional nursing intervention (CN, n=125), or no nursing intervention (DN, n=189). The 3 cohorts were followed over a 6-month period. RESULTS At 6 months post-intervention, patients in the QN and CN cohorts showed significant reductions in symptoms of fecal incontinence, constipation, and abdominal distension compared to the DN cohort. Additionally, defecation time decreased significantly in the QN and CN cohorts compared to both initial measures and the DN cohort. Notably, patients in the QN cohort demonstrated substantial improvement in overall quality of life scores compared to baseline, CN, and DN cohorts. The QN cohort also reported marked improvement in caregivers' satisfaction, surpassing that of caregivers in the CN and DN cohorts. CONCLUSIONS Six months of quantitative assessment-based nursing interventions significantly improved bowel function, quality of life, and caregiver satisfaction in SCI patients with NBD. This intervention appears beneficial for managing NBD in SCI patients and improving their quality of life and caregiver satisfaction.


Subject(s)
Intestinal Diseases , Quality of Life , Spinal Cord Injuries , Humans , East Asian People , Intestines/innervation , Intestines/physiopathology , Recovery of Function , Spinal Cord Injuries/complications , Intestinal Diseases/etiology , Intestinal Diseases/therapy
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