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1.
Chem Biol Interact ; 399: 111146, 2024 Jul 14.
Article in English | MEDLINE | ID: mdl-39002878

ABSTRACT

Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC50) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 µM and 117.40 µM, respectively. The IC50 value of asciminib against apixaban in RLM and HLM was 4.28 µM and 18.42 µM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs, where AUC(0-t), AUC(0-∞), t1/2, Tmax, and Cmax were increased, while CLz/F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban.

2.
J Clin Oncol ; : JCO2302261, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38950321

ABSTRACT

PURPOSE: To assess whether the integration of PD-1 inhibitor with total neoadjuvant therapy (iTNT) can lead to an improvement in complete responses (CRs) and favors a watch-and-wait (WW) strategy in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). PATIENTS AND METHODS: We conducted a prospective, multicenter, randomized, open-label, phase II trial using a pick-the-winner design. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly assigned to group A for short-course radiotherapy (SCRT) followed by six cycles of consolidation immunochemotherapy with capecitabine and oxaliplatin and toripalimab or to group B for two cycles of induction immunochemotherapy followed by SCRT and the rest four doses. Either total mesorectal excision or WW was applied on the basis of tumor response. The primary end point was CR which included pathological CR (pCR) after surgery and clinical CR (cCR) if WW was applicable, with hypothesis of an increased CR of 40% after iTNT compared with historical data of 25% after conventional TNT. RESULTS: Of the 130 patients enrolled, 121 pMMR/MSS patients were evaluable (62 in group A and 59 in group B). At a median follow-up of 19 months, CR was achieved at 56.5% in group A and 54.2% in group B. Both groups fulfilled the predefined statistical hypothesis (P < .001). Both groups reported a pCR rate of 50%. Respectively, 15 patients in each group underwent WW and remained disease free. The most frequent grade 3 to 4 toxicities were thrombocytopenia and neutropenia. Patients in group A had higher rate of cCR (43.5% v 35.6%) at restaging and lower rate of grade 3 to 4 thrombocytopenia (24.2% v 33.9%) during neoadjuvant treatment. CONCLUSION: The iTNT regimens remarkably improved CR rates in pMMR/MSS LARC compared with historical benchmark with acceptable toxicity. Up-front SCRT followed by immunochemotherapy was selected for future definitive study.

3.
Chem Res Toxicol ; 37(7): 1171-1186, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38870402

ABSTRACT

Exposure to anthropogenic aerosols has been associated with a variety of adverse health effects, increased morbidity, and premature death. Although cigarette smoke poses one of the most significant public health threats, the cellular toxicity of particulate matter contained in cigarette smoke has not been systematically interrogated in a size-segregated manner. In this study, we employed a refined particle size classification to collect cigarette aerosols, enabling a comprehensive assessment and comparison of the impacts exerted by cigarette aerosol extract (CAE) on SH-SY5Y, HEK293T, and A549 cells. Exposure to CAE reduced cell viability in a dose-dependent manner, with organic components having a greater impact and SH-SY5Y cells displaying lower tolerance compared to HEK293T and A549 cells. Moreover, CAE was found to cause increased oxidative stress, mitochondrial dysfunction, and increased levels of apoptosis, pyroptosis, and autophagy, leading to increased cell death. Furthermore, we found that rutin, a phytocompound with antioxidant potential, could reduce intracellular reactive oxygen species and protect against CAE-triggered cell death. These findings underscore the therapeutic potential of antioxidant drugs in mitigating the adverse effects of cigarette aerosol exposure for better public health outcomes.


Subject(s)
Aerosols , Cell Survival , Particle Size , Particulate Matter , Humans , Particulate Matter/toxicity , Cell Survival/drug effects , Reactive Oxygen Species/metabolism , Nicotiana/chemistry , Nicotiana/adverse effects , Oxidative Stress/drug effects , Tobacco Products/adverse effects , Air Pollution, Indoor/adverse effects , Apoptosis/drug effects
4.
Article in English | MEDLINE | ID: mdl-38607209

ABSTRACT

Background: Currently, there is a lot of discussion in clinical and scientific research over the best ways to delay meniscal degeneration and speed up its healing. Meniscal injury and degeneration are significant contributors to the development of knee osteoarthritis in a pathological state. Objective: To isolate, culture and characterize rat meniscal fibrochondrocytes in vitro, and to provide a simple and feasible cell culture method for the study of damage repair of rat meniscal fibrochondrocytes. Methods: The rat medial and lateral meniscus of both knees was surgically isolated. Trypsin and type II collagenase were used to remove the cells, and toluidine blue staining and type II collagen immunofluorescence were used to identify the cells. The cells were then routinely cultured in low-sugar DMEM complete culture medium. Results: At different time points, cells showed different physiological shapes, from polygonal or short spindle to spindle shape, and finally to triangle or ellipse, and cell proliferation ability gradually increased with time. The OD values of cells cultured at 48h and 72h were higher than those at 24h. Comparing OD values of cells cultured for 48h and 72h, although OD value of 72h increased. Toluidine blue staining and type I collagen immunofluorescence staining were positive. Conclusion: A more dependable technique for fibrochondrocyte isolation and culture is offered for the study of meniscus in molecular biology and tissue engineering. The cells cultured using this method are morphologically stable, have a strong proliferation ability, and possess the fundamental biological properties of fibrochondrocytes in vivo.

5.
Toxicol Appl Pharmacol ; 486: 116934, 2024 May.
Article in English | MEDLINE | ID: mdl-38663673

ABSTRACT

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.


Subject(s)
Adamantane , Dipeptides , Drug Interactions , Pyrimidines , Sildenafil Citrate , Sulfonamides , Sildenafil Citrate/pharmacokinetics , Sildenafil Citrate/pharmacology , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Dipeptides/pharmacokinetics , Dipeptides/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Humans , Adamantane/analogs & derivatives , Adamantane/pharmacokinetics , Adamantane/pharmacology , Male , Animals , Cytochrome P-450 CYP3A/metabolism , Molecular Docking Simulation , Microsomes, Liver/metabolism , Microsomes, Liver/drug effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dipeptidyl-Peptidase IV Inhibitors/pharmacology
6.
Nat Commun ; 15(1): 2525, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38514635

ABSTRACT

MicroRNAs (miRNAs) play fundamental roles in many developmental and physiological processes in eukaryotes. MiRNAs in plants generally regulate their targets via either mRNA cleavage or translation repression; however, which approach plays a major role and whether these two function modes can shift remains elusive. Here, we identify a miRNA, miR408-5p that regulates AUXIN/INDOLE ACETIC ACID 30 (IAA30), a critical repressor in the auxin pathway via switching action modes in rice. We find that miR408-5p usually inhibits IAA30 protein translation, but in a high auxin environment, it promotes the decay of IAA30 mRNA when it is overproduced. We further demonstrate that IDEAL PLANT ARCHITECTURE1 (IPA1), an SPL transcription factor regulated by miR156, mediates leaf inclination through association with miR408-5p precursor promoter. We finally show that the miR156-IPA1-miR408-5p-IAA30 module could be controlled by miR393, which silences auxin receptors. Together, our results define an alternative auxin transduction signaling pathway in rice that involves the switching of function modes by miR408-5p, which contributes to a better understanding of the action machinery as well as the cooperative network of miRNAs in plants.


Subject(s)
MicroRNAs , Oryza , Oryza/metabolism , Indoleacetic Acids/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Signal Transduction/genetics , RNA, Messenger/metabolism , Gene Expression Regulation, Plant
7.
ACS Chem Neurosci ; 15(7): 1484-1500, 2024 04 03.
Article in English | MEDLINE | ID: mdl-38483468

ABSTRACT

Although cigarette aerosol exposure is associated with various adverse health issues, its impact on Parkinson's disease (PD) remains elusive. Here, we investigated the effect of cigarette aerosol extract (CAE) on SH-SY5Y cells for the first time, both with and without α-synuclein (α-Syn) overexpression. We found that α-Syn aggravates CAE-induced cell death, oxidative stress, and mitochondrial dysfunction. Fluorescence cross-correlation spectroscopy (FCCS) revealed a dual distribution of α-Syn within the cells, with homogeneous regions indicative of monomeric α-Syn and punctated regions, suggesting the formation of oligomers. Moreover, we observed colocalization of α-Syn oligomers with lysosomes along with a reduction in autophagy activity. These findings suggest that α-Syn overexpression exacerbates CAE-induced intracellular cytotoxicity, mitochondrial dysfunction, and autophagy dysregulation, leading to elevated cell mortality. Our findings provide new insights into the pathogenic mechanisms linking exposure to cigarette aerosols with neurodegenerative diseases.


Subject(s)
Mitochondrial Diseases , Neuroblastoma , Parkinson Disease , Humans , alpha-Synuclein/metabolism , Cell Survival , Aerosols/pharmacology
8.
J Pharm Biomed Anal ; 243: 116079, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38471255

ABSTRACT

This aim of the work was to establish an acceptable sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentrations of iguratimod (IGR) and its metabolite M2 in rats, and to further investigate the effect of fluconazole on the pharmacokinetics of IGR and M2. The mobile phase consisted of acetonitrile and water with 0.1% formic acid, was used to separate IGR, M2 and internal standard (IS) fedratinib on a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm) with the flow rate of 0.4 mL/min. Positive ion mode and multiple reaction monitoring (MRM) were used to construct the quantitative analysis. The calibration standard of IGR and M2 covered 2-10000 and 1-1000 ng/mL respectively, with the lower limit of quantification (LLOQ) as 2 ng/mL and 1 ng/mL respectively. In addition, selectivity, recovery, accuracy, precision, matrix effect and stability of the method validation program were well accepted in this work. Subsequently, this approach was used to assess the effect of fluconazole on the pharmacokinetics of IGR and M2 in rats. In the presence of 20 mg/kg fluconazole (experimental group), we found the main pharmacokinetic parameters were significantly altered when compared with 2.5 mg/kg IGR alone (control group). Among them, AUC(0-∞) and Cmax of IGR in the experimental group was 1.43 and 1.08 times higher than that of the control group, respectively. Moreover, we also found that the other main pharmacokinetic parameters of M2 had no significant changes, except t1/2z and Tmax. In conclusion, fluconazole significantly altered the main pharmacokinetics of IGR and M2 in rats. It implys that we should pay more attention to the adverse reaction of IGR when the concomitant use of fluconazole and IGR occur in the future clinical practice.


Subject(s)
Chromones , Liquid Chromatography-Mass Spectrometry , Sulfonamides , Tandem Mass Spectrometry , Rats , Animals , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods , Fluconazole , Drug Interactions , Chromatography, High Pressure Liquid/methods , Reproducibility of Results
9.
J Opt Soc Am A Opt Image Sci Vis ; 40(12): 2146-2155, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-38086023

ABSTRACT

In this paper, an optical color single-channel asymmetric cryptosystem based on the non-negative matrix factorization (NMF) and a face biometric in cyan-magenta-yellow-black (CMYK) space is proposed. To the best of our knowledge, this is the first time that NMF has been introduced into optical color image encryption. In the proposed cryptosystem, the color image in CMYK space is first decomposed into four color channels: C, M, Y, and K. By performing NMF operations on the four color channels, the four basic and sparse matrices can be obtained, respectively, which achieves asymmetry and saves computational resources. The four basis matrices can be used as private keys, and the four coefficient matrices are synthesized by the inverse discrete wavelet transform for subsequent encryption. Finally, the synthesized image is encoded with double random phase encoding based on phase truncation (PT). Compared with the existing PT-based cryptosystems, our cryptosystem can improve security against a special attack. In addition, the chaotic random phase mask is generated by a face biometric, which is noncontact and unique. Numerical simulation results are shown to verify the feasibility and robustness of our cryptosystem. Further, the proposed cryptosystem can be extended to encrypt multiple images conveniently.

10.
BMJ Open ; 13(12): e075859, 2023 12 09.
Article in English | MEDLINE | ID: mdl-38070929

ABSTRACT

INTRODUCTION: Acute pancreatitis (AP) is characterised by inflammation of the exocrine pancreas, which potentially leads to local complications and organ failure resulting in significant morbidity and mortality. A long-term follow-up by an experienced team is needed. Currently, a variety of outcome measures are used in clinical trials for patients with AP. However, due to heterogeneous and selective outcome reporting across trials of interventions, it is hard to combine or compare the trial results compromising systematic evaluations of effectiveness and safety. A core outcome set is demanded to standardise reporting for the management of AP in clinical trials, so as to conduct systematic reviews and to improve the quality of the existing evidence base on the management of AP. We designed a study to establish a core outcome set (COS) on what indicators should be measured and reported in clinical trials of patients with AP (COS-AP). METHODS AND ANALYSIS: This study protocol outlines the following five phases: Phase I will be a systematic review of randomised control trials and semistructured interviews with patients to initially establish a preliminary list of potential outcomes. Phase II will be the recruitment of key stakeholders' groups comprising experts in pancreatic disease, clinical researchers, methodologists, journal editors and patients. Phase III will be two rounds of the Delphi surveys with key stakeholder groups. Phase IV will be a consensus on the outcomes that should be included in a final COS-AP. Phase V will be dissemination of COS-AP. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Biomedical Research Ethics Committee (BREC) of West China Hospital of Sichuan University (2020 No.691). The findings will be disseminated in peer-reviewed journals and meetings. TRIAL REGISTRATION: This study was registered with Core Outcome Measures in Effectiveness Trials (COMET) database as study 2573.


Subject(s)
Pancreatitis , Humans , Acute Disease , Pancreatitis/therapy , Research Design , Delphi Technique , Outcome Assessment, Health Care/methods , Treatment Outcome , Systematic Reviews as Topic
11.
Biomed Pharmacother ; 168: 115833, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37935069

ABSTRACT

The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti-tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague-Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID-14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC50 were 18.83 ± 1.06 µM and 16.15 ± 0.81 µM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC(0-t) and AUC(0-∞) of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CLz/F was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.


Subject(s)
Cytochrome P-450 CYP3A , Lurasidone Hydrochloride , Animals , Humans , Rats , Chromatography, Liquid , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Lurasidone Hydrochloride/pharmacokinetics , Microsomes, Liver , Polymorphism, Genetic , Rats, Sprague-Dawley , Tandem Mass Spectrometry
12.
J Int Med Res ; 51(11): 3000605231210657, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37994021

ABSTRACT

Empyema is a common complication of pneumonia, caused by the accumulation of purulent exudate due to pathogenic bacteria invading the pleural cavity. Parvimonas micra and Streptococcus constellatus are pathogens that rarely cause pneumonia with empyema. Herein, a case of severe empyema caused by these two pathogens, confirmed by metagenomic next-generation sequencing (mNGS) of pleural effusion cultures, is reported. A male Chinese patient in his late sixties presented with wheezing, cough, sputum expectoration, and fever. Blood and sputum cultures were negative for pathogens, but the pleural effusion culture was positive for S. constellatus, and was also found to contain P. micra, confirmed by mNGS. The patient's symptoms improved after treatment with cefoperazone/sulbactam and moxifloxacin. Pneumonia caused by P. micra and S. constellatus is rare; however, coinfection with these pathogens may cause severe pneumonia, with or without empyema.


Subject(s)
Coinfection , Empyema, Pleural , Pleural Effusion , Pneumonia , Streptococcus constellatus , Humans , Male , Streptococcus constellatus/genetics , Empyema, Pleural/complications , Empyema, Pleural/diagnosis , Empyema, Pleural/microbiology , Pneumonia/complications , Pneumonia/diagnosis
13.
BMC Nephrol ; 24(1): 350, 2023 11 29.
Article in English | MEDLINE | ID: mdl-38031052

ABSTRACT

BACKGROUND: Disability in activities of daily living (ADL) significantly increases the risk of mortality among patients undergoing hemodialysis. Malnutrition and decreased exercise capacity are closely correlated with ADL disability. Phase angle (PhA) has been proposed as a measure of nutritional status and exercise capacity. This study aims to investigate the prevalence of ADL disability in hemodialysis patients and its association with PhA. METHODS: A prospective, observational study was conducted, involving hemodialysis patients treated between November 2019 and January 2020 in an affiliated hospital of Chinese university. ADL was measured using both basic ADL (BADL) scales and instrumental ADL (IADL) scales. PhA measurements were obtained using a BIA device while the patients were in the supine position after dialysis. RESULTS: A total of 237 hemodialysis patients with a mean age of 60.01 ± 13.55 years were included in this study. The prevalence of disability in ADL was 43.5%. Multivariable analysis results showed a robust association between low PhA and disability in both BADL and IADL (for each unit decrease in PhA: odds ratio 4.83 [95% CI: 2.56-9.0], and 3.57 [95% CI: 2.14-5.95], respectively). The optimal cut-off values of PhA for disability in BADL and IADL were 4.8 and 5.4, with the area under the ROC curve (AUC) were 0.783 (0.727, 0.835) and 0.799 (0.743, 0.848), respectively. CONCLUSIONS: Low PhA is strongly associated with disability in ADL in hemodialysis patients. These findings suggest that PhA may serve as a potentially objective measure of ADL disability in hemodialysis patients.


Subject(s)
Activities of Daily Living , Disabled Persons , Renal Dialysis , Aged , Humans , Middle Aged , Prospective Studies
14.
Front Pharmacol ; 14: 1265252, 2023.
Article in English | MEDLINE | ID: mdl-38026954

ABSTRACT

Lacosamide, a third-generation novel antiepileptic drug, was first approved in 2008 as an adjunct to partial seizures. In 2014, the U.S. Food and Drug Administration (FDA) approved it as a single agent for partial seizures. Since epilepsy is a chronic condition, most patients need long-term antiepileptic medicinal products, so it is even more important to consider the drug-drug interactions (DDIs). For the purpose of this experiment, an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay with accuracy and simplicity was optimized and fully validated for the simultaneous quantitative determination of lacosamide and O-Desmethyl-lacosamide (ODL), and DDIs between lacosamide and nisoldipine in vivo and in vitro was researched. The protein was precipitated with acetonitrile, the analytes were eluted with acetonitrile and a 0.1% formic acid solution in a gradient program, and lacosamide, ODL, and lamotrigine (Internal Standard, IS) were successfully separated by chromatography. The findings of the biological analysis revealed that the lower limit of quantification (LLOQ) for lacosamide in samples was 2 ng/mL and the linearity ranged from 2 to 10000 ng/mL. The LLOQ for ODL was 1 ng/mL, while the linearity range for this substance was 1-1,000 ng/mL. In rat liver microsomes (RLM), the LLOQ of ODL was 80 ng/mL and the linear range was 80-40000 ng/mL. The selectivity, stability, matrix effect and recovery rate were all satisfied with the need of quantitative analysis of samples. Then, the UPLC-MS/MS assay was employed successfully on the interactions of lacosamide and nisoldipine in vivo and in vitro. The half-maximal inhibitory concentration (IC50) was 3.412 µM in RLM, where nisoldipine inhibited the metabolism of lacosamide with a mixture of inhibition mechanism. In rat pharmacokinetic experiments, it was found that nisoldipine could significantly change the pharmacokinetic characteristics of lacosamide, including AUC(0-t), AUC(0-∞), Tmax, CLz/F and Cmax, but had no significant effect on ODL. In summary, the UPLC-MS/MS method could accurately and sensitively quantify lacosamide and ODL, and could be used for the interaction between nisoldipine and lacosamide in vivo and in vitro.

15.
Plant Cell ; 35(10): 3697-3711, 2023 Sep 27.
Article in English | MEDLINE | ID: mdl-37378548

ABSTRACT

FLOWERING PROMOTING FACTOR1 (FPF1), a small protein without any known domains, promotes flowering in several plants; however, its functional mechanism remains unknown. Here, we characterized 2 FPF1-like proteins, FPL1 and FPL7, which, in contrast, function as flowering repressors in Brachypodium distachyon. FPL1 and FPL7 interact with the components of the florigen activation complex (FAC) and inhibit FAC activity to restrict expression of its critical target, VERNALIZATION1 (VRN1), in leaves, thereby preventing overaccumulation of FLOWERING LOCUS T1 (FT1) at the juvenile stage. Further, VRN1 can directly bind to the FPL1 promoter and repress FPL1 expression; hence, as VRN1 gradually accumulates during the late vegetative stage, FAC is released. This accurate feedback regulation of FPL1 by VRN1 allows proper FT1 expression in leaves and ensures sufficient FAC formation in shoot apical meristems to trigger timely flowering. Overall, we define a sophisticated modulatory loop for flowering initiation in a temperate grass, providing insights toward resolving the molecular basis underlying fine-tuning flowering time in plants.

16.
Plant Physiol ; 192(4): 2703-2722, 2023 08 03.
Article in English | MEDLINE | ID: mdl-37067917

ABSTRACT

Alternative splicing (AS) is a gene regulatory mechanism that generates multiple transcripts of the same gene precursor by the spliceosome complex, promoting messenger RNA complexity, and proteome diversity. Although AS is extensively studied in response to environmental stresses, whether it mediates age-dependent development and how it is adjusted by growth transitions are largely unknown. Here, we comprehensively explored the AS landscape at different developmental stages in the grass model plant Brachypodium (Brachypodium distachyon). We identified abundant coding genes and noncoding transcripts subject to dynamic AS regulation during juvenile, adult, and reproductive transitions. Moreover, we revealed that SC35-LIKE SPLICING FACTOR 33 (SCL33), a serine/arginine-rich splicing factor in spliceosomes, plays a redundant and antagonistic role with its putative paralog, SCL33L, in regulating intron assembly across distinct developmental stages. In addition, we determined global AS variations in microRNA156 (miR156)-overproducing plants, in which growth transitions are delayed, and found that SPLs were regulated by miR156 in intron retention alteration in addition to mRNA clearance and translation inhibition manners. Finally, we demonstrated a complex regulatory process of age-dependent AS events in B. distachyon that was coincidently or separately regulated by miR156 and SCL33/SCL33L. These results illustrate a substantial machinery of AS that mediates phase transitions in plants.


Subject(s)
Brachypodium , Brachypodium/genetics , Alternative Splicing/genetics , Introns , RNA Splicing Factors/genetics , Gene Expression Regulation, Plant
17.
Sci Total Environ ; 881: 163382, 2023 Jul 10.
Article in English | MEDLINE | ID: mdl-37054792

ABSTRACT

BACKGROUND: Copper (Cu) is a trace element that is engaged in various routine physiological processes. Excessive copper exposure can cause damage to organisms; however, it is unknown if the mechanisms underlying the response to Cu2+ among different species are conserved. METHODS: Aurelia coerulea polyps and mice models were exposed to Cu2+ to assess its effects on survival status and organ damage. Transcriptomic sequencing, BLAST, structural analysis, and real-time quantitative PCR were carried out to analyze the similarities and differences in the molecular composition and response mechanisms between two species when exposed to Cu2+. RESULTS: Excessive Cu2+ exposure led to toxic effects on both A. coerulea polyps and mice. The polyps were injured at a Cu2+ concentration of 3.0 mg L-1. In the mice, increasing Cu2+ concentrations were correlated with, the degree of liver damage, which manifested as hepatocyte apoptosis. In the 300 mg L-1 Cu2+ group of mice, livers cell death was primarily triggered by the phagosome and Toll-like signaling pathways. We found the glutathione metabolism was significantly altered in response to copper stress in both A. coerulea polyps and mice. Moreover, the similarity of gene sequences enriched at the two same sites in this pathway was as high as 41.05 %-49.82 % and 43.61 %-45.99 % respectively. Among them, there was a conservative region in the structure of A. coerulea polyps GSTK1 and mice Gsta2, but the overall difference is large. CONCLUSION: Glutathione metabolism is a conserved copper response mechanism in evolutionary distant organisms such as A. coerulea polyps and mice, although mammals have a more complex regulatory network when it comes to copper-induced cell death.


Subject(s)
Copper , Trace Elements , Animals , Mice , Copper/toxicity , Signal Transduction , Glutathione , Mammals
18.
Appl Opt ; 62(3): 665-674, 2023 Jan 20.
Article in English | MEDLINE | ID: mdl-36821270

ABSTRACT

In this paper, we propose an asymmetric optical double-image cryptosystem based on generalized singular value decomposition (GSVD) and five-dimensional (5D) hyperchaotic maps. In the proposed cryptosystem, the two plain images are first decomposed into five components by the GSVD operation. The two unitary matrices obtained by GSVD are encoded as a complex function, which is then modulated by the chaotic random phase masks (CRPMs). The private key and the final encryption result are generated by phase-truncation and amplitude-truncation operations. The GSVD operation can decompose two images at the same time and is used to generate the private key that enables the encryption process to be asymmetric. Compared with the existing phase-truncated-based cryptosystems, our cryptosystem can improve security against a special attack. In addition, the CRPMs are generated by 5D hyperchaotic maps, which have a larger parameter space and better randomness. Numerical simulation results are shown to verify the feasibility and robustness of our cryptosystem. Furthermore, the proposed cryptosystem can be extended to encrypt multiple images conveniently.

19.
Sci Total Environ ; 868: 161634, 2023 Apr 10.
Article in English | MEDLINE | ID: mdl-36669669

ABSTRACT

In the winter of 2018-2019, 75 air samples were collected through four ship-borne measurements in the Yellow Sea (YS) to assess the levels, confinement processes, and source distribution of volatile organic compounds (VOCs). A total of 41 were eventually detected, which mainly were non-methane hydrocarbons (NMHCs), volatile halogenated hydrocarbons (VHCs), oxygenated volatile organic compounds (OVOCs), and volatile organic sulfur compounds (VSCs). Aromatics (31.93 %) and alkenes (11.04 %) in the atmosphere of the YS accounted for a larger proportion of NMHCs compared with the coastal areas. C3-C5 alkanes, propylene, and chloroform exhibited strong latitudinal gradients and opposite latitudinal distributions in the North and South YS, highlighting the strong contribution of regional outflow to YS's atmosphere. The level of Σ41VOCs increased significantly during the heavy pollution period with some chemical monomers detected, which was further enhanced by the emissions from industrial parks near the Liaodong Peninsula and the Shandong Peninsula. Five main VOC sources were identified by the Positive matrix factorization (PMF) model, which were industrial emissions (13.33 %), fuel use and volatilization (6.67 %), Freon R-22 emissions (33.33 %), oil and gas production (20.00 %), and solvent volatilization (26.67 %). These observations revealed the strong causal relationship between coastal air mass transport and the atmosphere in the marginal sea and emphasized that full attention should be paid to the unintentional and unorganized emission of chemical monomers in the industrial process.

20.
Neuroscientist ; 29(2): 166-176, 2023 04.
Article in English | MEDLINE | ID: mdl-34612730

ABSTRACT

Enhancers are cis-acting elements that control the transcription of target genes and are transcribed into a class of noncoding RNAs (ncRNAs) termed enhancer RNAs (eRNAs). eRNAs have shorter half-lives than mRNAs and long noncoding RNAs; however, the frequency of transcription of eRNAs is close to that of mRNAs. eRNA expression is associated with a high level of histone mark H3K27ac and a low level of H3K27me3. Although eRNAs only account for a small proportion of ncRNAs, their functions are important. eRNAs can not only increase enhancer activity by promoting the formation of enhancer-promoter loops but also regulate transcriptional activation. Increasing numbers of studies have found that eRNAs play an important role in the occurrence and development of brain diseases; however, further research into eRNAs is required. This review discusses the concept, characteristics, classification, function, and potential roles of eRNAs in brain diseases.


Subject(s)
Brain Diseases , Transcription, Genetic , Humans , Enhancer Elements, Genetic/genetics , RNA , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Brain Diseases/genetics
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