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1.
EMBO J ; 41(6): e108544, 2022 03 15.
Article in English | MEDLINE | ID: mdl-34850409

ABSTRACT

Since numerous RNAs and RBPs prevalently localize to active chromatin regions, many RNA-binding proteins (RBPs) may be potential transcriptional regulators. RBPs are generally thought to regulate transcription via noncoding RNAs. Here, we describe a distinct, dual mechanism of transcriptional regulation by the previously uncharacterized tRNA-modifying enzyme, hTrmt13. On one hand, hTrmt13 acts in the cytoplasm to catalyze 2'-O-methylation of tRNAs, thus regulating translation in a manner depending on its tRNA-modification activity. On the other hand, nucleus-localized hTrmt13 directly binds DNA as a transcriptional co-activator of key epithelial-mesenchymal transition factors, thereby promoting cell migration independent of tRNA-modification activity. These dual functions of hTrmt13 are mutually exclusive, as it can bind either DNA or tRNA through its CHHC zinc finger domain. Finally, we find that hTrmt13 expression is tightly associated with poor prognosis and survival in diverse cancer patients. Our discovery of the noncatalytic roles of an RNA-modifying enzyme provides a new perspective for understanding epitranscriptomic regulation.


Subject(s)
RNA, Transfer , tRNA Methyltransferases , Humans , Methylation , RNA/metabolism , RNA Processing, Post-Transcriptional , RNA, Transfer/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , tRNA Methyltransferases/genetics , tRNA Methyltransferases/metabolism
2.
Plant J ; 2024 Sep 23.
Article in English | MEDLINE | ID: mdl-39312631

ABSTRACT

In plants, RNA silencing constitutes a strong defense against viral infection, which viruses counteract with RNA-silencing suppressors (RSSs). Understanding the interactions between viral RSSs and host factors is crucial for elucidating the molecular arms race between viruses and host plants. We report that the helicase motif (Hel) of the replicase encoded by apple stem grooving virus (ASGV)-the main virus affecting pear trees in China-is an RSS that can inhibit both local and systemic RNA silencing, possibly by binding double-stranded (ds) siRNA. The transcription factor related to ABSCISIC ACID INSENSITIVE3/VIVIPAROUS1 from pear (PbRAV1) enters the cytoplasm and binds Hel through its C terminus, thereby attenuating its RSS activity by reducing its binding affinity to 21- and 24-nt ds siRNA, and suppressing ASGV infection. PbRAV1 can also target p24, an RSS encoded by grapevine leafroll-associated virus 2 (GLRaV-2), with similar negative effects on p24's suppressive function and inhibition of GLRaV-2 infection. Moreover, like the positive role of the PbRAV1 homolog from grapevine (VvRAV1) in p24's previously reported RSS activity, ASGV Hel can also hijack VvRAV1 and employ the protein to sequester 21-nt ds siRNA, thereby enhancing its own RSS activity and promoting ASGV infection. Furthermore, PbRAV1 neither interacts with CP, an RSS encoded by grapevine inner necrosis virus, nor has any obvious effect on CP's RSS activity. Our results identify an RSS encoded by ASGV and demonstrate that PbRAV1, representing a novel type of RAV transcription factor, plays a defensive role against viral infection by targeting viral RSSs.

3.
Circulation ; 2024 Sep 25.
Article in English | MEDLINE | ID: mdl-39319450

ABSTRACT

BACKGROUND: Remote ischemic preconditioning (RIPC) has 2 time windows for organ protection: acute and delayed. Previous studies have mainly focused on the organoprotective effects of acute RIPC. We aimed to determine whether delayed RIPC can reduce the occurrence of acute kidney injury (AKI) and postoperative complications in patients undergoing cardiac surgery. METHODS: This prospective, single-center, double-blind, randomized controlled trial involved 509 patients at high risk for AKI who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass. Patients were randomized to receive RIPC (4 cycles of 5-minute inflation and 5-minute deflation on 1 upper arm with a blood pressure cuff) 24 hours before surgery or a sham condition (control group) that was induced by 4 cycles of 5-minute inflation to a pressure of 20 mm Hg followed by 5-minute cuff deflation. The primary end point was the incidence of AKI within the prior 7 days after cardiac surgery. The secondary end points included renal replacement therapy during hospitalization, change in urinary biomarkers of AKI and markers of myocardial injury, duration of intensive care unit stay and mechanical ventilation, and occurrence of nonfatal myocardial infarction, stroke, and all-cause mortality by day 90. RESULTS: A total of 509 patients (mean age, 65.2±8.2 years; 348 men [68.4%]) were randomly assigned to the RIPC group (n=254) or control group (n=255). AKI was significantly reduced in the RIPC group compared with the control group (69/254 [27.2%] versus 90/255 [35.3%]; odds ratio, 0.68 [95% CI, 0.47-1.00]; P=0.048). There were no significant between-group differences in the secondary end points of perioperative myocardial injury (assessed by the concentrations of cardiac troponin T, creatine kinase myocardial isoenzyme, and NT-proBNP [N-terminal pro-brain natriuretic peptide]), duration of stay in the intensive care unit and hospital, and occurrence of nonfatal myocardial infarction, stroke, and all-cause mortality by day 90. CONCLUSIONS: Among high-risk patients undergoing cardiac surgery, delayed RIPC significantly reduced the occurrence of AKI. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2000035568.

4.
Nano Lett ; 24(22): 6506-6512, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38789389

ABSTRACT

Early work demonstrated that some two-dimensional (2D) materials could kill bacteria by using their sharp edges to physically rupture the bacteria envelope, which presents distinct advantages over traditional antibiotics, as bacteria are not able to evolve resistance to the former. This mechano-bactericidal mode of action, however, suffers from low antibacterial efficiency, fundamentally because of random orientation of 2D materials outside the bacteria, where the desirable "edge-to-envelope" contacts occur with low probability. Here, we demonstrate a proof-of-concept approach to significantly enhance the potency of the mechano-bactericidal activity of 2D materials. This approach is in marked contrast with previous work, as the 2D materials are designed to be in situ generated inside the bacteria from a molecularly engineered monomer in a self-assembled manner, profoundly promoting the probability of the "edge-to-envelope" contacts. The rationale in this study sheds light on a mechanically new nanostructure-enabled antibacterial strategy to combat antibiotic resistance.


Subject(s)
Anti-Bacterial Agents , Nanostructures , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Nanostructures/chemistry , Escherichia coli/drug effects , Microbial Sensitivity Tests , Bacteria/drug effects
5.
J Biol Chem ; 299(5): 104704, 2023 05.
Article in English | MEDLINE | ID: mdl-37059185

ABSTRACT

Aminoacyl-tRNA synthetases (aaRSs) are essential components for mRNA translation. Two sets of aaRSs are required for cytoplasmic and mitochondrial translation in vertebrates. Interestingly, TARSL2 is a recently evolved duplicated gene of TARS1 (encoding cytoplasmic threonyl-tRNA synthetase) and represents the only duplicated aaRS gene in vertebrates. Although TARSL2 retains the canonical aminoacylation and editing activities in vitro, whether it is a true tRNA synthetase for mRNA translation in vivo is unclear. In this study, we showed that Tars1 is an essential gene since homozygous Tars1 KO mice were lethal. In contrast, when Tarsl2 was deleted in mice and zebrafish, neither the abundance nor the charging levels of tRNAThrs were changed, indicating that cells relied on Tars1 but not on Tarsl2 for mRNA translation. Furthermore, Tarsl2 deletion did not influence the integrity of the multiple tRNA synthetase complex, suggesting that Tarsl2 is a peripheral member of the multiple tRNA synthetase complex. Finally, we observed that Tarsl2-deleted mice exhibited severe developmental retardation, elevated metabolic capacity, and abnormal bone and muscle development after 3 weeks. Collectively, these data suggest that, despite its intrinsic activity, loss of Tarsl2 has little influence on protein synthesis but does affect mouse development.


Subject(s)
Amino Acyl-tRNA Synthetases , Protein Biosynthesis , Threonine-tRNA Ligase , Animals , Mice , Amino Acyl-tRNA Synthetases/metabolism , RNA, Transfer/metabolism , Threonine-tRNA Ligase/genetics , Threonine-tRNA Ligase/metabolism , Zebrafish/genetics , Zebrafish/metabolism
6.
Small ; : e2401369, 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39016116

ABSTRACT

Multidrug combination therapy in the inner ear faces diverse challenges due to the distinct physicochemical properties of drugs and the difficulties of overcoming the oto-biologic barrier. Although nanomedicine platforms offer potential solutions to multidrug delivery, the access of drugs to the inner ear remains limited. Micro/nanomachines, capable of delivering cargo actively, are promising tools for overcoming bio-barriers. Herein, a novel microrobot-based strategy to penetrate the round window membrane (RWM) is presented and multidrug in on-demand manner is delivered. The tube-type microrobot (TTMR) is constructed using the template-assisted layer-by-layer (LbL) assembly of chitosan/ferroferric oxide/silicon dioxide (CS/Fe3O4/SiO2) and loaded with anti-ototoxic drugs (curcumin, CUR and tanshinone IIA, TSA) and perfluorohexane (PFH). Fe3O4 provides magnetic actuation, while PFH ensures acoustic propulsion. Upon ultrasound stimulation, the vaporization of PFH enables a microshotgun-like behavior, propelling the drugs through barriers and driving them into the inner ear. Notably, the proportion of drugs entering the inner ear can be precisely controlled by varying the feeding ratios. Furthermore, in vivo studies demonstrate that the drug-loaded microrobot exhibits superior protective effects and excellent biosafety toward cisplatin (CDDP)-induced hearing loss. Overall, the microrobot-based strategy provides a promising direction for on-demand multidrug delivery for ear diseases.

7.
Small ; 20(13): e2307040, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37967337

ABSTRACT

The practical application of Li-S batteries is still severely restricted by poor cyclic performance caused by the intrinsic polysulfides shuttle effect, which is even more severe under the high-temperature condition owing to the inevitable increase of polysulfides' solubility and diffusion rate. Herein, tungsten-doped vanadium dioxide (W-VO2) micro-flowers are employed with first-order metal-insulator phase transition (MIT) property as a robust and multifunctional modification layer to hamper the shuttle effect and simultaneously improve the thermotolerance of the common separator. Tungsten doping significantly reduces the transition temperature from 68 to 35 °C of vanadium dioxide, which renders the W-VO2 easier to turn from the insulating monoclinic phase into the metallic rutile phase. The systematic experiments and theoretical analysis demonstrate that the temperature-induced in-suit MIT property endows the W-VO2 catalyst with strong chemisorption against polysulfides, low energy barrier for liquid-to-solid conversion, and outstanding diffusion kinetics of Li-ion under high temperatures. Benefiting from these advantages, the Li-S batteries with W-VO2 modified separator exhibit significantly improved rate and long-term cyclic performance under 50 °C. Remarkably, even at an elevated temperature (80 °C), they still exhibit superior electrochemical performance. This work opens a rewarding avenue to use phase-changing materials for high-temperature Li-S batteries.

8.
J Exp Bot ; 75(1): 300-315, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37738614

ABSTRACT

Aliphatic glucosinolates are a large group of plant secondary metabolites characteristic of Brassicaceae, including the model plant Arabidopsis. The diverse and complex degradation products of aliphatic glucosinolates contribute to plant responses to herbivory, pathogen attack, and environmental stresses. Most of the biosynthesis genes in the aliphatic glucosinolate pathway have been cloned in Arabidopsis, and the research focus has recently shifted to the regulatory mechanisms controlling aliphatic glucosinolate accumulation. Up till now, more than 40 transcriptional regulators have been identified as regulating the aliphatic glucosinolate pathway, but many more novel regulators likely remain to be discovered based on research evidence over the past decade. In the current study, we took a systemic approach to functionally test 155 candidate transcription factors in Arabidopsis identified by yeast one-hybrid assay, and successfully validated at least 30 novel regulators that could significantly influence the accumulation of aliphatic glucosinolates in our experimental set-up. We also showed that the regulators of the aliphatic glucosinolate pathway have balanced positive and negative effects, and glucosinolate metabolism and plant development can be coordinated. Our work is the largest scale effort so far to validate transcriptional regulators of a plant secondary metabolism pathway, and provides new insights into how the highly diverse plant secondary metabolism is regulated at the transcriptional level.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/genetics , Arabidopsis/metabolism , Glucosinolates , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Gene Expression Regulation, Plant
9.
Pharmacol Res ; 207: 107314, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39059614

ABSTRACT

The efficacy of PD-1 therapy in non-small cell lung cancer (NSCLC) patients remains unsatisfactory. Activating the STING pathway is a promising strategy to improve PD-1 inhibitor efficacy. Here, we found tetrandrine (TET), an anti-tumor compound extracted from a medicinal plant commonly used in traditional Chinese medicine, has the ability to inhibit NSCLC tumor growth. Mechanistically, TET induces nuclear DNA damage and increases cytosolic dsDNA, thereby activating the STING/TBK1/IRF3 pathway, which in turn promotes the tumor infiltration of dendritic cells (DCs), macrophages, as well as CD8+ T cells in mice. In vivo imaging dynamically monitored the increased activity of the STING pathway after TET treatment and predicted the activation of the tumor immune microenvironment. We further revealed that the combination of TET with αPD-1 monoclonal antibody (αPD-1 mAb) yields significant anti-cancer effects by promoting CD8+ T cell infiltration and enhancing its cell-killing effect, which in turn reduced the growth of tumors and prolonged survival of NSCLC mice. Therefore, TET effectively eliminates NSCLC cells and enhances immunotherapy efficacy through the activation of the STING pathway, and combining TET with anti-PD-1 immunotherapy deserves further exploration for applications.


Subject(s)
Benzylisoquinolines , Carcinoma, Non-Small-Cell Lung , Immune Checkpoint Inhibitors , Interferon Regulatory Factor-3 , Lung Neoplasms , Membrane Proteins , Programmed Cell Death 1 Receptor , Protein Serine-Threonine Kinases , Signal Transduction , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Humans , Membrane Proteins/metabolism , Interferon Regulatory Factor-3/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/drug effects , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Cell Line, Tumor , Immunotherapy/methods , Female , Mice, Inbred C57BL , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Tumor Microenvironment/drug effects , Mice, Inbred BALB C , Drug Synergism
10.
BMC Pediatr ; 24(1): 130, 2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38374004

ABSTRACT

OBJECTIVE: This study aims to translate the Pectus Excavatum Evaluation Questionnaire(PEEQ) into Chinese, and to comprehensively assess subjective outcomes in quality of life of children with pectus excavatum. METHODS: The PEEQ was translated from English to Chinese as according to the PRO translation guidelines. Structural validity and reliability of the questionnaire were examined by validated factor analysis and Cronbach's alpha coefficient analysis respectively. RESULTS: The results of the validation factor analysis for the Chinese PEEQ parent's and child's questionnaires demonstrated that the fit indicators for each dimension met the required criteria. The overall Cronbach's alpha coefficient of parent's and child's questionnaires were 0.840 and 0.854. Both the item-level content validity index (I-CVI) and scale-level content validity index (S-CVI) of each sub-questionnaire were 1. CONCLUSION: The Chinese version of the PEEQ parent's questionnaire is suitable as a proxy assessment for patients with PE, but the child's questionnaire needs further adjustments.


Subject(s)
Funnel Chest , Quality of Life , Child , Humans , Asian People , China , Psychometrics/methods , Reproducibility of Results , Surveys and Questionnaires
11.
J Craniofac Surg ; 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38299810

ABSTRACT

BACKGROUND: The repair of nasal alar defects is challenging for plastic surgeons, and there is currently no standard operation. Herein, the authors reported the clinical outcomes of a nasofacial groove pedicled flap for the reconstruction of alar defect. METHODS: This retrospective study included patients who underwent the nasofacial groove pedicled flap for the reconstruction of alar defect between January 2018 and June 2020. Photographs of standard facial postures were taken before and after surgery to record the surgical results of the patients. The patient's medical history was reviewed retrospectively. Self-reported satisfaction of patients on scar morphology and reconstructive effect were evaluated with a questionnaire survey. RESULTS: There were 26 eligible patients enrolled, and all patients were followed up for more than 1 year after surgery. All flaps were free of ischemia and necrosis and healed well. No patient experienced restricted nostril ventilation. Eight patients underwent reoperation to trim the flap pedicle and the scar. Eight patients (8/26) reported "very satisfied," and 17 patients (17/26) reported "satisfied" with the repair effect and scar morphology. One patient went through multiple laser treatments to improve her scars but still remained visible hyperpigmentation. She was dissatisfied with postoperative flap pigmentation but was satisfied with the correction effect. CONCLUSIONS: The clinical results indicated that the nasal groove flap was safe for the treatment of the lateral alar defect, and the patients were satisfied with the clinical results. The authors believe that this flap can be used as an alternative method for repairing the lateral alar defect. LEVEL OF EVIDENCE: Level -IV, therapeutic study.

12.
Alzheimers Dement ; 2024 Sep 25.
Article in English | MEDLINE | ID: mdl-39320044

ABSTRACT

INTRODUCTION: Electro-acupuncture (EA) has demonstrated potential in improving mild-to-moderate dementia in clinics, but the underlying scientific target remains unclear. METHODS: EA was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water maze cognitive functional tests. Brain magnetic resonance imaging-positron emission tomography (PET) scans using [18F]TZ4877 targeting sphingosine-1-phosphate receptor 1 (S1PR1) and [18F]AV45 targeting amyloid beta fibrils were conducted. The correlation between regional brain PET quantifications and cognitive functions was analyzed. RESULTS: EA significantly improved cognitive and memory functions of AD (p  = 0.04) and reduced the uptake of [18F]TZ4877 in the cortex (p  = 0.02) and hippocampus (p  = 0.03). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1. Furthermore, immunohistochemistry showed a significant reduction of interleukin 1ß and tumor necrosis factor α after EA treatment. DISCUSSION: EA may reverse AD by suppressing neuroinflammation, and the PET imaging of S1PR1 seemed potent in evaluating the treatment for AD patients HIGHLIGHTS: Electro-acupuncture (EA) was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water maze cognitive functional tests and positron emission tomography (PET) imaging quantifications. PET tracer [18F]AV45 was used to detect amyloid beta deposition. An increased uptake of [18F]AV45 was found in AD compared to WT mice, with significance observed only in the cortex and not in the hippocampus. EA treatment exhibited a trend toward reduced [18F]AV45 uptake in AD mouse brains post-treatment. However, statistical difference was not attained in most brain regions. EA "Baihui (DU20) and Sishencong (EX-HN1)" significantly improved cognitive and memory functions of AD (p = 0.04). Brain magnetic resonance imaging p(MRI)-positron emission tomography (PET) quantifications revealed that significantly reduced the uptake of [18F]TZ4877 in the cortex (p = 0.02) and hippocampus (p = 0.03) after EA treatment. The correlation between PET quantifications and cognitive functions was analyzed and the most notable correlations were found between escape latency (reaction cognitive and memory behavior) and volume distribution (VT) quantifications of [18F]TZ4877. VT quantifications of [18F]TZ4877 in key brain regions for cognitive and memory ability, such as the cortex and hippocampus, positively correlated with platform latency (cortex p < 0.01, r = 0.7102; hippocampus p < 0.01, r = 0.6891). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1 in the AD brain. And the EA treatment significantly reduced the signals in the cortex and hippocampus. Immunohistochemistry showed a significant reduction of interleukin 1ß and tumor necrosis factor α after EA treatment. EA reversed AD by suppressing neuroinflammation in the cortex and hippocampus. The S1PR1 targeting PET tracer [18F]TZ4877 showed promise in evaluating the pathological progression of AD in clinical settings.

13.
Int J Mol Sci ; 25(11)2024 May 30.
Article in English | MEDLINE | ID: mdl-38892217

ABSTRACT

Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1 substrate) plays a critical role in the microglial inflammatory response. To confirm this hypothesis, we used lipopolysaccharide (LPS)-and interferon-gamma (IFN-γ)-induced human microglia HMC3 cells as a representative indicator of the microglial in vitro inflammatory response. We found that C15orf39 was down-regulated when interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) expression increased in LPS/IFN-γ-stimulated HMC3 cells. Once C15orf39 was overexpressed, IL-6 and TNFα expression were reduced in LPS/IFN-γ-stimulated HMC3 cells. In contrast, C15orf39 knockdown promoted IL-6 and TNFα expression in LPS/IFN-γ-stimulated HMC3 cells. These results suggest that C15orf39 is a suppressive factor in the microglial inflammatory response. Mechanistically, C15orf39 interacts with the cytoplasmic protein arginine methyltransferase 2 (PRMT2). Thus, we termed C15orf39 a PRMT2 interaction protein (PRMT2 IP). Furthermore, the interaction of C15orf39 and PRMT2 suppressed the activation of NF-κB signaling via the PRMT2-IκBα signaling axis, which then led to a reduction in transcription of the inflammatory factors IL6 and TNF-α. Under inflammatory conditions, NF-κBp65 was found to be activated and to suppress C15orf39 promoter activation, after which it canceled the suppressive effect of the C15orf39-PRMT2-IκBα signaling axis on IL-6 and TNFα transcriptional expression. In conclusion, our findings demonstrate that in a steady condition, the interaction of C15orf39 and PRMT2 stabilizes IκBα to inhibit IL-6 and TNFα expression by suppressing NF-κB signaling, which reversely suppresses C15orf39 transcription to enhance IL-6 and TNFα expression in the microglial inflammatory condition. Our study provides a clue as to the role of C15orf39 in microglia-mediated inflammation, suggesting the potential therapeutic efficacy of C15orf39 in some central nervous system diseases.


Subject(s)
Inflammation , Interleukin-6 , Lipopolysaccharides , Microglia , Protein-Arginine N-Methyltransferases , Tumor Necrosis Factor-alpha , Humans , Cell Line , Inflammation/metabolism , Inflammation/genetics , Inflammation/pathology , Interferon-gamma/metabolism , Interferon-gamma/pharmacology , Interleukin-6/metabolism , Interleukin-6/genetics , Lipopolysaccharides/pharmacology , Microglia/metabolism , Microglia/drug effects , NF-kappa B/metabolism , Open Reading Frames , Protein-Arginine N-Methyltransferases/metabolism , Protein-Arginine N-Methyltransferases/genetics , Signal Transduction , Tumor Necrosis Factor-alpha/metabolism , Chromosomes, Human, Pair 15
14.
Int J Mol Sci ; 25(13)2024 Jul 01.
Article in English | MEDLINE | ID: mdl-39000360

ABSTRACT

Mitochondrial dysfunction has been increasingly recognized as a trigger for systemic lupus erythematosus (SLE). Recent bioinformatics studies have suggested Fam210b as a significant candidate for the classification and therapeutic targeting of SLE. To experimentally prove the role of Fam210b in SLE, we constructed Fam210b knockout (Fam210b-/-) mice using the CRISPR-Cas9 method. We found that approximately 15.68% of Fam210b-/- mice spontaneously developed lupus-like autoimmunity, which was characterized by skin ulcerations, splenomegaly, and an increase in anti-double-stranded DNA (anti-dsDNA) IgG antibodies and anti-nuclear antibodies(ANA). Single-cell sequencing showed that Fam210b was mainly expressed in erythroid cells. Critically, the knockout of Fam210b resulted in abnormal erythrocyte differentiation and development in the spleens of mice. Concurrently, the spleens exhibited an increased number of CD71+ erythroid cells, along with elevated levels of reactive oxygen species (ROS) in the erythrocytes. The co-culture of CD71+ erythroid cells and lymphocytes resulted in lymphocyte activation and promoted dsDNA and IgG production. In summary, Fam210b knockout leads to a low probability of lupus-like symptoms in mice through the overproduction of ROS in CD71+ erythroid cells. Thus, Fam210b reduction may serve as a novel key marker that triggers the development of SLE.


Subject(s)
Lupus Erythematosus, Systemic , Mice, Knockout , Animals , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Mice , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Reactive Oxygen Species/metabolism , Antibodies, Antinuclear , Mitochondrial Membranes/metabolism , Erythroid Cells/metabolism , Erythroid Cells/pathology , Disease Models, Animal , Immunoglobulin G/metabolism , Mice, Inbred C57BL , Spleen/metabolism , Spleen/pathology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Female
15.
Int J Mol Sci ; 25(10)2024 May 13.
Article in English | MEDLINE | ID: mdl-38791354

ABSTRACT

Aliphatic glucosinolates are an abundant group of plant secondary metabolites in Brassica vegetables, with some of their degradation products demonstrating significant anti-cancer effects. The transcription factors MYB28 and MYB29 play key roles in the transcriptional regulation of aliphatic glucosinolates biosynthesis, but little is known about whether BoMYB28 and BoMYB29 are also modulated by upstream regulators or how, nor their gene regulatory networks. In this study, we first explored the hierarchical transcriptional regulatory networks of MYB28 and MYB29 in a model plant, then systemically screened the regulators of the three BoMYB28 homologs in cabbage using a yeast one-hybrid. Furthermore, we selected a novel RNA binding protein, BoRHON1, to functionally validate its roles in modulating aliphatic glucosinolates biosynthesis. Importantly, BoRHON1 induced the accumulation of all detectable aliphatic and indolic glucosinolates, and the net photosynthetic rates of BoRHON1 overexpression lines were significantly increased. Interestingly, the growth and biomass of these overexpression lines of BoRHON1 remained the same as those of the control plants. BoRHON1 was shown to be a novel, potent, positive regulator of glucosinolates biosynthesis, as well as a novel regulator of normal plant growth and development, while significantly increasing plants' defense costs.


Subject(s)
Brassica , Gene Expression Regulation, Plant , Glucosinolates , Plant Proteins , RNA-Binding Proteins , Transcription Factors , Glucosinolates/metabolism , Brassica/metabolism , Brassica/genetics , Brassica/growth & development , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Plant Proteins/metabolism , Plant Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Gene Regulatory Networks , Plants, Genetically Modified
16.
Int Ophthalmol ; 44(1): 153, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38509410

ABSTRACT

PURPOSE: This study aimed to measure the Raman spectrum of the human corneal stroma lens obtained from small incision lenticule extraction surgery (SMILE) in Asian myopic eyes using a confocal Raman micro-spectrometer built in the laboratory. METHODS: Forty-three myopic patients who underwent SMILE with equivalent diopters between - 4.00 and - 6.00 D were selected, and the right eye data were collected. Corneal stroma lenses were obtained during surgery, and the Raman spectra were measured after air drying. The complete Raman spectrum of human myopic corneal stroma lens tissue was obtained within the range of 700-4000 cm-1. RESULTS: Thirteen characteristic peaks were found, with the stronger peaks appearing at 937 cm-1, corresponding to proline, valine, and the protein skeleton of the human myopic corneal stroma lens; 1243 cm-1, corresponding to collagen protein; 1448 cm-1, corresponding to the collagen protein and phospholipids; and 2940 cm-1, corresponding to the amino acid and lipids, which was the strongest Raman peak. CONCLUSION: These results demonstrated that Raman spectroscopy has much potential as a fast, cost-effective, and reliable diagnostic tool in the diagnosis and treatment of eye diseases, including myopia, keratoconus, and corneal infection.


Subject(s)
Corneal Surgery, Laser , Keratomileusis, Laser In Situ , Myopia , Humans , Corneal Stroma/surgery , Visual Acuity , Myopia/diagnosis , Myopia/surgery , Keratomileusis, Laser In Situ/methods , Collagen , Lasers, Excimer , Refraction, Ocular
17.
J Am Chem Soc ; 145(35): 19333-19337, 2023 Sep 06.
Article in English | MEDLINE | ID: mdl-37638550

ABSTRACT

The conventional approach toward molecules with large two-photon absorption (TPA) involves donor-acceptor conjugation. Herein we show a new strategy involving the use of hexa-branched nanographenes. We synthesized two hexa-branched nanographenes, one with six benzoaceanthrylene arms fused to the coronene core and the other with six pyrenyl arms fused to the coronene core. Neither of these hexa-branched nanographenes has a donor-acceptor structure, yet they exhibited high TPA values of 3.6 × 103 and 1.9 × 104 GM, respectively, which are the highest values recorded for heteroatom-free hydrocarbon molecules. Theoretical analysis suggests that the fused branched structures are responsible for the large TPA cross-section. These findings illustrate the importance of the topology of the fused conjugated skeleton in TPA and provide an alternative structural design toward large TPA.

18.
J Am Chem Soc ; 145(6): 3289-3293, 2023 Feb 15.
Article in English | MEDLINE | ID: mdl-36745399

ABSTRACT

Pentagonal cyclization at the bay positions of armchair-edged graphenic cores can build molecular bowls without the destruction of hexagonal lattices. However, this synthesis remains challenging due to unfavorable strain and the multiple reactions required. Here, we show that a new type of graphenic molecular bowl with a depth of 1.7 Å and a diameter of 1.2 nm is constructed by sextuple Se annulation at the bay positions of armchair-edged hexa-peri-hexabenzocoronene. This graphenic bowl is functionalized with phenylseleno groups that stack into a discrete bilayer dimer in solution. Such a dimer exhibits high stability and survives in the gas phase after laser ablation. Strikingly, the asymmetric one-dimensional supramolecular columns of graphenic bowl with coherent stacking configuration are observed in the solid state, which results in a strong second harmonic generation with prominent polarization dependence. Our findings present a concise synthesis of a giant molecular bowl with a graphenic core and demonstrate the unique supramolecular assembly of extended graphenic bowls.

19.
Mol Cancer ; 22(1): 131, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37563723

ABSTRACT

BACKGROUND: Chimeric antigen receptor (CAR) -T cell therapy is an efficient therapeutic strategy for specific hematologic malignancies. However, positive outcomes of this novel therapy in treating solid tumors are curtailed by the immunosuppressive tumor microenvironment (TME), wherein signaling of the checkpoint programmed death-1 (PD-1)/PD-L1 directly inhibits T-cell responses. Although checkpoint-targeted immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy. METHODS: We constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with an autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs. RESULTS: We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. PD-1-TREM2 scFv-secreting CAR-T cells resulted in highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Moreover, the PD-1-TREM2 scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life. CONCLUSIONS: Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.


Subject(s)
Colorectal Neoplasms , Immunotherapy, Adoptive , Single-Chain Antibodies , Animals , Mice , B7-H1 Antigen/metabolism , Cell Line, Tumor , Colorectal Neoplasms/therapy , Colorectal Neoplasms/metabolism , Single-Chain Antibodies/genetics , Single-Chain Antibodies/metabolism , T-Lymphocytes , Tumor Microenvironment
20.
Lancet ; 400(10357): 1020-1032, 2022 09 24.
Article in English | MEDLINE | ID: mdl-36154677

ABSTRACT

BACKGROUND: Despite the substantial burden caused by childhood cancer globally, childhood cancer incidence obtained in a nationwide childhood cancer registry and the accessibility of relevant health services are still unknown in China. We comprehensively assessed the most up-to-date cancer incidence in Chinese children and adolescents, nationally, regionally, and in specific population subgroups, and also examined the association between cancer incidence and socioeconomic inequality in access to health services. METHODS: In this national cross-sectional study, we used data from the National Center for Pediatric Cancer Surveillance, the nationwide Hospital Quality Monitoring System, and public databases to cover 31 provinces, autonomous regions, and municipalities in mainland China. We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China through stratified proportional estimation. We classified regions by socioeconomic status using the human development index (HDI). Incidence rates of 12 main groups, 47 subgroups, and 81 subtypes of cancer were reported and compared by sex, age, and socioeconomic status, according to the third edition of the International Classification of Childhood Cancer. We also quantified the geographical and population density of paediatric oncologists, pathology workforce, diagnoses and treatment institutions of paediatric cancer, and paediatric beds. We used the Gini coefficient to assess equality in access to these four health service indicators. We also calculated the proportions of cross-regional patients among new cases in our surveillance system. FINDINGS: We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China from Jan 1, 2018, to Dec 31, 2020. An estimated 121 145 cancer cases were diagnosed among children and adolescents in China between 2018 and 2020, with world standard age-standardised incidence rates of 122·86 (95% CI 121·70-124·02) per million for children and 137·64 (136·08-139·20) per million for adolescents. Boys had a higher incidence rate of childhood cancer (133·18 for boys vs 111·21 for girls per million) but a lower incidence of adolescent cancer (133·92 for boys vs 141·79 for girls per million) than girls. Leukaemias (42·33 per million) were the most common cancer group in children, whereas malignant epithelial tumours and melanomas (30·39 per million) surpassed leukaemias (30·08 per million) in adolescents as the cancer with the highest incidence. The overall incidence rates ranged from 101·60 (100·67-102·51) per million in very low HDI regions to 138·21 (137·14-139·29) per million in high HDI regions, indicating a significant positive association between the incidence of childhood and adolescent cancer and regional socioeconomic status (p<0·0001). The incidence in girls showed larger variation (48·45% from the lowest to the highest) than boys (36·71% from lowest to highest) in different socioeconomic regions. The population and geographical densities of most health services also showed a significant positive correlation with HDI levels. In particular, the geographical density distribution (Gini coefficients of 0·32-0·47) had higher inequalities than population density distribution (Gini coefficients of 0·05-0·19). The overall proportion of cross-regional patients of childhood and adolescent cancer was 22·16%, and the highest proportion occurred in retinoblastoma (56·54%) and in low HDI regions (35·14%). INTERPRETATION: Our study showed that the burden of cancer in children and adolescents in China is much higher than previously nationally reported from 2000 to 2015. The distribution of the accessibility of health services, as a social determinant of health, might have a notable role in the socioeconomic inequalities in cancer incidence among Chinese children and adolescents. With regards to achieving the Sustainable Development Goals, policy approaches should prioritise increasing the accessibility of health services for early diagnosis to improve outcomes and subsequently reduce disease burdens, as well as narrowing the socioeconomic inequalities of childhood and adolescent cancer. FUNDING: National Major Science and Technology Projects of China, National Natural Science Foundation of China, Chinese Academy of Engineering Consulting Research Project, Wu Jieping Medical Foundation, Beijing Municipal Administration of Hospitals Incubating Program.


Subject(s)
Leukemia , Neoplasms , Adolescent , Child , China/epidemiology , Cross-Sectional Studies , Female , Health Services , Health Services Accessibility , Humans , Incidence , Male , Neoplasms/diagnosis , Neoplasms/epidemiology , Socioeconomic Factors
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