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1.
Exp Biol Med (Maywood) ; 249: 10129, 2024.
Article in English | MEDLINE | ID: mdl-38993198

ABSTRACT

Neurological pain (NP) is always accompanied by symptoms of depression, which seriously affects physical and mental health. In this study, we identified the common hub genes (Co-hub genes) and related immune cells of NP and major depressive disorder (MDD) to determine whether they have common pathological and molecular mechanisms. NP and MDD expression data was downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (Co-DEGs) for NP and MDD were extracted and the hub genes and hub nodes were mined. Co-DEGs, hub genes, and hub nodes were analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the hub nodes, and genes were analyzed to obtain Co-hub genes. We plotted Receiver operating characteristic (ROC) curves to evaluate the diagnostic impact of the Co-hub genes on MDD and NP. We also identified the immune-infiltrating cell component by ssGSEA and analyzed the relationship. For the GO and KEGG enrichment analyses, 93 Co-DEGs were associated with biological processes (BP), such as fibrinolysis, cell composition (CC), such as tertiary granules, and pathways, such as complement, and coagulation cascades. A differential gene expression analysis revealed significant differences between the Co-hub genes ANGPT2, MMP9, PLAU, and TIMP2. There was some accuracy in the diagnosis of NP based on the expression of ANGPT2 and MMP9. Analysis of differences in the immune cell components indicated an abundance of activated dendritic cells, effector memory CD8+ T cells, memory B cells, and regulatory T cells in both groups, which were statistically significant. In summary, we identified 6 Co-hub genes and 4 immune cell types related to NP and MDD. Further studies are needed to determine the role of these genes and immune cells as potential diagnostic markers or therapeutic targets in NP and MDD.


Subject(s)
Computational Biology , Depressive Disorder, Major , Systems Biology , Humans , Depressive Disorder, Major/genetics , Computational Biology/methods , Gene Expression Profiling , Neuralgia/genetics , Neuralgia/metabolism , Gene Regulatory Networks , Gene Ontology , Protein Interaction Maps/genetics , Databases, Genetic
2.
Heliyon ; 10(11): e32532, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38961935

ABSTRACT

Background: Although previous studies have reported a bidirectional relationship between ischemic stroke (IS) and epilepsy, the existence of a causal nexus and its directionality remains a topic of controversy. Methods: The single nucleotide polymorphisms (SNPs) associated with IS were extracted from the Genome-Wide Association Study (GWAS) database. Pooled genetic data encompassing all epilepsy cases, as well as generalized and focal epilepsy subtypes, were acquired from the International League Against Epilepsy's GWAS study. In this study, the primary analysis approach utilized the inverse variance weighting (IVW) method as the main analytical technique. To enhance the robustness of the findings against potential pleiotropy, additional sensitivity analyses were conducted. Results: In the forward analysis, the IVW method demonstrated that IS was associated with an increased risk of all epilepsy (odds ratio (OR) = 1.127, 95 % confidence interval (CI) = 1.038-1.224, P = 0.004) and generalized epilepsy (IVW: OR = 1.340, 95 % CI = 1.162-1.546, P = 5.70 × 10-5). There was no substantial causal relationship observed between IS and focal epilepsy (P > 0.05). Furthermore, generalized epilepsy, focal epilepsy, and all epilepsy did not show a causal relationship with IS. Conclusion: This Mendelian randomization (MR) analysis demonstrates that IS increases the risk of developing epilepsy, especially generalized epilepsy. Conversely, no clear causal association was found between epilepsy and the onset of stroke. Therefore, the possible mechanisms of the effect of epilepsy on the pathogenesis of IS still need to be further investigated.

3.
Poult Sci ; 103(8): 103960, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38964270

ABSTRACT

Danzhou chicken (DZ) is a local breed in China noted for its strong adaptability, roughage resistance, strong wildness, and delicious taste, thus containing important genetic resources. In this study, genome re-sequencing data was generated from 200 DZ chickens. Combined with previously generated data from 72 additional chickens across six other exotic and local breeds, these data were used to systematically evaluate the germplasm characteristics of DZ chickens from a genomic perspective. Unlike exotic breeds, both DZ and southern local chicken varieties exhibited high genetic diversity, and the genetic distance between DZ and southern local chickens was smaller than the genetic distance between DZ and exotic chickens. A reconstructed Neighbor-Joining phylogenetic tree indicated that all sampled populations clustered into single independent populations, with DZ chickens showing clear evidence of intra-population differentiation, forming 2 subpopulations. Principal component analysis and ADMIXTURE analysis showed that DZ was significantly different from other breeds. These results indicate that DZ is a unique genetic resource that is different from other southern native and exotic chickens. The results of the study will improve our understanding of the genetic structure and current status of the DZ breed, which is of great significance in promoting the conservation of genetic resources of DZ chickens and fostering breed innovations and genetic improvement.

4.
Inorg Chem ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38965989

ABSTRACT

Solar photocatalytic H2 production from lignocellulosic biomass has attracted great interest, but it suffers from low photocatalytic efficiency owing to the absence of highly efficient photocatalysts. Herein, we designed and constructed ultrathin MoS2-modified porous TiO2 microspheres (MT) with abundant interface Ti-S bonds as photocatalysts for photocatalytic H2 generation from lignocellulosic biomass. Owing to the accelerated charge transfer related to Ti-S bonds, as well as the abundant active sites for both H2 and ●OH generation, respectively, related to the high exposed edge of MoS2 and the large specific surface area of TiO2, MT photocatalysts demonstrate good performance in the photocatalytic conversion of α-cellulose and lignocellulosic biomass to H2. The highest H2 generation rate of 849 µmol·g-1·h-1 and apparent quantum yield of 4.45% at 380 nm was achieved in α-cellulose aqueous solution for the optimized MT photocatalyst. More importantly, lignocellulosic biomass of corncob, rice hull, bamboo, polar wood chip, and wheat straw were successfully converted to H2 over MT photocatalysts with H2 generation rate of 10, 19, 36, 29, and 8 µmol·g-1·h-1, respectively. This work provides a guiding design approach to develop highly active photocatalysts via interface engineering for solar H2 production from lignocellulosic biomass.

5.
Front Pharmacol ; 15: 1405545, 2024.
Article in English | MEDLINE | ID: mdl-38978978

ABSTRACT

Cardiovascular diseases (CVD) remain the leading cause of death worldwide and represent a major public health challenge. YiyiFuzi Powder (YYFZ), composed of Coicis semen and Fuzi, is a classical traditional Chinese medicine prescription from the Synopsis of Golden Chamber dating back to the Han Dynasty. Historically, YYFZ has been used to treat various CVD, rooted in Chinese therapeutic principles. Network pharmacology analysis indicated that YYFZ may exhibit direct or indirect effects on mitochondria-endoplasmic reticulum (ER) interactions. This review, focusing on the cardiovascular protective effects of Coicis semen and Fuzi, summarizes the potential mechanisms by which YYFZ acts on mitochondria and the ER. The underlying mechanisms are associated with regulating cardiovascular risk factors (such as blood lipids and glucose), impacting mitochondrial structure and function, modulating ER stress, inhibiting oxidative stress, suppressing inflammatory responses, regulating cellular apoptosis, and maintaining calcium ion balance. The involved pathways include, but were not limited to, upregulating the IGF-1/PI3K/AKT, cAMP/PKA, eNOS/NO/cGMP/SIRT1, SIRT1/PGC-1α, Klotho/SIRT1, OXPHOS/ATP, PPARα/PGC-1α/SIRT3, AMPK/JNK, PTEN/PI3K/AKT, ß2-AR/PI3K/AKT, and modified Q cycle signaling pathways. Meanwhile, the MCU, NF-κB, and JAK/STAT signaling pathways were downregulated. The PERK/eIF2α/ATF4/CHOP, PERK/SREBP-1c/FAS, IRE1, PINK1-dependent mitophagy, and AMPK/mTOR signaling pathways were bidirectionally regulated. High-quality experimental studies are needed to further elucidate the underlying mechanisms of YYFZ in CVD treatment.

6.
Front Psychiatry ; 15: 1365231, 2024.
Article in English | MEDLINE | ID: mdl-38979499

ABSTRACT

Background: Neurodevelopmental disorders (NDDs) can cause debilitating impairments in social cognition and aberrant functional connectivity in large-scale brain networks, leading to social isolation and diminished everyday functioning. To facilitate the treatment of social impairments, animal models of NDDs that link N- methyl-D-aspartate receptor (NMDAR) hypofunction to social deficits in adulthood have been used. However, understanding the etiology of social impairments in NDDs requires investigating social changes during sensitive windows during development. Methods: We examine social behavior during adolescence using a translational mouse model of NMDAR hypofunction (SR-/-) caused by knocking out serine racemase (SR), the enzyme needed to make D-serine, a key NMDAR coagonist. Species-typical social interactions are maintained through brain-wide neural activation patterns; therefore, we employed whole-brain cFos activity mapping to examine network-level connectivity changes caused by SR deletion. Results: In adolescent SR-/- mice, we observed disinhibited social behavior toward a novel conspecific and rapid social habituation toward familiar social partners. SR-/- mice also spent more time in the open arm of the elevated plus maze which classically points to an anxiolytic behavioral phenotype. These behavioral findings point to a generalized reduction in anxiety-like behavior in both social and non-social contexts in SR-/- mice; importantly, these findings were not associated with diminished working memory. Inter-regional patterns of cFos activation revealed greater connectivity and network density in SR-/- mice compared to controls. Discussion: These results suggest that NMDAR hypofunction - a potential biomarker for NDDs - can lead to generalized behavioral disinhibition in adolescence, potentially arising from disrupted communication between and within salience and default mode networks.

7.
Article in English | MEDLINE | ID: mdl-38986535

ABSTRACT

Platelet-derived growth factor receptor α (PDGFRα) is often considered as a general marker of mesenchymal cells and fibroblasts, but also shows expression in a portion of osteoprogenitor cells. Within the skeleton, Pdgfrα+ mesenchymal cells have been identified in bone marrow and periosteum of long bones, where they play a crucial role in participating in fracture repair. A similar examination of Pdgfrα+ cells in calvarial bone healing has not been examined. Here, we utilize Pdgfrα-CreERTM;mT/mG reporter animals to examine the contribution of Pdgfrα+ mesenchymal cells to calvarial bone repair through histology and single-cell RNA sequencing (scRNA-Seq). Results showed that Pdgfrα+ mesenchymal cells are present in several cell clusters by scRNA-Seq, and by histology a dramatic increase in Pdgfrα+ cells populated the defect site at early timepoints to give rise to healed bone tissue overtime. Notably, diphtheria toxin-mediated ablation of Pdgfrα reporter+ cells resulted in significantly impaired calvarial bone healing. Our findings suggest that Pdgfrα-expressing cells within the calvarial niche play a critical role in the process of calvarial bone repair.

9.
Front Pharmacol ; 15: 1423629, 2024.
Article in English | MEDLINE | ID: mdl-38989149

ABSTRACT

Esophageal squamous cell carcinoma (ESCC) is a malignancy with high incidence in China. Due to the lack of effective molecular targets, the prognosis of ESCC patients is poor. It is urgent to explore the pathogenesis of ESCC to identify promising therapeutic targets. Metabolic reprogramming is an emerging hallmark of ESCC, providing a novel perspective for revealing the biological features of ESCC. In the hypoxic and nutrient-limited tumor microenvironment, ESCC cells have to reprogram their metabolic phenotypes to fulfill the demands of bioenergetics, biosynthesis and redox homostasis of ESCC cells. In this review, we summarized the metabolic reprogramming of ESCC cells that involves glucose metabolism, lipid metabolism, and amino acid metabolism and explore how reprogrammed metabolism provokes novel opportunities for biomarkers and potential therapeutic targets of ESCC.

10.
Curr Med Imaging ; 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38874027

ABSTRACT

BACKGROUND: Accurate identification of vascular lumen region founded the base of bubble detection and bubble grading, which played a significant role in the detection of vascular gas emboli for the diagnosis of decompression sickness. OBJECTIVES: To assist in the detection of vascular bubbles, it is crucial to develop an automatic algorithm that could identify vascular lumen areas in ultrasound videos with the interference of bubble presence. METHODS: This article proposed an automated vascular lumen region recognition (VLRR) algorithm that could sketch the accurate boundary between vessel lumen and tissues from dynamic 2D ultrasound videos. It adopts 2D ultrasound videos of the lumen area as input and outputs the frames with circled vascular lumen boundary of the videos. Normalized cross-correlation method, distance transform technique, and region growing technique were adopted in this algorithm. Results A double-blind test was carried out to test the recognition accuracy of the algorithm on 180 samples in the images of 6 different grades of bubble videos, during which, intersection over union and pixel accuracy were adopted as evaluation metrics. The average IOU on the images of different bubble grades reached 0.76. The mean PA on 6 of the images of bubble grades reached 0.82. CONCLUSION: It is concluded that the proposed method could identify the vascular lumen with high accuracy, potentially applicable to assist clinicians in the measurement of the severity of vascular gas emboli in clinics.

11.
Angew Chem Int Ed Engl ; : e202410974, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38940067

ABSTRACT

The development of polymer-based persistent luminescence materials with color-tunable organic afterglow and multiple responses is highly desirable for the applications in anti-counterfeiting, flexible displays and data-storage. However, achieving efficient persistent luminescence from a single-phosphor system with multiple responses remains a challenging task. Herein, a hierarchical dual-mode emission system is developed by doping 9H-pyrido[3,4-b]indole (PI2) into an amorphous polyacrylamide matrix, which exhibits color-tunable afterglow due to excitation-, temperature- and humidity-dependence. Notably, the coexistence of isolated state and J-aggregate state of the guest molecule not only provides excitation-dependent afterglow color, but also leads to hierarchical temperature-dependent afterglow color resulting from different thermally activated delayed fluorescence (TADF) and ultralong organic phosphorescence (UOP) behaviors of the isolated and aggregated states. The complex responsiveness based on the hierarchical dual-mode emission can serve for security features through inkjet printing and ink-writing. These findings may provide further insight into the regulated persistent luminescence by isolated and aggregated phosphors in doped polymer systems and expand the scope of stimuli-responsive organic afterglow materials for broader applications.

12.
Int J Mol Sci ; 25(12)2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38928355

ABSTRACT

The pathology of medication-related osteonecrosis of the jaw (MRONJ), often associated with antiresorptive therapy, is still not fully understood. Osteocyte networks are known to play a critical role in maintaining bone homeostasis and repair, but the exact condition of these networks in MRONJ is unknown. On the other hand, the local application of E-coli-derived Recombinant Human Bone Morphogenetic Protein 2/ß-Tricalcium phosphate (E-rhBMP-2/ß-TCP) has been shown to promote bone regeneration and mitigate osteonecrosis in MRONJ-like mouse models, indicating its potential therapeutic application for the treatment of MRONJ. However, the detailed effect of BMP-2 treatment on restoring bone integrity, including its osteocyte network, in an MRONJ condition remains unclear. Therefore, in the present study, by applying a scanning electron microscope (SEM) analysis and a 3D osteocyte network reconstruction workflow on the alveolar bone surrounding the tooth extraction socket of an MRONJ-like mouse model, we examined the effectiveness of BMP-2/ß-TCP therapy on the alleviation of MRONJ-related bone necrosis with a particular focus on the osteocyte network and alveolar bone microstructure (microcrack accumulation). The 3D osteocyte dendritic analysis showed a significant decrease in osteocyte dendritic parameters along with a delay in bone remodeling in the MRONJ group compared to the healthy counterpart. The SEM analysis also revealed a notable increase in the number of microcracks in the alveolar bone surface in the MRONJ group compared to the healthy group. In contrast, all of those parameters were restored in the E-rhBMP-2/ß-TCP-treated group to levels that were almost similar to those in the healthy group. In summary, our study reveals that MRONJ induces osteocyte network degradation and microcrack accumulation, while application of E-rhBMP-2/ß-TCP can restore a compromised osteocyte network and abrogate microcrack accumulation in MRONJ.


Subject(s)
Bone Morphogenetic Protein 2 , Calcium Phosphates , Disease Models, Animal , Osteocytes , Recombinant Proteins , Animals , Bone Morphogenetic Protein 2/pharmacology , Bone Morphogenetic Protein 2/metabolism , Osteocytes/drug effects , Calcium Phosphates/pharmacology , Mice , Recombinant Proteins/pharmacology , Recombinant Proteins/administration & dosage , Bisphosphonate-Associated Osteonecrosis of the Jaw/etiology , Bisphosphonate-Associated Osteonecrosis of the Jaw/pathology , Humans , Bone Regeneration/drug effects , Male , Tooth Extraction/adverse effects , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/pharmacology , Alveolar Process/drug effects , Alveolar Process/pathology
13.
J Chromatogr A ; 1730: 465078, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38889582

ABSTRACT

A novel fluorinated triazine-based covalent organic frameworks (F-CTFs) was designed and synthesized by using melamine and 2,3,5,6-tetrafluoroterephthalaldehydeas as organic ligands for selective pipette tip solid-phase extraction (PT-SPE) of amphiphilic fluoroquinolones (FQs). The competitive adsorption experiment and mechanism study were carried out and verified that this F-CTFs possesses favorable adsorption affinity for FQs. The abundant fluorine affinity sites endowed the F-CTFs high selectivity to FQs extraction through F-F interactions. The adsorption capacity of F-CTFs can reach up to 109.1 mg g-1 for enrofloxacin. The detailed characterization of the F-CTFs adsorbent involved the application of various techniques to examine its morphology and structure. Under optimized conditions, a method combining F-CTF-based PT-SPE with high-performance liquid chromatography (PT-SPE-HPLC) was established, which exhibited a broad linear range, excellent precision, and an impressively low limit of detection, and could be used for the determination of six FQs in milk, with LODs as low as 0.0010 µg mL-1. The recovery rates during extraction varied between 92.1% and 111.4%, exhibiting RSDs below 6.8% at different spiked concentrations.

14.
ACS Omega ; 9(23): 24489-24499, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38882117

ABSTRACT

The surface of para-aramid fibers (AFs) was modified via air-assisted heat pretreatment and solution impregnation by varying the glycidyl polyhedral oligomeric silsesquioxane (POSS) content. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy showed an ester group, confirming the graft reaction between glycidyl POSS and oxidized AFs. The mechanical properties of AFs could be altered by varying the glycidyl POSS content. The modified AFs exhibited an optimal tensile strength after embedding 5 wt % glycidyl POSS on the fiber surface. The thermal stability of the modified fibers decreased; however, no obvious changes in crystallinity were observed by varying the glycidyl POSS content. Moreover, the tensile strength of monofilament increased from 23.8 to 25.8 cN·dtex-1, the thickness of the grafted layer on the fiber surface was above 30-40 nm after the graft modification with 5 wt % glycidyl POSS, and the interfacial shear strength (IFSS) increased by 62.55% to 26.22 MPa. Thus, the modified glycidyl AFs can be used for the reinforcement of composite materials.

15.
Angew Chem Int Ed Engl ; : e202406677, 2024 Jun 02.
Article in English | MEDLINE | ID: mdl-38825572

ABSTRACT

The microtubule-associated protein tau participates in neurotransmission regulation via its interaction with synaptic vesicles (SVs). The precise nature and mechanics of tau's engagement with SVs, especially regarding alterations in vesicle dynamics, remain a matter of discussion. We report an electrochemical method using a synapse-mimicking nanopipette to monitor vesicle dynamics induced by tau. A model vesicle of ~30 nm is confined within a lipid-modified nanopipette orifice with a comparable diameter to mimic the synaptic lipid environment. Both tau and phosphorylated tau (p-tau) present two-state dynamic behavior in this biomimetic system, showing typical ionic current oscillation, induced by lipid-tau interaction. The results indicate that p-tau has a stronger affinity to the lipid vesicles in the confined environment, blocking the vesicle movement to a higher degree. Taken together, this method bridges a gap for sensing synaptic vesicle dynamics in a confined lipid environment, mimicking vesicle movement near the synaptic membrane. These findings contribute to understanding how different types of tau protein regulate synaptic vesicle motility and to underlying its functional and pathological behaviours in disease.

16.
Eur J Cancer ; 207: 114147, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38834016

ABSTRACT

BACKGROUND: We aim to compare the prognostic value of organ-specific dynamics with the sum of the longest diameter (SLD) dynamics in patients with metastatic colorectal cancer (mCRC). METHODS: All datasets are accessible in Project Data Sphere, an open-access platform. The tumor growth inhibition models developed based on organ-level SLD and SLD were used to estimate the organ-specific tumor growth rates (KGs) and SLD KG. The early tumor shrinkage (ETS) from baseline to the first measurement after treatment was also evaluated. The relationship between organ-specific dynamics, SLD dynamics, and survival outcomes (overall survival, OS; progression-free survival, PFS) was quantified using Kaplan-Meier analysis and Cox regression. RESULTS: This study included 3687 patients from 6 phase III mCRC trials. The liver emerged as the most frequent metastatic site (2901, 78.7 %), with variable KGs across different organs in individual patients (liver 0.0243 > lung 0.0202 > lymph node 0.0127 > other 0.0118 [week-1]). Notably, the dynamics for different organs did not equally contribute to predicting survival outcomes. In liver metastasis cases, liver KG proved to be a superior prognostic indicator for OS and surpasses the predictive performance of SLD, (C-index, liver KG 0.610 vs SLD KG 0.606). A similar result can be found for PFS. Moreover, liver ETS also outperforms SLD ETS in predicting survival. Cox regression analysis confirmed liver KG is the most significant variable in survival prediction. CONCLUSIONS: In mCRC patients with liver metastasis, liver dynamics is the primary prognostic indicator for both PFS and OS. In future drug development for mCRC, greater emphasis should be directed towards understanding the dynamics of liver metastasis development.

17.
Biochem Pharmacol ; 225: 116335, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38824968

ABSTRACT

Drugs specifically targeting YKL-40, an over-expressed gene (CHI3L1) in various diseases remain developed. The current study is to create a humanized anti-YKL-40 neutralizing antibody and characterize its potentially therapeutic signature. We utilized in silico CDR-grafting bioinformatics to replace the complementarity determining regions (CDRs) of human IgG1 with mouse CDRs of our previously established anti-YKL-40 antibody (mAY). In fifteen candidates (VL1-3/VH1-5) of heavy and light chain variable region combination, one antibody L3H4 named Rosazumab demonstrated strong binding affinity with YKL-40 (KD = 4.645 × 10-8 M) and high homology with human IgG (80 %). In addition, we established different overlapping amino acid peptides of YKL-40 and found that Rosazumab specifically bound to residues K337, K342, and R344, the KR-rich functional domain of YKL-40. Rosazumab inhibited migration and tube formation of YKL-40-expressing tumor cells and induced tumor cell apoptosis. Mechanistically, Rosazumab induced interaction of N-cadherin with ß-catenin and activation of downstream MST1/RASSF1/Histone H2B axis, leading to chromosomal DNA breakage and cell apoptosis. Treatment of xenografted tumor mice with Rosazumab twice a week for 4 weeks inhibited tumor growth and angiogenesis, but induced tumor apoptosis. Rosazumab injected in mice distributed to blood, tumor, and other multiple organs, but did not impact in function or structure of liver and kidney, indicating non-detectable toxicity in vivo. Collectively, the study is the first one to demonstrate that a humanized YKL-40 neutralizing antibody offers a valuable means to block tumor development.


Subject(s)
Chitinase-3-Like Protein 1 , Animals , Humans , Chitinase-3-Like Protein 1/antagonists & inhibitors , Mice , Female , Xenograft Model Antitumor Assays/methods , Antibodies, Monoclonal, Humanized/pharmacology , Cell Line, Tumor , Mice, Nude , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use
18.
J Med Chem ; 67(12): 9927-9949, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38847373

ABSTRACT

Wee1 is a kinase that regulates cell cycle arrest in response to DNA damage. Wee1 inhibition is a potential strategy to suppress the growth of tumors with defective p53 or DNA repair pathways. However, the development of Wee1 inhibitors faces some challenges. AZD1775, the first-in-class Wee1 inhibitor, has poor kinase selectivity and dose-limiting toxicity. Here, we report the discovery of 12h, a highly selective and potent Wee1 inhibitor with a favorable pharmacokinetic profile. 12h showed strong antiproliferative effects against Lovo cells, a colorectal cancer cell line, both in vitro and in vivo. Moreover, 12h showed a clean kinase profile and effectively induced cell apoptosis. Our results suggest that 12h is a promising drug candidate for further development as a novel anticancer agent.


Subject(s)
Antineoplastic Agents , Cell Cycle Proteins , Cell Proliferation , Drug Design , Protein Kinase Inhibitors , Protein-Tyrosine Kinases , Humans , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/chemistry , Animals , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Cell Proliferation/drug effects , Apoptosis/drug effects , Mice , Structure-Activity Relationship , Mice, Nude
19.
Cell Death Dis ; 15(6): 420, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886383

ABSTRACT

The regeneration of the mammalian skeleton's craniofacial bones necessitates the action of intrinsic and extrinsic inductive factors from multiple cell types, which function hierarchically and temporally to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse calvarial suture recently identified a suture mesenchymal progenitor population with previously unappreciated tendon- or ligament-associated gene expression profile. Here, we developed a Mohawk homeobox (MkxCG; R26RtdT) reporter mouse and demonstrated that this reporter identifies an adult calvarial suture resident cell population that gives rise to calvarial osteoblasts and osteocytes during homeostatic conditions. Single-cell RNA sequencing (scRNA-Seq) data reveal that Mkx+ suture cells display a progenitor-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx+ cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in calvarial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Localized deletion of Mkx in vivo also resulted in robustly increased calvarial defect repair. We further showed that mechanical stretch dynamically regulates Mkx expression, in turn regulating calvarial cell osteogenesis. Together, we define Mkx+ cells within the suture mesenchyme as a progenitor population for adult craniofacial bone repair, and Mkx acts as a mechanoresponsive gene to prevent osteogenic differentiation within the stem cell niche.


Subject(s)
Cell Differentiation , Homeodomain Proteins , Osteogenesis , Skull , Animals , Mice , Homeodomain Proteins/metabolism , Homeodomain Proteins/genetics , Osteogenesis/genetics , Skull/metabolism , Osteoblasts/metabolism , Osteoblasts/cytology , Cranial Sutures/metabolism , Stem Cells/metabolism , Stem Cells/cytology , Biomarkers/metabolism
20.
ACS Appl Mater Interfaces ; 16(26): 33404-33415, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38904481

ABSTRACT

Triboelectric nanogenerators (TENGs) have garnered substantial attention in breeze wind energy harvesting. However, how to improve the output performance and reduce friction and wear remain challenging. To this end, a blade-type triboelectric-electromagnetic hybrid generator (BT-TEHG) with a double frequency up-conversion (DFUC) mechanism is proposed. The DFUC mechanism enables the TENG to output a high-frequency response that is 15.9 to 300 times higher than the excitation frequency of 10 to 200 rpm. Coupled with the collisions between tribomaterials, a higher surface charge density and better generating performance are achieved. The magnetization direction and dimensional parameters of the BT-TEHG were optimized, and its generating characteristics under varying rotational speeds and electrical boundary conditions were studied. At wind speeds of 2.2 and 10 m/s, the BT-TEHG can generate, respectively, power of 1.30 and 19.01 mW. Further experimentation demonstrates its capacity to charge capacitors, light up light emitting diodes (LEDs), and power wireless temperature and humidity sensors. The demonstrations show that the BT-TEHG has great potential applications in self-powered wireless sensor networks (WSNs) for environmental monitoring of intelligent agriculture.

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