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1.
Appl Environ Microbiol ; : e0189222, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36722969

RESUMO

Tobacco bacterial wilt, which is caused by Ralstonia solanacearum, is a devastating soilborne disease of tobacco worldwide and is widespread in the continuously acidic fields of southern China. Here, the fumigation activity under different pH conditions, component identification, and bioactivity of the volatile organic compounds (VOCs) produced by an acid-tolerant strain, Pseudomonas protegens CLP-6, were investigated. There was a wide antimicrobial spectrum of the VOCs against phytopathogens, including four bacteria, eight fungi, and two oomycetes. The antagonistic activity of the VOCs against R. solanacearum was proportionally correlated with the concentration of the inoculum, amount, culture time, and culture pH for CLP-6. The number of gene copies of R. solanacearum was significantly inhibited by VOCs produced at pH 5.5 in vivo. The control effect of VOCs emitted at pH 5.5 was 78.91% for tobacco bacterial wilt, which was >3-fold greater than that at pH 7.0. Finally, the main volatile compounds were identified by solid-phase microextraction (SPME)-gas chromatography-mass spectroscopy (GC-MS) as S-methyl thioacetate, methyl thiocyanate, methyl disulfide, 1-decene, 2-ethylhexanol, 1,4-undecadiene, 1-undecene, 1,3-benzothiazole, and 2,5-dimethylpyrazine, and the inhibition rates of 1,3-benzothiazole, 2-ethylhexanolmethyl thiocyanate, dimethyl disulfide, and S-methyl thioacetate were 100%, 100%, 88.91%, 67.64%, and 53.29%, respectively. S-Methyl thioacetate was detected only at pH 5.5. In summary, VOCs produced by P. protegens CLP-6 had strong antagonistic activities against phytopathogens, especially R. solanacearum, under acidic conditions and could be used to develop a safe and additive fumigant against R. solanacearum on tobacco and even other Solanaceae crop bacterial wilt diseases in acidic fields. IMPORTANCE VOCs produced by beneficial bacteria penetrate the rhizosphere to inhibit the growth of plant-pathogenic microorganisms; thus, they have the potential to be used as biological agents in controlling plant diseases. Tobacco bacterial wilt, which is caused by the acidophilic pathogen R. solanacearum, is a major bacterial disease in southern China and is prevalent in acidic soil. In this study, we discovered that the VOCs produced by P. protegens CLP-6 had excellent inhibitory effects on important plant pathogens. Moreover, two of the VOCs, namely, 1,3-benzothiazole and 2-ethylhexanol, had excellent inhibitory effect on R. solanacearum, and another VOC substance, methyl thiocyanate, was produced only at pH 5.5. The VOCs produced by the acid-tolerant strain P. protegens CLP-6 may have potential as environment-friendly microbial fumigant agents for bacterial wilt of tobacco or even other Solanaceae crops in acidic soils in China.

2.
Nanomaterials (Basel) ; 13(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36677978

RESUMO

Perovskite quantum dots (PQDs) have shown great promise in optoelectronic device applications. Typically, a traditional hot-injection method with heating and high vacuum pressure is used to synthesize these colloidal nanoparticles. In this article, we report a low-cost synthetic method for FAPbI3 PQDs in air at atmospheric pressure with the assistance of ZnI2. Compared with the FAPbI3 PQDs synthesized under vacuum/N2 condition, the air-synthesized Zn:FAPbI3 PQDs exhibit the same crystalline structure with a similar preferential crystallographic orientation but demonstrate higher colloidal stability and higher production yield. Furthermore, we examine the influence of ZnI2 during the synthesis process on morphologies and optoelectronic properties. The results show that the mean size of the obtained FAPbI3 PQDs is decreased by increasing the amount of added ZnI2. More importantly, introducing an optimal amount of ZnI2 into the Pb source precursor enables increasing the carrier lifetime of FAPbI3 PQDs, showing the potential beneficial effect on device performance.

3.
Plant Physiol ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652388

RESUMO

Carbon and nitrogen are the two main nutrients in maize (Zea mays L.) kernels, and kernel filling and metabolism determine seed formation and germination. However, the molecular mechanisms underlying the relationship between kernel filling and corresponding carbon and nitrogen metabolism remain largely unknown. Here, we found that HEAT SHOCK PROTEIN 90.6 (HSP90.6) is involved in both seed filling and the metabolism processes of carbon and nitrogen. A single-amino acid mutation within the HATPase_c domain of HSP90.6 led to small kernels. Transcriptome profiling showed that the expression of amino acid biosynthesis- and carbon metabolism-related genes was significantly downregulated in the hsp90.6 mutant. Further molecular evidence showed strong interactions between HSP90.6 and the 26S proteasome subunits REGULATORY PARTICLE NON-ATPASE6 (RPN6) and PROTEASOME BETA SUBUNITD2 (PBD2). The mutation of hsp90.6 significantly reduced the activity of the 26S proteasome, resulting in the accumulation of ubiquitinated proteins and defects in nitrogen recycling. Moreover, we verified that HSP90.6 is involved in carbon metabolism through interacting with the 14-3-3 protein GENERAL REGULATORY FACTOR14-4 (GF14-4). Collectively, our findings revealed that HSP90.6 is involved in seed filling and development by interacting with the components controlling carbon and nitrogen metabolism.

4.
Phytomedicine ; 110: 154626, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36603342

RESUMO

BACKGROUND: Ganoderma lucidum polysaccharide (GLP) has many biological properties, however, the anti-fibrosis effect of GLP is unknown at present. PURPOSE: This study aimed to examine the anti-fibrogenic effect of GLP and its underlying molecular mechanisms in vivo and in vitro. STUDY DESIGN: Both CCl4-induced mouse and TGF-ß1-induced HSC-T6 cellular models of fibrosis were established to examine the anti-fibrogenic effect of a water-soluble GLP (25 kDa) extracted from the sporoderm-removed spores of G. lucidum.. METHOD: Serum markers of liver injury, histology and fibrosis of liver tissues, and collagen formation were examined using an automatic biochemical analyzer, H&E staining, Sirius red staining, immunohistochemistry, immunofluorescence, ELISA, Western blotting, and qRT-PCR. RNA-sequencing, enrichment pathway analysis, Western blotting, qRT-PCR, and flow cytometry were employed to identify the potential molecular targets and signaling pathways that are responsible for the anti-fibrotic effect of GLP. RESULTS: We showed that GLP (150 and 300 mg/kg) significantly inhibited hepatic fibrogenesis and inflammation in CCl4-treated mice as mediated by the TLR4/NF-κB/MyD88 signaling pathway. We further demonstrated that GLP significantly inhibited hepatic stellate cell (HSCs) activation in mice and in TGF-ß1-induced HSC-T6 cells as manifested by reduced collagen I and a-SMA expressions. RNA-sequencing uncovered inflammation, apoptosis, cell cycle, ECM-receptor interaction, TLR4/NF-κB, and TGF-ß/Smad signalings as major pathways suppressed by GLP administration. Further studies demonstrated that GLP elicits anti-fibrotic actions that are associated with a novel dual effect on apoptosis in vivo (inhibit) or in vitro (promote), suppression of cell cycle in vivo, induction of S phase arrest in vitro, and attenuation of ECM-receptor interaction-associated molecule expressions including integrins ITGA6 and ITGA8. Furthermore, GLP significantly inhibited the TGF-ß/Smad signaling in mice, and reduced TGF-ß1 or its agonist SRI-011381-induced Smad2 and Smad3 phosphorylations, but increased Samd7 expression in HSC-T6 cells. CONCLUSION: This study provides the first evidence that GLP could be a promising dietary strategy for treating liver fibrosis, which protects against liver fibrosis and HSC activation through targeting inflammation, apoptosis, cell cycle, and ECM-receptor interactions that are mediated by TGF-ß/Smad signaling.


Assuntos
Reishi , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Smad/metabolismo , Células Estreladas do Fígado , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Colágeno Tipo I/metabolismo , Ciclo Celular , Inflamação/metabolismo , Apoptose , RNA/metabolismo
5.
Cell ; 186(1): 98-111.e21, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36608662

RESUMO

In eukaryotes, DNA replication initiation requires assembly and activation of the minichromosome maintenance (MCM) 2-7 double hexamer (DH) to melt origin DNA strands. However, the mechanism for this initial melting is unknown. Here, we report a 2.59-Å cryo-electron microscopy structure of the human MCM-DH (hMCM-DH), also known as the pre-replication complex. In this structure, the hMCM-DH with a constricted central channel untwists and stretches the DNA strands such that almost a half turn of the bound duplex DNA is distorted with 1 base pair completely separated, generating an initial open structure (IOS) at the hexamer junction. Disturbing the IOS inhibits DH formation and replication initiation. Mapping of hMCM-DH footprints indicates that IOSs are distributed across the genome in large clusters aligning well with initiation zones designed for stochastic origin firing. This work unravels an intrinsic mechanism that couples DH formation with initial DNA melting to license replication initiation in human cells.


Assuntos
Replicação do DNA , Humanos , Proteínas de Ciclo Celular/metabolismo , Microscopia Crioeletrônica , Proteínas de Ligação a DNA/metabolismo , Proteínas de Manutenção de Minicromossomo/metabolismo , Origem de Replicação
6.
Artigo em Inglês | MEDLINE | ID: mdl-36719841

RESUMO

Co3O4 is a potential high-capacity anode material for lithium-ion batteries (LIBs) and potassium-ion batteries (PIBs), but the poor electrical conductivity and large volume fluctuations during long-term cycling severely limit its cycle durability and rate capabilities, especially for PIBs with large K-ion size. Here, we propose a sulfur template route to fabricate an integral 3D porous Co3O4/MXene (Ti3C2Tx) foam using simple vacuum co-filtrating an aqueous dispersion of Co3O4, S and MXene followed by calcining to remove the S template. The 3D porous structure can easily accommodate the large volume changes of Co3O4 while maintains electrode structural integrity, allowing to realize outstanding long-term cycle stability when tested as anodes for both LIBs (620.4 mA h g-1 after 1000 cycles at 1 A g-1) and PIBs (134.1 mA h g-1 after 1000 cycles at 0.5 A g-1). The high metallic conductivity of the 3D porous MXene network further facilitates the electron/ion transmission, resulting in an improved rate capability of 390 mA h g-1 at 13 A g-1 for LIBs and 125.3 mA h g-1 at 1 A g-1 for PIBs. The robust performance of the 3D porous Co3O4/MXene foam reflects its perspective as a high-performance anode material for both LIBs and PIBs.

7.
J Clin Med ; 12(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36615158

RESUMO

(1) Background: There are few studies on people at high risk for clinical pancreatic cancer (PC). We aimed to explore the risk factors of PC and establish a scale for identifying high-risk populations of clinical PC. (2) Methods: We conducted a matched case-control study, retrospectively collecting demographic data and common clinical indicators from all subjects. Logistic regression was used to explore the risk factors of PC. Based on these factors, we created a high-risk population rating scale, which showed a higher diagnostic value. (3) Results: 385 cases and 428 controls were finally enrolled in our study. Multivariate analysis showed that body mass index (BMI) below 18.5 kg/m2 (OR 5.944, 95%CI: 1.759~20.084), smoking (OR 2.745, 95%CI: 1.555~4.844), new-onset diabetes (OR 5.239, 95%CI: 2.091~13.125), low high-density lipoprotein cholesterol (HDL-C) levels (OR 1.790, 95%CI: 1.044~3.069), and carbohydrate antigen 19-9 (CA19-9) levels no less than 35 U/mL (OR 160.328, 95%CI: 83.392~308.243) were associated with an increased risk of PC, whereas high total cholesterol (TC) levels were related to a lower risk of PC (OR 0.392, 95%CI: 0.211~0.730). The high-risk population scale, whose area under the receiver operating curve reached 0.948 (p < 0.001), showed a greater clinical diagnostic value. (4) Conclusions: Smoking history, new-onset diabetes, BMI, TC, HDL-C, and CA19-9 levels were associated with the risk of PC. The high-risk population rating scale might be used for early clinical PC screening.

8.
Biomimetics (Basel) ; 8(1)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36648825

RESUMO

Wall attachment has great potential in a broad range of applications such as robotic grasping, transfer printing, and asteroid sampling. Herein, a new type of underactuated bionic microspines gripper is proposed to attach to an irregular, rough wall. Experimental results revealed that the gripper, profiting from its flexible structure and underactuated linkage mechanism, is capable of adapting submillimeter scale roughness to centimeter scale geometry irregularity in both normal and tangential attachment. The rigid-flexible coupling simulation analysis validated that the rough adaptation was achieved by the passive deformation of the zigzag flexible structure, while the centimeter-scale irregularity adaptation come from the underactuated design. The attachment test of a spine confirmed that a 5 mm sliding distance of the spine tip on the fine brick wall promises a saturated tangential attachment force, which can guide the stiffness design of flexible structure and parameter selection of underactuated linkage. Furthermore, the developed microspines gripper was successfully demonstrated to grasp irregular rocks, tree trunks, and granite plates. This work presents a generally applicable and dexterous passive adaption design to achieve rough wall attachment for flat and curved objects, which promotes the understanding and application of wall attachment.

9.
World J Clin Cases ; 11(2): 479-481, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36686359

RESUMO

Hypertriglyceridemia is a well-recognized etiology of acute pancreatitis, and the incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) has increased in frequency worldwide in response to lifestyle changes. It is crucial to identify hypertriglyceridemia as the cause of pancreatitis and initiate appropriate treatment. Insulin treatment produces effective lowering of triglycerides, but in our opinion, non-diabetic patients with HTG-AP require separate consideration to avoid hypoglycemia.

10.
Adv Mater ; : e2209824, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681865

RESUMO

(Living creatures possess complex geometries, exceptional adaptability, and continuous growing and regenerating characteristics, which are difficult for synthetic materials to imitate simultaneously. We report a living polymer network with these features. The polymer can be digitally printed into arbitrary 3D shapes and subsequently undergo growth via living polymerization of a monomer as the nutrient. This leads to macroscopic dimensional growth and transforms the printed amorphous network into a crystallizable network, resulting in geometric adaptability via a shape memory mechanism. By controlling the localized growth, an initial homogeneous structure can be converted into a geometrically different heterogeneous structure composed of materials with different properties (crystallization and mechanical properties). After growth, the original network can be chemically regenerated for regrowth. With this regenerative living 4D printing, one 3D printed seed template can be turned into different derivatives with distinct geometries and mechanical properties when repeated regeneration is conducted in different localized regions and the degree of regrowth is varied). This article is protected by copyright. All rights reserved.

11.
Brief Bioinform ; 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681902

RESUMO

Identification of potential targets for known bioactive compounds and novel synthetic analogs is of considerable significance. In silico target fishing (TF) has become an alternative strategy because of the expensive and laborious wet-lab experiments, explosive growth of bioactivity data and rapid development of high-throughput technologies. However, these TF methods are based on different algorithms, molecular representations and training datasets, which may lead to different results when predicting the same query molecules. This can be confusing for practitioners in practical applications. Therefore, this study systematically evaluated nine popular ligand-based TF methods based on target and ligand-target pair statistical strategies, which will help practitioners make choices among multiple TF methods. The evaluation results showed that SwissTargetPrediction was the best method to produce the most reliable predictions while enriching more targets. High-recall similarity ensemble approach (SEA) was able to find real targets for more compounds compared with other TF methods. Therefore, SwissTargetPrediction and SEA can be considered as primary selection methods in future studies. In addition, the results showed that k = 5 was the optimal number of experimental candidate targets. Finally, a novel ensemble TF method based on consensus voting is proposed to improve the prediction performance. The precision of the ensemble TF method outperforms the individual TF method, indicating that the ensemble TF method can more effectively identify real targets within a given top-k threshold. The results of this study can be used as a reference to guide practitioners in selecting the most effective methods in computational drug discovery.

12.
Brief Bioinform ; 24(1)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36642412

RESUMO

Machine learning-based scoring functions (MLSFs) have become a very favorable alternative to classical scoring functions because of their potential superior screening performance. However, the information of negative data used to construct MLSFs was rarely reported in the literature, and meanwhile the putative inactive molecules recorded in existing databases usually have obvious bias from active molecules. Here we proposed an easy-to-use method named AMLSF that combines active learning using negative molecular selection strategies with MLSF, which can iteratively improve the quality of inactive sets and thus reduce the false positive rate of virtual screening. We chose energy auxiliary terms learning as the MLSF and validated our method on eight targets in the diverse subset of DUD-E. For each target, we screened the IterBioScreen database by AMLSF and compared the screening results with those of the four control models. The results illustrate that the number of active molecules in the top 1000 molecules identified by AMLSF was significantly higher than those identified by the control models. In addition, the free energy calculation results for the top 10 molecules screened out by the AMLSF, null model and control models based on DUD-E also proved that more active molecules can be identified, and the false positive rate can be reduced by AMLSF.


Assuntos
Proteínas , Proteínas/metabolismo , Bases de Dados Factuais , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica
13.
Cancers (Basel) ; 15(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36672487

RESUMO

Breast cancer is the most common cancer in women around the world. Emerging evidence has indicated the important roles that non-coding RNAs play in regulating tumor development and progression in breast cancer. Herein, we found a dual function of long non-coding RNA (LncRNA) CCAT2 in the luminal subtype of breast cancer, depending on its subcellular distribution. CCAT2 showed an overall downregulation in the tumor tissues from luminal breast cancer patients. Transient overexpression of CCAT2 in the luminal subtype of breast cancer cell MCF-7 or T47D significantly suppressed cell proliferation in vitro and inhibited tumor growth in vivo. Gene expression analysis of cancer stem cell markers including OCT4, NANOG, h-TERT, SOX2 and KLF4; flow cytometry analysis of breast cancer stem cell population, and mammosphere formation assay demonstrated inhibition of cancer cell stemness with transient transfection of CCAT2 in which exogenous CCAT2 mainly distributed in the cytoplasm and regulated miR-221-p27 signaling via RNA sequence interaction. However, overexpression of CCAT2 in MCF-7 cells through pMX retroviral nuclear expression vector accumulated CCAT2 in the nucleus, leading to upregulation of OCT4-PG1, a pseudogene of stem gene OCT4, thereby promoting the cancer cell stemness. In conclusion, the current study, for the first time, revealed a dual function of lncRNA CCAT2 as a tumor suppressor or oncogene depending upon its subcellular distribution. It also demonstrated the regulatory mechanism of cytoplasmic CCAT2 in suppressing tumorigenesis in the luminal subtype of breast cancer.

14.
Small ; : e2207487, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36693783

RESUMO

Benefiting from the proton's small size and ultrahigh mobility in water, aqueous proton batteries are regarded as an attractive candidate for high-power and ultralow-temperature energy storage devices. Herein, a new-type C4 N polymer with uniform micropores and a large specific surface area is prepared by sulfuric acid-catalyzed ketone amine condensation reaction and employed as the electrode of proton batteries. Multi-walled carbon nanotubes (MWCNT) are introduced to induce the in situ growth of C4 N, and reaped significantly enhanced porosity and conductivity, and thus better both room- and low-temperature performance. When coupled with MnO2 @Carbon fiber (MnO2 @CF) cathode, MnO2 @CF//C4 N-50% MWCNT full battery shows unprecedented cycle stability with a capacity retention of 98% after 11 000 cycles at 10 A g-1 and even 100% after 70 000 cycles at 20 A g-1 . Additionally, a novel anti-freezing electrolyte (5 m H2 SO4  + 0.5 m MnSO4 ) is developed and showed a high ionic conductivity of 123.2 mS cm-1 at -70 °C. The resultant MnO2 @CF//C4 N-50% MWCNT battery delivers a specific capacity of 110.5 mAh g-1 even at -70 °C at 1 A g-1 , the highest in all reported proton batteries under the same conditions. This work is expected to offer a package solution for constructing high-performance ultralow-temperature aqueous proton batteries.

15.
Mol Cells ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694914

RESUMO

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. Despite a good prognosis, approximately a quarter of PTC patients are likely to relapse. Previous reports suggest an association between S-phase kinase-associated protein 2 (SKP2) and the prognosis of thyroid cancer. SKP1 is related to apoptosis of PTC cells; however, its role in PTC remains largely elusive. This study aimed to understand the expression and molecular mechanism of SKP2 in PTC. SKP2 expression was upregulated in PTC tissues and closely associated with clinical diagnosis. In vitro and in vivo knockdown of SKP2 expression in PTC cells suppressed cell growth and proliferation and induced apoptosis. SKP2 depletion promoted cell autophagy under glucose deprivation. SKP2 interacted with PH domain leucine-rich repeat protein phosphatase-1 (PHLPP1), triggering its degradation by ubiquitination. Furthermore, SKP2 activates the AKT-related pathways via PHLPP1, which leads to the cytoplasmic translocation of SKP2, indicating a reciprocal regulation between SKP2 and AKT. In conclusion, the upregulation of SKP2 leads to PTC proliferation and survival, and the regulatory network among SKP2, PHLPP1, and AKT provides novel insight into the molecular basis of SKP2 in tumor progression.

16.
Plant Cell Environ ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36691352

RESUMO

High temperatures (HT) cause pollen abortion and poor floret fertility in rice, which is closely associated with excessive accumulation of reactive oxygen species (ROS) in the developing anthers. However, the relationships between accumulation of abscisic acid (ABA) and ROS, and their effects on tapetum-specific programmed cell death (PCD) in HT-stressed anthers are poorly characterized. Here, we determined the spatiotemporal changes in ABA and ROS levels, and their relationships with tapetal PCD under HT exposure. Mutants lacking ABA-activated protein kinase 2 (SAPK2) functions and exogenous ABA treatments were used to explore the effects of ABA signaling on the induction of PCD and ROS accumulation during pollen development. HT-induced pollen abortion was tightly associated with ABA accumulation and oxidative stress. The higher ABA level in HT-stressed anthers resulted in the earlier initiation of PCD induction and subsequently abnormal tapetum degeneration by activating ROS accumulation in developing anthers. Interactions between SAPK2 and DEAD-box ATP-dependent RNA helicase elF4A-1 (RH4) were required for ABA-induced ROS generation in developing anthers. The OsSAPK2 knockout mutants showed the impaired PCD responses in the absence of HT. However, the deficiency of SAPK2 functions did not suppress the ABA-mediated ROS generation in HT-stressed anthers. This article is protected by copyright. All rights reserved.

18.
BMC Med ; 21(1): 2, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36600247

RESUMO

BACKGROUND: HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations. METHODS: This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5-18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D. RESULTS: Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months. CONCLUSIONS: The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov number: NCT03973151.


Assuntos
Melanoma , Quinases de Proteína Quinase Ativadas por Mitógeno , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas de Membrana/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
19.
Sci Total Environ ; 869: 161738, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36690096

RESUMO

Evidence suggests that fluoride-induced neurodevelopment damage is linked to mitochondrial disorder, yet the detailed mechanism remains unclear. A cohort of Sprague-Dawley rats developmentally exposed to sodium fluoride (NaF) was established to simulate actual exposure of human beings. Using high-input proteomics and small RNA sequencing technology in rat hippocampus, we found mitochondrial translation as the most striking enriched biological process after NaF treatment, which involves the differentially expressed Required Meiotic Nuclear Division 1 homolog (RMND1) and neural-specific miR-221-3p. Further experiments in vivo and in vitro neuroendocrine pheochromocytoma (PC12) cells demonstrated that NaF impaired mitochondrial translation and function, as shown by declined mitochondrial membrane potential and inhibited expression of mitochondrial translation factors, mitochondrial translation products, and OXPHOS complexes, which was concomitant with decreased RMND1 and transcription factor c-Fos in mRNA and proteins as well as elevated miR-221-3p. Notably, RMND1 overexpression alleviated the NaF-elicited mitochondrial translation impairment by up-regulating translation factors, but not vice versa. Interestingly, ChIP-qPCR confirmed that c-Fos specifically controls the RMND1 transcription through direct binding with Rmnd1 promotor. Interference of gene expression verified c-Fos as an upstream positive regulator of RMND1, implicating in fluoride-caused mitochondrial translation impairment. Furthermore, dual-luciferase reporter assay evidenced that miR-221-3p targets c-Fos by binding its 3' untranslated region. By modulating the miR-221-3p expression, we identified miR-221-3p as a critical negative regulator of c-Fos. More importantly, we proved that miR-221-3p inhibitor improved mitochondrial translation and mitochondrial function to combat NaF neurotoxicity via activating the c-Fos/RMND1 axis, whereas miR-221-3p mimic tended towards opposite effects. Collectively, our data suggest fluoride impairs mitochondrial translation by dysregulating the miR-221-3p/c-Fos/RMND1 axis to trigger mitochondrial dysfunction, leading to neuronal death and neurodevelopment defects.

20.
Environ Pollut ; 320: 120995, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36603756

RESUMO

Inflammation mediates the neurological deficits caused by fluoride. Thus, whether inflammation is the underlying mechanism of dental fluorosis (DF) in school-aged children is worth exploring. A cross-sectional study was conducted to investigate the association between inflammation and the prevalence and severity of DF with low-to-moderate fluoride exposure. Fasting morning urine and venous blood samples were collected from 593 children aged 7-14 years. The fluoride content in the water and urine samples was measured using a fluoride ion-selective electrode assay. The levels of interleukin-1ß (IL-1ß) and C-reactive protein (CRP) were detected using an enzyme-linked immunosorbent assay. The Dean's index was used when performing dental examinations. Regression, stratified, and mediation analyses were performed to analyze the association between fluoride exposure, inflammation, and DF prevalence. In the adjusted regression models, the prevalence of mild DF was 1.723-fold (95% confidence interval [CI]:1.612, 1.841) and 1.594-fold (1.479, 1.717) greater than that of normal DF for each 1 mg/L increase in water and urinary fluoride content, respectively. The prevalence of mild DF increased by 3.3% for each 1 pg/mL increase in the IL-1ß level and by 26.0% for each 1 mg/L increase in the CRP level. Stratified analysis indicated a weaker association between fluoride concentration and DF prevalence in boys than in girls, and susceptibility in the boys was reflected by the association of IL-1ß with very mild and moderate DF prevalence. For every 1 mg/L increase in water and urinary fluoride levels, the proportion of IL-1ß-mediated effects on the prevalence of mild DF was 10.0% (6.1%, 15.8%) and 8.7% (4.8%, 15.2%), respectively, and the proportion of CRP-mediated effects was 9.2% (5.5%, 14.9%) and 6.1% (3.3%, 11.0%), respectively. This study indicates that the DF prevalence may be sex-specific. Inflammatory factors may partially mediate the increased prevalence of mild DF in school-aged children with low-to-moderate fluoride exposure.

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