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1.
J Hepatol ; 81(1): 93-107, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38403027

ABSTRACT

BACKGROUND & AIMS: The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC. METHODS: Gene expression in HCC specimens from 10 patients receiving anti-PD-1 therapy was identified by RNA-sequencing. A total of 404 HCC samples from tissue microarrays were analyzed by immunohistochemistry. Transgenic mice (Alb-Cre/Trp53fl/fl) received hydrodynamic tail vein injections of a CRKL-overexpressing vector. Mass cytometry by time of flight was used to profile the proportion and status of different immune cell lineages in the mouse tumor tissues. RESULTS: CRKL was identified as a candidate anti-PD-1-resistance gene using a pooled genetic screen. CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block the infiltration and function of CD8+ T cells. PD-L1+ TANs were found to be an essential subset of TANs that were regulated by CRKL expression and display an immunosuppressive phenotype. Mechanistically, CRKL inhibits APC (adenomatous polyposis coli)-mediated proteasomal degradation of ß-catenin by competitively decreasing Axin1 binding, and thus promotes VEGFα and CXCL1 expression. Using human HCC samples, we verified the positive correlations of CRKL/ß-catenin/VEGFα and CXCL1. Targeting CRKL using CRISPR-Cas9 gene editing (CRKL knockout) or its downstream regulators effectively restored the efficacy of anti-PD-1 therapy in an orthotopic mouse model and a patient-derived organotypic tumor spheroid model. CONCLUSIONS: Activation of the CRKL/ß-catenin/VEGFα and CXCL1 axis is a critical obstacle to successful anti-PD-1 therapy. Therefore, CRKL inhibitors combined with anti-PD-1 could be useful for the treatment of HCC. IMPACT AND IMPLICATIONS: Here, we found that CRKL was overexpressed in anti-PD-1-resistant hepatocellular carcinoma (HCC) and that CRKL upregulation promotes anti-PD-1 resistance in HCC. We identified that upregulation of the CRKL/ß-catenin/VEGFα and CXCL1 axis contributes to anti-PD-1 tolerance by promoting infiltration of tumor-associated neutrophils. These findings support the strategy of bevacizumab-based immune checkpoint inhibitor combination therapy, and CRKL inhibitors combined with anti-PD-1 therapy may be developed for the treatment of HCC.


Subject(s)
Adaptor Proteins, Signal Transducing , Carcinoma, Hepatocellular , Drug Resistance, Neoplasm , Immune Checkpoint Inhibitors , Liver Neoplasms , Neutrophil Infiltration , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/immunology , Liver Neoplasms/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Animals , Humans , Mice , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Mice, Transgenic , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Male , Chemokine CXCL1/metabolism , Chemokine CXCL1/genetics
2.
Cell Commun Signal ; 22(1): 409, 2024 Aug 21.
Article in English | MEDLINE | ID: mdl-39169379

ABSTRACT

BACKGROUND: Melanoma, one of the most lethal forms of skin cancer, has the potential to develop in any area where melanocytes are present. Currently, postoperative recurrence due to the emergence of systemic drug resistance represents a significant challenge in the treatment of melanoma. In this study, terphenyllin (TER), a distinctive inhibitory impact on melanoma cells was identified from the natural p-terphenyl metabolite. This study aimed to elucidate the intrinsic mechanism of this inhibitory effect, which may facilitate the discovery of novel chemotherapeutic agents. METHODS: A transcriptome sequencing and metabolomic analysis of TER-treated A375 cells was conducted to identify potential pathways of action. The key proteins were knocked out and backfilled using CRISPR-Cas9 technology and molecular cloning. Subsequently, the results of cytosolic viability, LDH release, immunofluorescence and flow cytometry were employed to demonstrate the cell death status of the drug-treated cells. RESULTS: The p53 signalling pathway was markedly upregulated following TER treatment, leading to the activation of CASP3 via the intrinsic apoptotic pathway. The activated CASP3 initiated apoptosis, while simultaneously continuing to cleave the GSDME, thereby triggering pyroptosis. The knockout of p53, a key protein situated upstream of this pathway, resulted in a significant rescue of TER-induced cell death, as well as an alleviation of the decrease in cell viability. However, the knockout of key proteins situated downstream of the pathway (CASP3 and GSDME) did not result in a rescue of TER-induced cell death, but rather a transformation of the cells from apoptosis and pyroptosis. CONCLUSIONS: The induction of apoptosis and pyroptosis in A375 cells by TER is mediated via the p53-BAX/FAS-CASP3-GSDME signalling pathway. This lays the foundation for TER as a potential anti-melanoma drug in the future. It should be noted that CASP3 and GSDME in this pathway solely regulate the mode of cell death, rather than determine whether cell death occurs. This distinction may prove valuable in future studies of apoptosis and pyroptosis.


Subject(s)
Apoptosis , Caspase 3 , Pyroptosis , Tumor Suppressor Protein p53 , Up-Regulation , Humans , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Pyroptosis/drug effects , Pyroptosis/genetics , Apoptosis/drug effects , Up-Regulation/drug effects , Caspase 3/metabolism , Cell Line, Tumor , Melanoma/metabolism , Melanoma/genetics , Melanoma/pathology , Signal Transduction/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Gasdermins
3.
J Nanobiotechnology ; 21(1): 452, 2023 Nov 27.
Article in English | MEDLINE | ID: mdl-38012616

ABSTRACT

BACKGROUND: Spinal cord injury (SCI) remains a significant health concern, with limited available treatment options. This condition poses significant medical, economic, and social challenges. SCI is typically categorized into primary and secondary injuries. Inflammation, oxidative stress, scar formation, and the immune microenvironment impede axon regeneration and subsequent functional restoration. Numerous studies have shown that the destruction of the blood-brain barrier (BBB) and microvessels is a crucial factor in severe secondary injury. Additionally, reactive oxygen species (ROS)-induced lipid peroxidation significantly contributes to endothelial cell death. Pericytes are essential constituents of the BBB that share the basement membrane with endothelial cells and astrocytes. They play a significant role in the establishment and maintenance of BBB. RESULTS: Immunofluorescence staining at different time points revealed a consistent correlation between pericyte coverage and angiogenesis, suggesting that pericytes promote vascular repair via paracrine signaling. Pericytes undergo alterations in cellular morphology and the transcriptome when exposed to hypoxic conditions, potentially promoting angiogenesis. We simulated an early ischemia-hypoxic environment following SCI using glucose and oxygen deprivation and BBB models. Co-culturing pericytes with endothelial cells improved barrier function compared to the control group. However, this enhancement was reduced by the exosome inhibitor, GW4869. In vivo injection of exosomes improved BBB integrity and promoted motor function recovery in mice following SCI. Subsequently, we found that pericyte-derived exosomes exhibited significant miR-210-5p expression based on sequencing analysis. Therefore, we performed a series of gain- and loss-of-function experiments in vitro. CONCLUSION: Our findings suggest that miR-210-5p regulates endothelial barrier function by inhibiting JAK1/STAT3 signaling. This process is achieved by regulating lipid peroxidation levels and improving mitochondrial function, suggesting a potential mechanism for restoration of the blood-spinal cord barrier (BSCB) after SCI.


Subject(s)
MicroRNAs , Spinal Cord Injuries , Mice , Animals , Pericytes/metabolism , Endothelial Cells/metabolism , Lipid Peroxidation , Axons , Nerve Regeneration , Spinal Cord Injuries/metabolism , Signal Transduction , MicroRNAs/genetics , MicroRNAs/metabolism
4.
Hepatobiliary Pancreat Dis Int ; 22(5): 444-451, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37308360

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally and imposed a heavy economic burden on society and individuals. To date, the pathological process of NAFLD is not yet fully elucidated. Compelling evidences have demonstrated the pivotal role of gut microbiota in the pathogenesis of NAFLD, and gut dysbiosis has been commonly observed in patients with NAFLD. Gut dysbiosis impairs gut permeability, allowing the translocation of bacterial products such as lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), and ethanol to the liver via portal blood flow. This review aimed to shed light on the underlying mechanisms by which gut microbiota influences the development and progression of NAFLD. In addition, the potential application of gut microbiome as a non-invasive diagnostic tool and a novel therapeutical target was reviewed.


Subject(s)
Gastrointestinal Microbiome , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/diagnosis , Dysbiosis/pathology , Liver/pathology
5.
Virol J ; 19(1): 151, 2022 09 20.
Article in English | MEDLINE | ID: mdl-36127711

ABSTRACT

BACKGROUND: ß-Amyloid (Aß) protein is a pivotal pathogenetic factor in Alzheimer's disease (AD). However, increasing evidence suggests that the brain has to continuously produce excessive Aß to efficaciously prevent pathogenic micro-organism infections, which induces and accelerates the disease process of AD. Meanwhile, Aß exhibits activity against herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) replication, but not against other neurotropic viruses. Enterovirus A71 (EV-A71) is the most important neurotropic enterovirus in the post-polio era. Given the limitation of existing research on the relationship between Aß and other virus infections, this study aimed to investigate the potent activity of Aß on EV-A71 infection and extended the potential function of Aß in other unenveloped viruses may be linked to Alzheimer's disease or infectious neurological diseases. METHODS: Aß peptides 1-42 are a major pathological factor of senile plaques in Alzheimer's disease (AD). Thus, we utilized Aß1-42 as a test subject to perform our study. The production of monomer Aß1-42 and their high-molecular oligomer accumulations in neural cells were detected by immunofluorescence assay, ELISA, or Western blot assay. The inhibitory activity of Aß1-42 peptides against EV-A71 in vitro was detected by Western blot analysis or qRT-PCR. The mechanism of Aß1-42 against EV-A71 replication was analyzed by time-of-addition assay, attachment inhibition assay, pre-attachment inhibition analysis, viral-penetration inhibition assay, TEM analysis of virus agglutination, and pull-down assay. RESULTS: We found that EV-A71 infection induced Aß production and accumulation in SH-SY5Y cells. We also revealed for the first time that Aß1-42 efficiently inhibited the RNA level of EV-A71 VP1, and the protein levels of VP1, VP2, and nonstructural protein 3AB in SH-SY5Y, Vero, and human rhabdomyosarcoma (RD) cells. Mechanistically, we demonstrated that Aß1-42 primarily targeted the early stage of EV-A71 entry to inhibit virus replication by binding virus capsid protein VP1 or scavenger receptor class B member 2. Moreover, Aß1-42 formed non-enveloped EV-A71 particle aggregates within a certain period and bound to the capsid protein VP1, which partially caused Aß1-42 to prevent viruses from infecting cells. CONCLUSIONS: Our findings unveiled that Aß1-42 effectively inhibited nonenveloped EV-A71 by targeting the early phase of an EV-A71 life cycle, thereby extending the potential function of Aß in other non-envelope viruses linked to infectious neurological diseases.


Subject(s)
Alzheimer Disease , Enterovirus A, Human , Enterovirus Infections , Enterovirus , Neuroblastoma , Amyloid beta-Peptides , Antigens, Viral/genetics , Capsid Proteins/genetics , Enterovirus/genetics , Enterovirus A, Human/genetics , Humans , Peptide Fragments , RNA , Receptors, Scavenger/metabolism
6.
Ecotoxicol Environ Saf ; 246: 114154, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36228354

ABSTRACT

Nitrogen (N) deposition plays a significant role in soil cadmium (Cd) phytoremediation, and poplar has been considered for the remediation of contaminated soil because of its enormous biomass and strong Cd resistance. To reveal the underlying physiological and root phenotypic mechanisms of N deposition affecting Cd phytoextraction in poplar, we assessed root phenotypic characteristics, Cd absorption and translocation, chlorophyll fluorescence performance, and antioxidant enzyme activities of a clone of Populus deltoides × P. nigra through combined greenhouse Cd and N experiments. Our results showed that Cd significantly changed the root phenotype by reducing root length, tip number, and diameter. Cd also caused the peroxidation of lipids, damaged the photosystem II (PSII) reaction centre, and reduced photosynthetic capacity, resulting in a decrease in biomass accumulation in poplar. The N60 (60 kg N·ha-1·yr-1) and N90 (90 kg N·ha-1·yr-1) treatments promoted the net photosynthetic rate of poplar by increasing the activity of antioxidant enzymes and proline content and repairing the PSII reaction centre, thus increasing the biomass accumulation of poplar exposed to Cd stress. Simultaneously, the N60 and N90 treatments might have increased Cd uptake from the soil by upregulating total root length, root tips, and fine root length. Cd mainly accumulated in roots and stems but not in leaves. The N30 (30 kg N·ha-1·yr-1) treatment had no obvious effects on these parameters compared with the single Cd treatment. Consequently, our study suggested that adequate N can improve biomass and Cd accumulation to enhance the phytoremediation capacity of poplar for Cd, which might be related to the improvement of leaf physiological defence and the change in root phenotypic characteristics.


Subject(s)
Populus , Soil Pollutants , Cadmium/toxicity , Populus/physiology , Biodegradation, Environmental , Biomass , Antioxidants , Soil Pollutants/toxicity , Soil Pollutants/analysis , Soil , Nitrogen , Plant Roots/chemistry
7.
Financ Res Lett ; 38: 101838, 2021 Jan.
Article in English | MEDLINE | ID: mdl-36569651

ABSTRACT

We investigate the impact of COVID-19 on Chinese stock market by an event study and examine the effect of individual investor sentiment on returns. The pandemic has an overall negative effect on stock market during the post-event window, which can't be explained by real losses. Results show a stronger positive correlation between individual investor sentiment and stock returns than usual. The impact on individual investor sentiment on stock returns is more significant for enterprises with high PB, PE and CMV, low net asset, and low institutional shareholding. Only 7 industries related to pharmacy, digitalization, and agriculture are boosted.

8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 1001-1004, 2020 Sep 10.
Article in Zh | MEDLINE | ID: mdl-32820516

ABSTRACT

OBJECTIVE: To carry out genetic and metabolite analysis for an infant with cerebral creatine deficiency syndrome type 2 (CCDS2). METHODS: Clinical data of the child was collected. Whole-exome sequencing was carried out to identify potential variants by next generation sequencing. Candidate variants were confirmed by Sanger sequencing. Metabolites were determined by tandem mass spectrometry and magnetic resonance spectroscopy. Treatment was carried out following the diagnosis and genetic counseling for the affected family. RESULTS: Two novel heterozygous variants (c.289delC and c.392-1G>C) of the GAMT gene were identified in the proband, which were respectively inherited from her father and mother. In silico analysis suggested both variants to be pathogenic. Creatine (Cr) level of the child was very low, and cerebral guanidinoacetate (GAA) level was slightly increased. But both had recovered to normal in two weeks, and cerebral Cr level was significantly improved after two months. Intellectual and motor development of the child were significantly improved. CONCLUSION: The child was diagnosed with CCDS type 2, for which pathogenic variants of the GAMT gene may be accountable. Treatment has attained a satisfactory effect for the patient.


Subject(s)
Brain Diseases, Metabolic, Inborn/genetics , Creatine/deficiency , Guanidinoacetate N-Methyltransferase/genetics , Language Development Disorders/genetics , Movement Disorders/genetics , Female , Humans , Infant
9.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(5): 482-487, 2020 May.
Article in Zh | MEDLINE | ID: mdl-32434645

ABSTRACT

This article reports the clinical and genetic features of two cases of cerebral creatine deficiency syndrome I (CCDSI) caused by SLC6A8 gene mutations. Both children were boys. Boy 1 (aged 2 years and 10 months) and Boy 2 (aged 8 years and 11 months) had the clinical manifestations of delayed mental and motor development, and convulsion. Their older brothers had the same symptoms. The mother of the boy 1 had mild intellectual disability. The genetic analysis showed two novel homozygous mutations, c.200G>A(p.Gly67Asp) and c.626_627delCT(p.Pro209Argfs*87), in the SLC6A8 gene on the X chromosome, both of which came from their mothers. These two novel mutations were rated as possible pathogenic mutations and were not reported in the literature before. This study expands the mutation spectrum of the SLC6A8 gene and has great significance in the diagnosis of boys with delayed development, and epilepsy.


Subject(s)
Mutation , Nerve Tissue Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/genetics , Child , Child, Preschool , Creatine , Epilepsy , Genetic Testing , Humans , Male , Syndrome
10.
Chem Biodivers ; 16(1): e1800491, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30411487

ABSTRACT

Investigation of the branches and leaves of Tabernaemontana bufalina Lour. led to afford an undescribed monoterpenoid indole alkaloid, namely (3R,7S,14R,19S,20R)-19-hydroxypseudovincadifformine (1), and nine known metabolites (2-10). Their structures were determined by analysis of their NMR and ESI-MS spectra, and modified Mosher's and calculated electronic circular dichroism (ECD) methods were used for establishing the absolute configuration of compound 1. Their cytotoxic activities were assayed using two cancer cell lines. As the results, cytotoxic activities on MDA-MB-231 and B16 cells showed IC50 values of 8.9 and 0.13 µm for 6, and of 20.3 and 11.7 µm for 9, respectively.


Subject(s)
Plant Extracts/pharmacology , Plant Leaves/chemistry , Tabernaemontana/chemistry , Animals , Cell Line, Tumor , Circular Dichroism , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Plant Extracts/isolation & purification , Proton Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization
11.
Ageing Res Rev ; 101: 102508, 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39303877

ABSTRACT

BACKGROUND: Mild cognitive impairment (MCI) is a critical time window for implementing prevention strategies to attenuate or delay cognitive decline. Non-invasive brain stimulation (NIBS) techniques are promising non-pharmacological therapies for improving the cognitive function of MCI, but it is unclear which type of NIBS protocol is most effective. This study aimed to compare and rank the beneficial effect of different NIBS methods/protocols on cognitive function and examine the acceptability of NIBS in patients with MCI. METHODS: Electronic search of PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure, Wanfang Database, and Chongqing VIP Database up to November 2023. Patients with diagnosis of MCI were included. The primary outcomes were acceptability and pre-post treatment changes in global cognitive function, and the secondary outcomes were specific cognitive domains (language and executive function). All network meta­analysis procedures were performed under the frequentist model. A protocol for this systematic review was registered in PROSPERO (Registration number: CRD42023441448). RESULTS: A network meta-analysis was conducted on 19 eligible RCTs consisting of 599 subjects. Compared with the sham stimulation, Repetitive Transcranial Magnetic Stimulation over the Bilateral dorsolateral prefrontal cortex (rTMS-F3F4) showed the strongest improvement in global cognitive function in MCI patients (SMD =1.52[95 %CIs =0.49-2.56]), followed by rTMS over the left dorsolateral prefrontal cortex (rTMS-F3) (SMD =1.25[95 %CIs =0.57-1.93]); Moreover, rTMS-F3F4 showed more significant efficacy in language function (SMD =0.96[95 %CIs = 0.20-1.72]); No statistically significant differences were found among the other cognitive domains. Compared with the rTMS-F4, rTMS-F3F4 showed a stronger improvement in global cognitive function in MCI patients (SMD =1.80[95 %CIs =0.02-3.59]). Similar results were obtained in subgroup analyses of cognitive function. All the methods were well-tolerated with an acceptable safety profile. CONCLUSION: The present findings provide evidence of the benefits of NIBS, especially TMS stimulating the bilateral dorsolateral prefrontal cortex, for the beneficial effect on cognitive and language function in patients with MCI. However, because few studies were available for inclusion, additional well-designed, large-scale RCTs are warranted to support exploring longer-term dynamic effects.

12.
J Coll Physicians Surg Pak ; 34(9): 1090-1095, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39262011

ABSTRACT

This study was a meta-analysis of patient data to investigate the therapeutic effects of inclisiran on LDL-C, PCSK9, and TC in patients with atherosclerosis. Authors searched the Cochrane Library, Pubmed, EMBASE, and Web of Science databases for randomised controlled trials. Data of 4,731 subjects from five randomised clinical trials were included in this analysis. Patients treated with the PCSK9 inhibitor inclisiran had significantly lower LDL-C levels than those treated with placebo or a statin (mean difference (MD) -1.477; 95% CI -1.551 to -1.403; p <0.001; I2 = 7.2%). The average level of PCSK9 was also relatively lower ((MD) -2.579; 95% CI -2.694 to -2.464; p <0.001; I2 = 36%). They exhibited significant reductions in total cholesterol protein levels ((MD) -1.477; 95% CI -1.585 to -1.369; p <0.001; I2 = 46.7%). Inclisiran reduced LDL-C and PCSK9 levels as well as TC and Apo B levels significantly in patients with atherosclerotic cardiovascular disease (ASCVD). Key Words: Inclisiran, Low-density lipoprotein cholesterol, Atherosclerosis, Adverse events, Meta-analysis.


Subject(s)
Cardiovascular Diseases , Cholesterol, LDL , PCSK9 Inhibitors , Humans , Cardiovascular Diseases/prevention & control , Cholesterol, LDL/blood , Atherosclerosis/prevention & control , Proprotein Convertase 9 , Randomized Controlled Trials as Topic , RNA, Small Interfering
13.
Arch Med Res ; 56(1): 103086, 2024 Sep 25.
Article in English | MEDLINE | ID: mdl-39326160

ABSTRACT

BACKGROUND AND AIMS: As global demographics shift toward an older population, cognitive impairment is becoming increasingly critical. Transcranial Direct Current Stimulation (tDCS), an innovative brain stimulation technique, has the potential to significantly improve cognitive function. Our main aim is to comprehensively analyze the existing literature, identify key aspects of tDCS research in the rehabilitation of cognitive impairment, and predict future trends in this field. METHODS: We used the Web of Science (WOS) database to search for English articles and reviews relevant to this topic. For visual analysis of the literature, we employed the WOS analysis tool, CiteSpace, along with VOSviewer software to ensure comprehensive analysis. RESULTS: We included 2940 articles published between 1998 and 2023. Over 25 years, annual publications and citations in this field increased steadily, peaking at 379 articles in 2021. Michael A. Nitsche was a major contributor. Most articles came from developed countries, primarily North America and Europe, and journals generally had modest impact factors. Research in this field primarily aims to treat cognitive impairment resulting from pathological aging or neuropsychiatric disorders, with a particular focus on specific brain regions. Recently, researchers have integrated various treatment modalities with tDCS techniques to actively investigate effective strategies to mitigate cognitive impairments associated with pathological aging. CONCLUSION: This study presents the first bibliometric analysis of the literature on tDCS in the rehabilitation of cognitive impairment, highlighting key areas of research and emerging trends. These findings provide critical insights for future tDCS interventions targeting cognitive impairment associated with pathological aging.

14.
J Colloid Interface Sci ; 664: 74-83, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38460386

ABSTRACT

Active pharmaceutical ingredients (APIs) crystal preparation is a significant issue for the pharmaceutical development attributed to the effect on anti-inflammatory, anti-bacteria, and anti-viral, etc. While, the massive preparation of API crystal with high polymorphism selectivity is still a pendent challenge. Here, we firstly proposed a criterion according to the molecular aggregation, molecular orientation, and hydrogen bond energy between INA molecules from molecular dynamics (MD) simulations, which predicted the hydrogen bond architecture in crystal under different electric fields, hinting the recognition of crystal polymorphism. Then, an electric field governing confined liquid crystallization was constructed to achieve the INA crystal polymorphism screening relying on the criterion. Further, magnifying confined liquid volume by 5000 times from 1.0 µL to 5.0 mL realized the massive preparation of INA crystal with high polymorphic purity (>98.4%), giving a unique pathway for crystal engineering and pharmaceutical industry on the development of innovative and generic API based drugs.

15.
PLoS One ; 19(4): e0299054, 2024.
Article in English | MEDLINE | ID: mdl-38574027

ABSTRACT

Wheat straw returning is widely practiced in agriculture; therefore, it is critical to determine the physicochemical and bacterial indicators in soil for the organic carbon storage, accumulative C mineralization, total nitrogen improvement, and nitrogen mineralization in various soil types after wheat straw returning. This study evaluated the influenced indicators of wheat straw addition on soil organic carbon and nitrogen transformation in diverse soil types. For this purpose, an incubation experiment was conducted to analyze the carbon and nitrogen transformation in soil from eight Chinese provinces treated with the same dry weight of wheat straw. The results indicated that the primary physicochemical and bacterial indicators that predict the carbon and nitrogen transformations in the acidic and alkaline soils were different. Of all the natural physicochemical properties of soil, cation exchange capacity and clay content were significantly correlated with organic carbon, mineralized carbon, total nitrogen, and mineralized nitrogen in the alkaline soil. In the acidic soil, the initial C/N ratio of soil was the most significant indicator of carbon and nitrogen transformation. From the perspective of the carbon- and nitrogen-relating bacterial communities, Proteobacteria were largely responsible for the accumulative C mineralization in both types of soil. Furthermore, Proteobacteria strongly regulated the organic carbon storage in the acidic soil after wheat straw addition, whereas Gemmatimonadetes was the main predicted indicator in the alkaline soil. Additionally, total nitrogen and mineralized nitrogen levels were largely explained by Bifidobacterium and Luteimonas in the alkaline soil and by Nitrospira and Bdellovibrio in the acidic soil. Soil physicochemical and biological properties significantly influence soil carbon and nitrogen transformation, which should be considered crucial indicators to guide the rational regulation of straw return in several areas.


Subject(s)
Carbon , Soil , Soil/chemistry , Triticum , Nitrogen/analysis , Agriculture/methods , Bacteria , Proteobacteria , Fertilizers
16.
Int J Biol Macromol ; 280(Pt 3): 135877, 2024 Sep 22.
Article in English | MEDLINE | ID: mdl-39317290

ABSTRACT

Phanerochaete chrysosporium were immobilized in magnetic Fe3O4 nanoparticles and calcium alginate to form MC microspheres. The obtained MC microsphere was characterized by SEM, EDS, XRD, BET, VSM and TGA. The results indicated that MC microsphere was a three-dimensional structure with relatively large specific surface area and good porosity. MC microspheres had excellent magnetic recovery performance and thermal stability. The characteristics and performance of MC microspheres on adsorption of Cu2+ were evaluated based on batch adsorption experiments. The maximum adsorption capacity of Cu2+ by MC microspheres was 35.07 mg g-1 at pH of 5.0, temperature of 35 °C and adsorption time of 8 h. MC microspheres can still effectively adsorb Cu2+ at 400 mg L-1. Integrating simulation results from pseudo-second-order kinetic model, Intra-particle diffusion model and Freundlich model, the process was mainly dominated by chemical adsorption, and it is a multi-molecular layer adsorption. The results of XPS and FTIR showed that complexation, ion replacement, and reduction are important mechanisms for adsorption of Cu2+ on MC microspheres. -OH and C-O/C=O mainly complexes with Cu2+ in the biosorption process. After five adsorption-desorption cycles, the adsorption efficiency can still reach 32.40 %. Therefore, MC microspheres are a potential adsorbent that can achieve effective recovery.

17.
Bioact Mater ; 41: 221-238, 2024 Nov.
Article in English | MEDLINE | ID: mdl-39149592

ABSTRACT

A detrimental feedback loop between hypoxia and oxidative stress consistently drives macrophage polarization toward a pro-inflammatory M1 phenotype, thus persistently aggravating rheumatoid arthritis (RA) progression. Herein, an enzyme-catalyzed nanoplatform with synergistic hypoxia-relieving and reactive oxygen species (ROS)-scavenging properties was developed using bovine serum albumin-bilirubin-platinum nanoparticles (BSA-BR-Pt NPs). Bilirubin was employed to eliminate ROS, while platinum exhibited a synergistic effect in scavenging ROS and simultaneously generated oxygen. In mice RA model, BSA-BR-Pt NPs treatment exhibited superior effects, resulting in significant improvements in joint inflammation, cartilage damage, and bone erosion, compared to methotrexate, the most widely used antirheumatic drug. Mechanistically, RNA-sequencing data and experimental results elucidated that BSA-BR-Pt NPs induced a re-polarization of hypoxic M1 macrophages to M2 macrophages via switching glycolysis to oxidative phosphorylation through the inhibition of HIF-1α pathway. Collectively, this research for the first time elaborated the underlying mechanism of enzyme-catalyzed nanoplatform in orchestrating macrophage polarization, and identified a novel therapeutic strategy for RA and other inflammatory disorders.

18.
Oncogene ; 2024 Sep 09.
Article in English | MEDLINE | ID: mdl-39251847

ABSTRACT

Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.

19.
BMJ Open ; 13(11): e076196, 2023 11 21.
Article in English | MEDLINE | ID: mdl-37989387

ABSTRACT

INTRODUCTION: Interventions at the mild cognitive impairment (MCI) stage prevent or delay the progression of cognitive decline. In recent years, several studies have shown that physical exercise combined with transcranial direct current stimulation (tDCS) effectively delays the disease and promotes cognitive recovery in patients with MCI. This study aims to determine whether Tai Chi (TC) combined with tDCS can significantly improve memory in patients with MCI compared with TC or tDCS alone. METHODS AND ANALYSIS: This clinical trial will use a 2×2 factorial design, enrolling 128 community-dwelling MCI patients, randomly categorised into four groups: TC, tDCS, TC combined with tDCS and the health education group. Outcome measures will include the Chinese Wechsler Memory Scale-Revised, Auditory Verbal Learning Test and Rey-Osterrieth Complex Figure Test. All assessments will be conducted at baseline and 3 months after the intervention. All analyses will use intention-to-treat or per-protocol methods. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the Affiliated Rehabilitation Hospital of the Fujian University of Traditional Chinese Medicine (2022KY-002-01). The results of the study will be disseminated through peer-reviewed publications and at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200059316.


Subject(s)
Cognitive Dysfunction , Tai Ji , Transcranial Direct Current Stimulation , Humans , Transcranial Direct Current Stimulation/methods , Cognitive Dysfunction/therapy , Research Design , Outcome Assessment, Health Care , Cognition , Randomized Controlled Trials as Topic
20.
Natl Sci Rev ; 10(10): nwad169, 2023 Oct.
Article in English | MEDLINE | ID: mdl-38034397

ABSTRACT

Isolation of triplet pnictinidenes, which bear two unpaired electrons at the pnictogen centers, has long been a great challenge due to their intrinsic high reactivity. Herein, we report the syntheses and characterizations of two bismuthinidenes MsFluindtBu-Bi (3) and MsFluind*-Bi (4) stabilized by sterically encumbered hydrindacene ligands. They were facilely prepared through reductions of the corresponding dichloride precursors with 2 molar equivalents of potassium graphite. The structural analyses revealed that 3 and 4 contain a one-coordinate bismuth atom supported by a Bi-C single σ bond. As a consequence, the remaining two Bi 6p orbitals are nearly degenerate, and 3 and 4 possess triplet ground states. Experimental characterizations with multinuclear magnetic resonance, magnetometry and near infrared spectroscopy coupled to wavefunction based ab initio calculations concurred to evidence that there exist giant and positive zero field splittings (>4300 cm-1) in their S = 1 ground states. Hence even at room temperature the systems almost exclusively populate the lowest-energy nonmagnetic Ms = 0 level, which renders them seemingly diamagnetic.

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