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1.
J Ethnopharmacol ; 334: 118532, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38972527

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV (AS), a key active ingredient obtained from Chinese herb Astragalus mongholicus Bunge, exerts potent neuroprotective and anti-inflammatory effects for treating neurodegenerative diseases. However, mechanisms of AS on improvement of ischemic brain tissue repair remain unclear. AIM OF THE STUDY: This research aims at using magnetic resonance imaging (MRI) to noninvasively determine whether AS facilitates brain tissue repair, and investigating whether AS exerts brain remodeling through adenosine monophosphate-activated protein kinase (AMPK) metabolic signaling regulating key glycolytic enzymes and energy transporters, thereby impacting microglia polarization. MATERIALS AND METHODS: Ischemic stroke model in male Sprague-Dawley rats were induced through permanent occlusion of the middle cerebral artery (MCAO). Infarct volume, the alterations of brain microstructure and nerve fibers reorganization were examined by multi-parametric MRI. The pathological damages of myelinated axons and microglia polarization surrounding infarct tissue were detected using pathological techniques. Furthermore, M1/M2 microglia polarization associated protein, glycolytic rate-limiting enzymes, energy transporters and AMPK/mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) signal were examined both in ischemic stroke rats and BV2 microglia treated with lipopolysaccharide (LPS) + interferon-γ (IFN-γ) by western blotting. RESULTS: MRI revealed that AS obviously decreased infarct volume, relieved brain microstructure damage and improved nerve fibers reorganization in ischemic stroke rats. Histological tests supported MRI findings. Notably, AS promoted microglia M2 and reduced M1 polarization, induced the AMPK activation accompanied with decreased levels of phosphorylated mTOR and HIF-1α. Moreover, AS suppressed the expression of glycolytic rate-limiting enzymes and energy transporters in ischemic stroke rats and BV2 microglia. In contrast, these beneficial effects were greatly blocked by AMPK inhibitor compound C. CONCLUSION: Overall, these results collectively suggested that AS facilitated tissue remodeling that may be partially through modulating polarization of microglia in AMPK- dependent metabolic pathways after ischemic stroke.

2.
Med Dosim ; 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38902140

RESUMO

Rectal toxicity is a significant concern in cervical cancer radiotherapy. Despite advancements in image-guided brachytherapy (IGBT), rectal morbidity remains a challenge. Injectable hydrogel showed promise in creating a space between the vagina and rectum, reducing rectal radiation dose; however, the traditional ultrasound-guided injection revealed some problems, such as the inadequate separation of the upper edge of the cervix, which can be mitigated through adopting CT-guided injection. This case report presents the successful use of computed tomography (CT)-guided hydrogel injection to limit rectal doses and improve treatment outcomes. A forty-year-old female with stage IIIC1r cervical cancer received external-beam radiotherapy and concurrent chemotherapy. Due to the proximity of the tumor to the rectum, a CT-guided hydrogel injection was performed to increase the distance between the cervix and rectum. Post-injection, magnetic resonance imaging (MRI) demonstrated increased distances between the cervix and rectum. Subsequent MRI-based IGBT achieved high clinical target volume doses while limiting rectal doses. During the six-month follow-up, the patient reported only mild adverse effects. CT-guided hydrogel injection offers advantages over ultrasound-guided injection in cervical cancer radiotherapy. The technique allows for better puncture position adjustment, reduced reliance on specialized ultrasound expertise, and shorter puncture distances. This case report highlights the potential of hydrogel injection as a viable method to reduce rectal morbidity and improve treatment outcomes in a broader range of cervical cancer patients. Further studies are warranted to validate these findings and explore its applicability in larger cohorts.

3.
Aging (Albany NY) ; 16(12): 10348-10365, 2024 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-38874497

RESUMO

Exploring the molecular mechanisms of PD-1/PDL-1 blockade for non-small cell lung cancer (NSCLC) would facilitate understanding for tumor microenvironment (TME) and development of individualized medicine. To date, biomarkers of response to PD-1 blockade therapy were still limited. In this study, we hypothesize that cell type in the tumor microenvironment can influence the effect of PD-1 blockade immunotherapy through specific genes. Therefore, we re-analyze the single-cell RNA sequencing data and validation in tissue from lung adenocarcinoma patients. Dynamic changes of cellular subpopulation were observed after anti-PD-1 immunotherapy among TMEs between primary/metastasis or good/poor response patients. Non-exhausted CD8 T cells and dysregulated genes were observed in responsing patients from PD-1 blockade therapy. Among all changed genes, JUN, involved in PD-1 blockade immunotherapy pathway, and could be considered as a PD-1 responsing biomarker.


Assuntos
Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Análise de Célula Única , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Análise de Sequência de RNA , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Imunoterapia/métodos , Masculino , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Feminino
4.
J Thorac Dis ; 16(5): 3213-3227, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38883654

RESUMO

Background: Although immunotherapy has revolutionized the treatment landscape of lung cancer and improved the prognosis of this malignancy, many patients with lung cancer still are not able to benefit from it because of many different reasons. The expression of programmed death ligand-1 (PD-L1) in tumor cells has been approved for the prediction of immunotherapy efficacy; however, its clinical application has been limited by the invasiveness of PD-L1 determination and the heterogeneity of tumor cells. As a promising technology, radiomics has made significant progress in the diagnosis and treatment of lung cancer. Thus, we constructed a noninvasive predictive model which based on radiomics to predict the immunotherapy efficacy of lung caner patients. Methods: Data of 82 patients with stage IIIa/IVb NSCLC who received immunotherapy at the First Affiliated Hospital of Soochow University from December 2019 to January 2023 were retrospectively collected. These patients were followed up for durable clinical benefit (DCB), as defined by whether progression-free survival (PFS) reached 12 months. The least absolute shrinkage and selection operator (LASSO) algorithm was used to screen for the radiomic features in the training set, and a radiomics score (Rad-score) was calculated. The clinical baseline data were analyzed, and the peripheral blood inflammation indices were calculated. Univariate and multivariate analyses were performed to identify the applicable indices, which were combined with the Rad-score to create a comprehensive forecasting model (CFM) and nomograms. Internal validation was performed in the validation set. Results: Up to the last follow-up time, 48 of 82 patients had a PFS of more than 12 months. The area under the receiver operating characteristic (ROC) curve (AUC) of the Rad-score was 0.858 and 0.812, respectively, in the training set and validation set. A systemic immune-inflammation index (SII) score of <500.88 after two cycles of immunotherapy was a protective factor for PFS >12 months [odds ratio (OR) 0.054; P=0.003]. The CFM had an AUC of 0.930 and 0.922, respectively, in the training and validation sets. The calibration curves and decision curve analysis (DCA) demonstrated the reliability and clinical applicability of the model, respectively. Conclusions: The radiomics model performed well in predicting whether patients with locally advanced or metastatic NSCLC can achieve DCB after receiving immunotherapy. The CFM had good predictive performance and reliability.

5.
J Microbiol Biotechnol ; 34(6): 1328-1339, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38754999

RESUMO

Cadmium (Cd) is a prevalent environmental contaminant that poses a potential hazard to the health of both humans and animals. In this study, biosynthesized selenium-enriched Lactobacillus plantarum and selenium nanoparticles (SeNPs) were developed and evaluated for their protective effects against Cd-induced hepatic injury in mice through oral administration for 4 weeks. Cadmium exposure resulted in severe impairment of liver function, as evidenced by increased levels of serum markers of liver injury and, oxidative stress and significant damage to liver tissue, and a notable decrease in the diversity of the intestinal microbiota. Oral administration of Se-enriched L. plantarum (LS) reduced cadmium accumulation in the liver by 49.5% and, restored other cadmium-induced damage markers to normal levels. A comparison of the effects with those of L. plantarum (L) and SeNPs isolated from LS revealed that LS could more effectively alleviate hepatic oxidative stress and reduce the intrahepatic inflammatory responses of the liver, further protecting against cadmium-induced liver injury. These findings suggest that the development of LS may be effective at protecting the liver and intestinal tract from cadmium-induced damage.


Assuntos
Cádmio , Doença Hepática Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Lactobacillus plantarum , Fígado , Estresse Oxidativo , Selênio , Animais , Cádmio/toxicidade , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Nanopartículas , Substâncias Protetoras/farmacologia , Probióticos/administração & dosagem , Probióticos/farmacologia
6.
Discov Oncol ; 15(1): 195, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38809316

RESUMO

INTRODUCTION: Lung cancer (LC) is the most common solid tumor and is currently considered the primary cause of cancer-related deaths worldwide. In clinical efficacy studies, it was not difficult to find that the combination of SFI and chemotherapy could improve the general condition of patients, reduce the side effects of chemotherapy drugs, and have a cooperative antitumor effect in NSCLC patients. However, whether SFI can be used as a novel antitumor drug is still unknown. METHODS: First, meta-analysis aimed to explore the efficacy of SFI in NSCLC patients, and SFI was identified by ultra-performance liquid chromatography‒mass spectrometry (UPLC‒MS). Cell proliferation, migration, and invasion were explored by Cell Counting Kit-8 (CCK-8), scratch healing, and Transwell assays, respectively. Cell cycle and apoptosis assays were performed by flow cytometry. Transcriptome sequencing analysis was performed in four NSCLC cell lines. Differential expression analysis was used to identify potential targets. Apoptosis-related protein levels were detected by Western blotting assays. The effects of SFI in NSCLC were further investigated by mouse xenografts. RESULTS: SFI could markedly improve the chemotherapy efficacy of NSCLC patients. The main active ingredients include flavonoids and terpenoids, which can effectively exert antitumor effects. SFI could not only inhibit tumor cell proliferation and cell migration/invasion but also regulate the cell cycle and promote tumor cell apoptosis. In NSCLC, SFI could enhance the transcription level of the CHOP gene, thereby upregulating the expression of the proapoptotic proteins Bax and caspase 3, and inhibiting the expression of the antiapoptotic protein Bcl-2. SFI hindered the growth of mouse NSCLC xenografts in vivo. CONCLUSIONS: SFI hindered tumor progression and might promote apoptosis by increasing the expression of Bax, caspase 3 and decreasing the level of Bcl-2 in NSCLC.

7.
Viruses ; 16(5)2024 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-38793587

RESUMO

A massive mortality event concerning farmed Chinese tongue soles occurred in Tianjin, China, and the causative agent remains unknown. Here, a novel Cynoglossus semilaevis papillomavirus (CsPaV) and parvovirus (CsPV) were simultaneously isolated and identified from diseased fish via electron microscopy, virus isolation, genome sequencing, experimental challenges, and fluorescence in situ hybridization (FISH). Electron microscopy showed large numbers of virus particles present in the tissues of diseased fish. Viruses that were isolated and propagated in flounder gill cells (FG) induced typical cytopathic effects (CPE). The cumulative mortality of fish given intraperitoneal injections reached 100% at 7 dpi. The complete genomes of CsPaV and CsPV comprised 5939 bp and 3663 bp, respectively, and the genomes shared no nucleotide sequence similarities with other viruses. Phylogenetic analysis based on the L1 and NS1 protein sequences revealed that CsPaV and CsPV were novel members of the Papillomaviridae and Parvoviridae families. The FISH results showed positive signals in the spleen tissues of infected fish, and both viruses could co-infect single cells. This study represents the first report where novel papillomavirus and parvovirus are identified in farmed marine cultured fish, and it provides a basis for further studies on the prevention and treatment of emerging viral diseases.


Assuntos
Doenças dos Peixes , Linguados , Genoma Viral , Papillomaviridae , Infecções por Parvoviridae , Parvovirus , Filogenia , Animais , Doenças dos Peixes/virologia , Doenças dos Peixes/mortalidade , China , Linguados/virologia , Infecções por Parvoviridae/veterinária , Infecções por Parvoviridae/virologia , Parvovirus/genética , Parvovirus/isolamento & purificação , Parvovirus/classificação , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/classificação , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/veterinária , Hibridização in Situ Fluorescente
8.
Int J Biol Macromol ; 269(Pt 2): 131894, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677674

RESUMO

N-methyl-morpholine-N-oxide (NMMO) was initially created as a plasticizer for starch to produce thermoplastic wheat starch. Subsequently, talc powder was used as a reinforcing filler to enhance the mechanical strength of thermoplastic biomass-based composite plastics. The chemical structure, crystal structure, and microscopic morphology were analyzed using Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy. Additionally, the thermal properties were explored through thermogravimetric analysis, differential scanning calorimetry, and dynamic mechanical analysis. The hydrated NMMO plasticizer demonstrated an outstanding plasticizing effect on starch, resulting in a composite with remarkable mechanical properties. In fact, the pure thermoplastic wheat starch plasticized with hydrated NMMO exhibited the highest mechanical strength recorded so far, with a tensile strength of up to 9.4 MPa. In addition, talcum powder displayed a noticeable reinforcing effect. When the talcum powder content reached 30 wt%, the targeted composite achieved a tensile strength of 20.5 MPa and a Young's modulus of 177.9 MPa. These values were 118 % and 48 % higher, respectively, than those of the pure thermoplastic starch sample. This innovative plasticizing method opens up a new avenue for the development of high-mechanical-strength thermoplastic biomass-based composite plastics with promising potential applications.


Assuntos
Biomassa , Plastificantes , Plásticos , Amido , Talco , Resistência à Tração , Triticum , Amido/química , Talco/química , Triticum/química , Plásticos/química , Plastificantes/química , Pós , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Fenômenos Mecânicos , Difração de Raios X
9.
Food Funct ; 15(8): 4527-4537, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38576413

RESUMO

Artificial sweeteners (ASs) have been widely added to food and beverages because of their properties of low calories and sweet taste. However, whether the consumption of ASs is causally associated with cancer risk is not clear. Here, we utilized the two-sample Mendelian randomization (MR) method to study the potential causal association. Genetic variants like single-nucleotide polymorphisms (SNPs) associated with exposure (AS consumption) were extracted from a genome-wide association study (GWAS) database including 64 949 Europeans and the influence of confounding was removed. The outcome was from 98 GWAS data and included several types of cancers like lung cancer, colorectal cancer, stomach cancer, breast cancer, and so on. The exposure-outcome SNPs were harmonized and then MR analysis was performed. The inverse-variance weighted (IVW) with random effects was used as the main analytical method accompanied by four complementary methods: MR Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses consisted of heterogeneity, pleiotropy, and leave-one-out analysis. Our results demonstrated that ASs added to coffee had a positive association with high-grade and low-grade serous ovarian cancer; ASs added to tea had a positive association with oral cavity and pharyngeal cancers, but a negative association with malignant neoplasm of the bronchus and lungs. No other cancers had a genetic causal association with AS consumption. Our MR study revealed that AS consumption had no genetic causal association with major cancers. Larger MR studies or RCTs are needed to investigate small effects and support this conclusion.


Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neoplasias , Polimorfismo de Nucleotídeo Único , Edulcorantes , Humanos , Feminino , Neoplasias/genética , Edulcorantes/efeitos adversos , Chá , Café , Neoplasias Ovarianas/genética , Fatores de Risco
10.
Mol Pain ; 20: 17448069241254201, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38670551

RESUMO

It has been widely recognized that electroacupuncture (EA) inducing the release of ß-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC) in the hypothalamus is a vital component of the endogenous opioid peptide system. Serving as an integration center, the periaqueductal gray (PAG) receives neural fiber projections from the frontal cortex, insular cortex, and ARC. However, the specific mechanisms how EA facilitates the release of ß-endorphin within the ARC, eliciting analgesic effects are yet to be elucidated. In this study, we conducted in vivo and in vitro experiments by transcriptomics, microdialysis, photogenetics, chemical genetics, and calcium imaging, combined with transgenic animals. Firstly, we detected 2 Hz EA at the Zusanli (ST36) increased the level of ß-endorphin and transcriptional level of proopiomelanocortin (POMC). Our transcriptomics profiling demonstrated that 2 Hz EA at the ST36 modulates the expression of c-Fos and Jun B in ARC brain nuclear cluster, and the transcriptional regulation of 2 Hz EA mainly occur in POMC neurons by Immunofluorescence staining verification. Meaning while, 2 Hz EA specifically activated the cAMP-PKA-CREB signaling pathway in ARC which mediating the c-Fos and Jun B transcription, and 2 Hz EA analgesia is dependent on the activation of cAMP-PKA-CREB signaling pathway in ARC. In order to investigate how the ß-endorphin produced in ARC transfer to integration center PAG, transneuronal tracing technology was used to observe the 2 Hz EA promoted the neural projection from ARC to PAG compared to 100 Hz EA and sham mice. Inhibited PAGGABA neurons, the transfer of ß-endorphin from the ARC nucleus to the PAG nucleus through the ARCPOMC-PAGGABA neural circuit. Furthermore, by manipulating the excitability of POMC neurons from ARCPOMC to PAGGABA using inhibitory chemogenetics and optogenetics, we found that this inhibition significantly reduced transfer of ß-endorphin from the ARC nucleus to the PAG nucleus and the effectiveness of 2 Hz EA analgesia in neurological POMC cyclization recombination enzyme (Cre) mice and C57BL/6J mice, which indicates that the transfer of ß-endorphin depends on the activation of POMC neurons prefect from ARCPOMC to PAGGABA. These findings contribute to our understanding of the neural circuitry underlying the EA pain-relieving effects and maybe provide valuable insights for optimizing EA stimulation parameters in clinical pain treatment using the in vivo dynamic visual investigating the central analgesic mechanism.


Assuntos
Núcleo Arqueado do Hipotálamo , Eletroacupuntura , Substância Cinzenta Periaquedutal , Pró-Opiomelanocortina , beta-Endorfina , Animais , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Substância Cinzenta Periaquedutal/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Eletroacupuntura/métodos , beta-Endorfina/metabolismo , Masculino , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Neurônios/metabolismo
11.
IUBMB Life ; 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38450584

RESUMO

Particulate matter 2.5 (PM2.5) has been implicated in lung injury and various cancers, yet its precise mechanistic role remains elusive. To elucidate the key signaling pathways underpinning PM2.5-induced lung cancer progression, we embarked on a study examining the impact of PM2.5 both in vitro and in vivo. Lung cancer cell lines, A549 and H157, were employed for the in vitro investigations. Overexpression or knockdown techniques targeting the hnRNPA2B1 protein were implemented. Lung cancer cells were treated with a medium containing PM2.5 and subsequently prepared for in vitro evaluations. Cell growth, invasion, and migration were gauged using transwell and CCK-8 assays. Apoptosis was ascertained through flow cytometry and western blotting of pertinent proteins. Seahorse analyses probed the influence of PM2.5 on lung cancer energy metabolism. The RNA stability assay was employed to discern the impact of PM2.5 on the stability of oxidative phosphorylation-related genes in lung cancer. Our findings revealed that PM2.5 augmented cell proliferation, migration, and invasion rates. Similarly, a diminished apoptosis rate was observed in PM2.5-treated cells. Elevated expression of hnRNPA2B1 was detected in lung cancer cells exposed to PM2.5. Moreover, in cells treated with PM2.5, hnRNPA2B1 knockdown markedly curtailed cell proliferation by inducing G1-S cell cycle arrest and bolstered lung cancer cell apoptosis in vitro; it also curbed xenograft tumor growth. Mechanistically, our data suggest that PM2.5 undermines the stability of mRNA transcripts associated with oxidative phosphorylation (OXPHOS) and augments the formation of processing bodies (P-bodies), leading to an upsurge in OXPHOS levels. In conclusion, PM2.5 appears to drive lung cancer progression and migration by modulating the energy metabolism of lung cancer in a hnRNPA2B1-dependent manner.

12.
Fitoterapia ; 174: 105876, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38431027

RESUMO

Nine polyacetylenes, including five new compounds named sadivaethynes E-I (1-5), were isolated from the roots of Saposhnikovia divaricata. Structural elucidation of compounds 1-5 was established by extensive spectroscopic analysis, quantum chemical calculations and DP4+ probability analysis. Among them, the absolute configuration of compound 1-2, 4-5 was unambiguous determined by ECD. Also, all compounds were evaluated for cytotoxicity against two human cancer cell lines (A549, HEPG2) in vitro, compound 9 showed moderate inhibitory effect with an IC50 value of 11.66 µM against HEPG2.


Assuntos
Apiaceae , Poli-Inos , Humanos , Estrutura Molecular , Poli-Inos/farmacologia , Poli-Inos/análise , Poli-Inos/química , Raízes de Plantas/química , Extratos Vegetais/química , Apiaceae/química
13.
Transpl Immunol ; 84: 102021, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38452984

RESUMO

BACKGROUND: Antibody-mediated rejection (ABMR) emerged as a major cause of graft loss in renal transplantation. Needle biopsy is the gold standard for diagnosis of ABMR in renal allografts. Thus, noninvasive diagnosis methods of ABMR with high accuracy are urgently needed to prevent unnecessary biopsies. METHODS: We collected peripheral blood transcriptome data from two independent renal transplantation cohorts with patients with ABMR, stable well-functioning transplants (STA), and T-cell mediated rejection (TCMR). Differentially expressed genes (DEGs) were identified by comparing the ABMR group with the STA group. In addition, functional enrichment analysis and gene set enrichment analysis were performed to seek new key underlying mechanisms in ABMR. Subsequently, we utilized a Boruta algorithm and least absolute shrinkage and selection operator logistic algorithm to establish a diagnostic model which was then evaluated and validated in an independent cohort. RESULTS: According to functional enrichment analysis, autophagy was found to be the primary upregulated biological process in ABMR. Based on algorithms, three autophagy-associated genes, ubiquitin specific peptidase 33 (USP33), Ras homolog mTORC1 binding (RHEB), and ABL proto-oncogene 2 (ABL2), were selected to establish the diagnostic model in the training cohort. This autophagy-related gene model possessed good diagnostic value in distinguishing ABMR from STA blood samples in the training cohort (AUC = 0.907) and in the validation cohort (AUC = 0.972). In addition, this model also showed good discernibility in distinguishing ABMR from TCMR in the training and validation cohorts (AUCs = 0.908 and 0.833). CONCLUSION: We identified and validated an autophagy-associated diagnostic model with high accuracy for renal transplant patients with ABMR. Our study provided a new potential test for the non-invasive diagnosis of ABMR in clinical practice and highlighted the importance of autophagy in ABMR.


Assuntos
Autofagia , Rejeição de Enxerto , Transplante de Rim , Humanos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Autofagia/imunologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Proto-Oncogene Mas , Transcriptoma , Isoanticorpos/imunologia , Isoanticorpos/sangue
14.
Antibiotics (Basel) ; 13(3)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38534644

RESUMO

The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor (RUP4) that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe3+) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that RUP4 is active against both Klebsiella pneumoniae and Acinetobacter baumannii, with this activity being dependent on direct Fe3+ chelation and enhanced under Fe3+-limiting conditions. Genetic deletion studies in K. pneumoniae reveal that RUP4 gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that RUP4 exhibits bactericidal synergy against K. pneumoniae when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting ß-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe3+-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance.

15.
Cell Death Dis ; 15(3): 215, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38485986

RESUMO

The invasion-metastasis cascade in head and neck squamous cell carcinoma (HNSCC) is predominantly caused by the interaction between tumor cells and tumor microenvironment, including hypoxia as well as stromal cells. However, the mechanism of hypoxia-activated tumor-stroma crosstalk in HNSCC metastasis remains to be deciphered. Here, we demonstrated that HIF1α was upregulated in HNSCC specimens compared with adjacent normal tissues, whose overexpression was associated with lymph node metastasis and predicted unfavorable prognosis. HIF1α expression correlated positively with the levels of miR-5100 as well as α-SMA, the marker of CAFs. Hypoxia/HIF1α regulated transcriptionally miR-5100 to promote the degradation of its target gene QKI, which acts as a tumor suppressor in HNSCC. Hypoxic HNSCC-derived exosomal miR-5100 promoted the activation of CAFs by orchestrating QKI/AKT/STAT3 axis, which further facilitated HNSCC metastasis. Additionally, miR-5100 derived from plasma exosomes indicated HNSCC malignant progression. In conclusion, our findings illuminate a novel HIF1α/miR-5100/QKI pathway in HNSCC metastasis, and suggest that miR-5100 might be a potential biomarker and therapeutic target for HNSCC.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma de Células Escamosas , Exossomos , Neoplasias de Cabeça e Pescoço , MicroRNAs , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas/patologia , MicroRNAs/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Exossomos/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Hipóxia/metabolismo , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Microambiente Tumoral/genética
17.
Sci Transl Med ; 16(731): eadi3883, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38266106

RESUMO

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature-the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.


Assuntos
Neoplasias , Humanos , Reprodutibilidade dos Testes , Neoplasias/diagnóstico , Neoplasias/genética , Elementos Nucleotídeos Curtos e Dispersos , Aprendizado de Máquina , Aneuploidia
18.
Plant Physiol Biochem ; 206: 108222, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38016371

RESUMO

Hydrogen cyanide has been extensively used worldwide for bud dormancy break in fruit trees, consequently enhancing fruit production via expedited cultivation, especially in areas with controlled environments or warmer regions. A novel and safety nanotechnology was developed since the hazard of hydrogen cyanide for the operators and environments, there is an urgent need for the development of novel and safety approaches to replace it to break bud dormancy for fruit trees. In current study, we have systematically explored the potential of iron oxide nanoparticles, specifically α-Fe2O3, to modulate bud dormancy in sweet cherry (Prunus avium). The synthesized iron oxide nanoparticles underwent meticulous characterization and assessment using various techniques, including Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), and ultraviolet-visible infrared (UV-Vis) spectroscopy. Remarkably, when applied at a concentration of 10 mg L-1 alongside gibberellin (GA4+7), these iron oxide nanoparticles exhibited a substantial 57% enhancement in bud dormancy release compared to control groups, all achieved within a remarkably short time span of 4 days. Our RNA-seq analyses further unveiled that 2757 genes within the sweet cherry buds were significantly up-regulated when treated with 10 mg L-1 α-Fe2O3 nanoparticles in combination with GA, while 4748 genes related to dormancy regulation were downregulated in comparison to the control. Moreover, we discovered an array of 58 transcription factor families among the crucial differentially expressed genes (DEGs). Through hormonal quantification, we established that the increased bud burst was accompanied by a reduced concentration of abscisic acid (ABA) at 761.3 ng/g fresh weight in the iron oxide treatment group, coupled with higher levels of gibberellins (GAs) in comparison to the control. Comprehensive transcriptomic and metabolomic analyses unveiled significant alterations in hormone contents and gene expression during the bud dormancy-breaking process when α-Fe2O3 nanoparticles were combined with GA. In conclusion, our findings provide valuable insights into the intricate molecular mechanisms underlying the impact of iron oxide nanoparticles on achieving uniform bud dormancy break in sweet cherry trees.


Assuntos
Prunus avium , Prunus avium/metabolismo , Giberelinas/farmacologia , Giberelinas/metabolismo , Cianeto de Hidrogênio/metabolismo , Flores/genética , Proteínas de Plantas/genética , Nanopartículas Magnéticas de Óxido de Ferro , Regulação da Expressão Gênica de Plantas , Dormência de Plantas
19.
Photoacoustics ; 34: 100573, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38076438

RESUMO

A proof-of-concept gas sensor based on a miniaturized and integrated fiber-optic photoacoustic detection module was introduced and demonstrated for the purpose of developing a custom tuning-fork (TF)-enhanced photoacoustic gas sensor. Instead of piezoelectric quartz tuning fork (QTF) in conventional quartz-enhanced photoacoustic spectroscopy (QEPAS), a low-cost custom aluminum alloy TF fabricated by mechanical processing was employed as a photoacoustic transducer and the vibration of TF was measured by fiber-optic Fabry-Pérot (FP) interferometer (FPI). The mechanical processing-based TF design scheme greatly increases the flexibility of the TF design with respect to the complex and expensive manufacture process of custom QTFs, and thus it can be better exploited to detect gases with slow vibrational-translational (V-T) relaxation rates and combine with light sources with poor beam quality. The resonance frequency and the quality factor of the designed custom TF at atmospheric pressure were experimentally determined to be 7.3 kHz and 4733, respectively. Dual-prong differential measurement method was proposed to double the photoacoustic signal and suppress the external same-direction noise. After detailed optimizing and investigating for the operating parameters by measuring H2O, the feasibility of the developed sensor for gas detection was demonstrated with a H2O minimum detection limit (MDL) of 1.2 ppm, corresponding to a normalized noise equivalent absorption (NNEA) coefficient of 3.8 × 10-8 cm-1 W/Hz1/2, which are better than the QTF-based photoacoustic sensors. The proposed gas sensing approach combined the advantages of QEPAS and fiber-optic sensing, which can greatly expand the application domains of PAS-based gas sensors.

20.
Nanomaterials (Basel) ; 13(24)2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38133048

RESUMO

Cellulose-based carbon (CBC) is widely known for its porous structure and high specific surface area and is liable to adsorb gas molecules and macromolecular pollutants. However, the application of CBC in gas sensing has been little studied. In this paper, a ZnO/CBC heterojunction was formed by means of simple co-precipitation and high-temperature carbonization. As a new ammonia sensor, the prepared ZnO/CBC sensor can detect ammonia that the previous pure ZnO ammonia sensor cannot at room temperature. It has a great gas sensing response, stability, and selectivity to an ammonia concentration of 200 ppm. This study provides a new idea for the design and synthesis of biomass carbon-metal oxide composites.

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