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1.
J Environ Sci (China) ; 147: 512-522, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39003067

RESUMO

To better understand the migration behavior of plastic fragments in the environment, development of rapid non-destructive methods for in-situ identification and characterization of plastic fragments is necessary. However, most of the studies had focused only on colored plastic fragments, ignoring colorless plastic fragments and the effects of different environmental media (backgrounds), thus underestimating their abundance. To address this issue, the present study used near-infrared spectroscopy to compare the identification of colored and colorless plastic fragments based on partial least squares-discriminant analysis (PLS-DA), extreme gradient boost, support vector machine and random forest classifier. The effects of polymer color, type, thickness, and background on the plastic fragments classification were evaluated. PLS-DA presented the best and most stable outcome, with higher robustness and lower misclassification rate. All models frequently misinterpreted colorless plastic fragments and its background when the fragment thickness was less than 0.1mm. A two-stage modeling method, which first distinguishes the plastic types and then identifies colorless plastic fragments that had been misclassified as background, was proposed. The method presented an accuracy higher than 99% in different backgrounds. In summary, this study developed a novel method for rapid and synchronous identification of colored and colorless plastic fragments under complex environmental backgrounds.


Assuntos
Monitoramento Ambiental , Aprendizado de Máquina , Plásticos , Espectroscopia de Luz Próxima ao Infravermelho , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Monitoramento Ambiental/métodos , Plásticos/análise , Análise dos Mínimos Quadrados , Análise Discriminante , Cor
2.
J Environ Sci (China) ; 149: 374-385, 2025 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-39181650

RESUMO

Electrocatalytic reduction of nitrate to ammonia has been considered a promising and sustainable pathway for pollutant treatment and ammonia has significant potential as a clean energy. Therefore, the method has received much attention. In this work, Cu/Fe 2D bimetallic metal-organic frameworks were synthesized by a facile method applied as cathode materials without high-temperature carbonization. Bimetallic centers (Cu, Fe) with enhanced intrinsic activity demonstrated higher removal efficiency. Meanwhile, the 2D nanosheet reduced the mass transfer barrier between the catalyst and nitrate and increased the reaction kinetics. Therefore, the catalysts with a 2D structure showed much better removal efficiency than other structures (3D MOFs and Bulk MOFs). Under optimal conditions, Cu/Fe-2D MOF exhibited high nitrate removal efficiency (87.8%) and ammonium selectivity (89.3%) simultaneously. The ammonium yielded up to significantly 907.2 µg/(hr·mgcat) (7793.8 µg/(hr·mgmetal)) with Faradaic efficiency of 62.8% at an initial 100 mg N/L. The catalyst was proved to have good stability and was recycled 15 times with excellent effect. DFT simulations confirm the reduced Gibbs free energy of Cu/Fe-2D MOF. This study demonstrates the promising application of Cu/Fe-2D MOF in nitrate reduction to ammonia and provides new insights for the design of efficient electrode materials.


Assuntos
Amônia , Cobre , Ferro , Estruturas Metalorgânicas , Nitratos , Poluentes Químicos da Água , Amônia/química , Cobre/química , Nitratos/química , Estruturas Metalorgânicas/química , Ferro/química , Poluentes Químicos da Água/química , Catálise , Modelos Químicos , Oxirredução , Cinética
3.
World J Clin Oncol ; 15(9): 1177-1187, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39351462

RESUMO

BACKGROUND: Hemorrhage, which is not a rare complication in patients with gastric cancer (GC)/gastroesophageal junction cancer (GEJC), can lead to a poor prognosis. However, no study has examined the effectiveness and safety of chemotherapy as an initial therapy for GC/GEJC patients with overt bleeding (OB). AIM: To investigate the impact of OB on the survival and treatment-related adverse events (TRAEs) of GC/GEJC patients. METHODS: Patients with advanced or metastatic GC/GEJC who received systematic treatment at Peking University Third Hospital were enrolled in this study. Propensity score matching (PSM) analysis was performed. RESULTS: After 1:2 PSM analysis, 93 patients were assessed, including 32 patients with OB before treatment (OBBT) and 61 patients without OBBT. The disease control rate was 90.6% in the group with OBBT and 88.5% in the group without OBBT, and this difference was not statistically significant. There was no difference in the incidence of TRAEs between the group with OBBT and the group without OBBT. The median overall survival (mOS) was 15.2 months for patients with OBBT and 23.7 months for those without OBBT [hazard ratio (HR) = 1.101, 95% confidence interval (CI): 0.672-1.804, log rank P = 0.701]. The mOS was worse for patients with OB after treatment (OBAT) than for those without OBAT (11.4 months vs 23.7 months, HR = 1.787, 95%CI: 1.006-3.175, log rank P = 0.044). CONCLUSION: The mOS for GC/GEJC patients with OBBT was similar to that for those without OBBT, but the mOS for patients with OBAT was worse than that for those without OBAT.

4.
J Clin Oncol ; : JCO2302742, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39353163

RESUMO

PURPOSE: We evaluated the efficacy and safety of roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, for chemotherapy-induced anemia (CIA) in patients with nonmyeloid malignancies receiving multicycle treatments of chemotherapy. PATIENTS AND METHODS: In this open-label, noninferiority phase III study conducted at 44 sites in China, 159 participants age ≥18 years with CIA nonmyeloid malignancy and CIA were randomly assigned (1:1) to oral roxadustat or subcutaneous recombinant human erythropoietin-α (rHuEPO-α) three times a week for 12 weeks. Roxadustat starting dosages were 100, 120, and 150 mg three times a week for participants weighing 40-<50, 50-60, and >60 kg, respectively. rHuEPO-α starting dosage for all participants was 150 IU/kg three times a week. Both roxadustat and rHuEPO-α dosages could be modified. The primary end point was least-squares mean (LSM) change in hemoglobin (Hb) concentration from baseline to the concentration averaged over weeks 9-13. RESULTS: Of the 159 participants randomly assigned, 140 were included in the per-protocol set (roxadustat, n = 78; rHuEPO-α, n = 62). The LSM (95% two-sided CI) change from baseline to weeks 9-13 in Hb concentration was 17.1 (13.58 to 20.71) g/L with roxadustat and 15.4 (11.34 to 19.50) g/L with rHuEPO-α (mean difference [95% CI], 1.7 [-3.39 to 6.84]). The lower bound of the one-sided 97.5% CI for the treatment difference (‒3.4 g/L) was greater than the predefined noninferiority margin of ‒6.6 g/L, establishing noninferiority. Noninferiority was supported by five of six key secondary end points. Rates of adverse events were generally comparable between treatments and consistent with previous findings. CONCLUSION: Roxadustat was noninferior to rHuEPO-α in treating CIA in participants with nonmyeloid malignancies receiving multicycle treatments of myelosuppressive chemotherapy. The oral formulation of roxadustat may potentially increase compliance.

5.
Ther Clin Risk Manag ; 20: 677-687, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39355234

RESUMO

Objective: To observe whether maintaining the appropriate depth of anesthesia with Bispectral Index (BIS) can improve the prognosis of Spinal Cord stimulation (SCS) implantation in patients with chronic Disorders of consciousness (DoC). Methods: 103 patients with DoC undergoing SCS implantation were reviewed, and 83 patients with DoC were included according to the standard of inclusion and exclusion Criteria. Patients were divided into a BIS group (n =45) and a non-BIS group (n =38) according to whether BIS monitoring was used during the operation. The depth of anesthesia in the BIS group was maintained between 40-60. The anesthesiologist adjusted the depth of anesthesia in the non-BIS group according to clinical experience. Relevant information such as disease course, cause, anesthesia time, and operation time were collected. Preoperative CRS-R(preoperative) score, postoperative CRS-R(24h), and postoperative CRS-R(3m) changes were collected. Results: The CRS-R(3m) score in the BIS group was higher than that in the non-BIS group (preoperative), and the difference was statistically significant (P < 0.05). In CRS-R (24h), the BIS group was higher than the non-BIS group, and the difference was statistically significant (X2=8.787, P =0.004). The improvement of consciousness was included in the multivariate Logistic regression analysis model, and it was found that the thalamus was an independent factor affecting the improvement of consciousness (P < 0.05). During follow-up, 1 patient in the BIS group had a decrease in consciousness from MCS- to VS/ UWS and 2 patients in the non-BIS group died during follow-up. Conclusion: Patients can be benefit in hearing in CRS-R (24h). We recommend the use of BIS to monitor the depth of anesthesia in patients with DoC to improve patient outcomes.

6.
Waste Manag ; 190: 251-260, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39357305

RESUMO

Rapid characterization of solid waste using near-infrared hyperspectral imaging (HSI) coupled with machine learning models has been increasingly investigated to replace the traditional time- and labor-intensive methods. However, contamination by waste-derived leachates or other fractions etc., can cause the spectra evolutions and significantly influences the identification performance, which has not been investigated before. The first attempt was made by using hyperspectral unmixing (HU) to extract the endmember components and demonstrate their contributions (abundance) to solid waste, taking the non-linear reflectance changes due to the O-H vibration of water and unclear variation associated with oil and leachates as an example. The HSI spectra of various solid waste components influenced by pure water, oil and three kinds of leachates were acquired. A novel method based on HU models, including multivariate curve resolution with alternating least squares and state-of-the-art autoencoder architectures (deep learning models), was developed to estimate the spectra of endmembers as well as their abundances in individual pixel. Their spatial distribution overview in solid waste was then yielded. The selected models were validated via an independent test data set, with lower spectral angle distance, 12.3° ± 6.5°, indicating the similarity of the predicted endmembers with real components. And the lowest root of mean square error on endmember distribution maps was 0.17. The non-linear liquid's effects by water and oil on spectra variations of solid waste were clearly illuminated. Additionally, the proposed method can extract information from mixed spectroscopic images and generate reconstructed spectra.

7.
Nature ; 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39358510

RESUMO

The Ruddlesden-Popper (R-P) bilayer nickelate, La3Ni2O7, was recently found to show signatures of high-temperature superconductivity (HTSC) at pressures above 14 GPa (ref. 1). Subsequent investigations achieved zero resistance in single-crystalline and polycrystalline samples under hydrostatic pressure conditions2-4. Yet, obvious diamagnetic signals, the other hallmark of superconductors, are still lacking owing to the filamentary nature with low superconducting volume fraction2,4,5. The presence of a new 1313 polymorph and competing R-P phases obscured proper identification of the phase for HTSC6-9. Thus, achieving bulk HTSC and identifying the phase at play are the most prominent tasks. Here we address these issues in the praseodymium (Pr)-doped La2PrNi2O7 polycrystalline samples. We find that substitutions of Pr for La effectively inhibit the intergrowth of different R-P phases, resulting in a nearly pure bilayer structure. For La2PrNi2O7, pressure-induced orthorhombic to tetragonal structural transition takes place at Pc ≈ 11 GPa, above which HTSC emerges gradually on further compression. The superconducting transition temperatures at 18-20 GPa reach T c onset = 82.5 K and T c zero = 60 K , which are the highest values, to our knowledge, among known nickelate superconductors. Importantly, bulk HTSC was testified by detecting clear diamagnetic signals below about 75 K with appreciable superconducting shielding volume fractions at a pressure of above 15 GPa. Our results not only resolve the existing controversies but also provide directions for exploring bulk HTSC in the bilayer nickelates.

8.
Chem Sci ; 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39360009

RESUMO

Fungal phytotoxins cause significant harm to agricultural production or lead to plant diseases. Discovering new phytotoxins, dissecting their formation mechanism and understanding their action mode are important for controlling the harmful effects of fungal phytopathogens. In this study, a long-term unsolved cluster (polyketide synthase 16, PKS16 cluster) from Fusarium species was thoroughly investigated and a series of new metabolites including both complex α-pyrone-polyketide glycosides and simple polyketide carboxylates were identified from F. proliferatum. The whole pathway reveals an unusual assembly and inactivation process for phytotoxin biosynthesis, with key points as follows: (1) a flavin dependent monooxygenase catalyzes Baeyer-Villiger oxidation on the linear polyketide side chain of α-pyrone-polyketide glycoside 8 to form ester bond compound 1; (2) a ß-glucosidase unexpectedly mediates the ester bond hydrolysis of 1 to generate polyketide carboxylate phytotoxin 2; (3) oxidation occurring on the terminal inert carbons of 2 by intracellular oxidase(s) eliminates its phytotoxicity. Our work identifies the chemical basis of the PKS16 cluster in phytotoxicity, shows that polyketide carboxylate is a new structural type of phytotoxin in Fusarium and importantly uncovers a rare ester bond hydrolysis function of ß-glucosidase family enzymes.

9.
Gastroenterol Nurs ; 47(5): 338-348, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39356121

RESUMO

This study investigates the role of self-perceived burden as a mediating factor in the association between perceived partner responsiveness and fertility intentions in women of reproductive age diagnosed with inflammatory bowel disease. A sample of 366 female inflammatory bowel disease patients from Changsha, China, was recruited using convenience sampling. Participants completed assessments, including the Impact of Perceived Partner Responsiveness Scale, Self-Perceived Burden Scale, Fertility Intentions Questionnaire, and a demographic questionnaire. Results indicated a moderate-to-low level of fertility intentions (mean score: 5.33 ± 2.21), with corresponding moderate levels of self-perceived burden (mean score: 30.01 ± 10.02) and perceived partner responsiveness (mean score: 52.80 ± 17.03). Positive correlations were observed between perceived partner responsiveness and fertility intentions and negative correlations between self-perceived burden and fertility intentions. The relationship between perceived partner responsiveness and fertility intentions was found to be partially mediated by self-perceived burden. These findings highlight the significance of perceived partner responsiveness and self-perceived burden in shaping fertility intentions among women with inflammatory bowel disease.


Assuntos
Doenças Inflamatórias Intestinais , Intenção , Humanos , Feminino , Adulto , Doenças Inflamatórias Intestinais/psicologia , Adulto Jovem , Fertilidade , Autoimagem , Inquéritos e Questionários , China , Efeitos Psicossociais da Doença , Pessoa de Meia-Idade , Parceiros Sexuais/psicologia , Estudos Transversais
10.
J Inflamm Res ; 17: 6781-6796, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39372592

RESUMO

Background: Diabetes mellitus (DM) is known to inhibit skin self-renewal and hair follicle stem cell (HFSC) activation, which may be key in the formation of chronic diabetic wounds. This study aimed to investigate the reasons behind the suppression of HFSC activation in DM mice. Methods: Type 1 DM (T1DM) was induced in 6-week-old mice via streptozotocin, and hair follicle growth was subsequently monitored. RNA sequencing, bioinformatics analyses, qRT‒PCR, immunostaining, and cellular experiments were carried out to investigate the underlying mechanisms involved. Results: T1DM inhibited HFSC activation, which correlated with an increase in caspase-dependent programmed cell death. Additionally, T1DM triggered apoptosis and pyroptosis, predominantly in HFSCs and epidermal regions, with pyroptosis being more pronounced in the inner root sheath of hair follicles. Notably, significant cutaneous immune imbalances were observed, particularly in macrophages. Cellular experiments demonstrated that M1 macrophages inhibited HaCaT cell proliferation and induced cell death, whereas high-glucose environments alone did not have the same effect. Conclusion: T1DM inhibits HFSC activation via macrophage reprogramming-mediated caspase-dependent pyroptosis, and there is a significant regional characterization of cell death. Moreover, T1DM-induced programmed cell death in the skin may be more closely related to immune homeostasis imbalance than to hyperglycemia itself. These findings shed light on the pathogenesis of diabetic ulcers and provide a theoretical basis for the use of hair follicle grafts in wound repair.

11.
Int Immunopharmacol ; 143(Pt 1): 113320, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39378653

RESUMO

We previously discovered that macrophages (MΦs), especially tumor-associated MΦs (tMΦs), contribute to chemotherapy resistance in multiple myeloma (MM). However, the mechanism underlying MΦ-mediated chemotherapy resistance in MM needs further elucidation, and the identification of factors that preferentially abrogate MΦ-induced inhibition of MM chemotherapy may have important clinical significance. In this study, we showed that the expression of FASN and SCD2, the enzymes that synthesize palmitic acid and convert it to palmitoleic acid, was decreased in tMΦs compared with MΦs. Interestingly, palmitic acid abrogated the MΦ-mediated protection of MM cells from the effects of bortezomib and melphalan in vitro. Combination treatment with palmitic acid and bortezomib or melphalan further inhibited MM tumor growth in vivo. Mechanistically, palmitic acid treatment increased ALOX12 expression in MΦs. ALOX12 inhibition partially abrogated the palmitic acid-induced decrease in MΦ-mediated MM cell survival. Palmitic acid treatment inhibited AMPK signaling in MΦs, and ALOX12 knockdown activated the AMPK signaling pathway in MΦs. AMPK inhibition decreased the MΦ-mediated protection of drug-treated MM cells, and AMPK activation partially abolished the palmitic acid-induced inhibition of MΦ-mediated protection. ALOX12 converts arachidonic acid (AA) to 12-HETE. Moreover, treatment with AA but not 12-HETE partially abrogated the inhibitory effect of palmitic acid on MΦ-mediated MM cell survival in response to bortezomib or melphalan. Overall, we identified palmitic acid as a factor that inhibits MΦ-mediated resistance to bortezomib and melphalan in MM, which may have clinical significance.

12.
Chem Rev ; 124(19): 10619-10622, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39380397
13.
J Phys Chem Lett ; : 10442-10450, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39388532

RESUMO

Terahertz (THz) coherent phonons have emerged as promising candidates for the next generation of high-speed, low-energy information carriers in atomically thin phononic or phonon-integrated on-chip devices. However, effectively manipulating THz coherent phonons remains a significant challenge. In this study, we investigated THz coherent phonon generation in exfoliated van der Waals (vdW) flakes of Fe3GeTe2, Fe5GeTe2, and FePS3. We successfully generated the THz A1g coherent phonon mode in these vdW flakes. An innovative approach involved partially exfoliating vdW flakes on a gold substrate and partially on a silicon (Si) substrate to compare the THz coherent phonon generation between both sides. Interestingly, we observed a significantly enhanced THz coherent phonon in the vdW/gold area compared with that in the vdW/Si area. Frequency-domain Raman mapping across the vdW flakes corroborated these findings. Numerical simulations further indicated a stronger enhanced surface field in vdW/gold structures than in vdW/Si structures. Consequently, we attribute the observed enhancement in THz coherent phonon generation to the increased surface field on the gold substrate. This enhancement was consistent across the three different vdW materials studied, suggesting the universality of this strategy. Our results hold promise for advancing the design of THz phononic and phonon-integrated devices.

14.
Signal Transduct Target Ther ; 9(1): 281, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39384753

RESUMO

Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.


Assuntos
Proteína Axina , Fator Regulador 3 de Interferon , Proteína Axina/genética , Proteína Axina/imunologia , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/patologia , Imunidade Inata/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Animais , Ubiquitinação/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Células HEK293 , Camundongos , Antivirais/farmacologia , Separação de Fases , Fragmentos de Peptídeos , Sialoglicoproteínas
15.
Neurol Sci ; 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39382625

RESUMO

BACKGROUND: Large Hemispheric Infarction (LHI) is a devastating disease with high mortality. This study aimed to use electroencephalography (EEG) to evaluate the death risk of LHI patients and identify suitable evaluation time. METHODS: This study retrospectively collected clinical and EEG data from 73 LHI patients, dividing them into death and survival group at discharge. EEG data was classified as 1-5 days and 6-14 days after onset according to the time intervals of cerebral edema. Regression and receiver operator characteristic curve (ROC) analysis were applied to explore the impact of temporal changes in various EEG and clinical features on death. RESULTS: The areas under ROC curve (AUC) of death prediction for non-α frequency on non-infarct side at 6-14 days after onset was significantly higher than that at 1-5 days (p = 0.004). And there was no significant difference between the AUC of seizure activity for death prediction at 1-5 days and 6-14 days (p = 0.418). Multivariate regression analysis revealed that non-α frequency on non-infarct side and seizure activity at 6-14 days after onset were the independent risk factors for the death of LHI patients. Additionally, above two EEG features significantly improved the death predictive efficacy of clinical features in LHI patients with the integrated discrimination improvement index (IDI) of 0.174 (p = 0.015) and the net reclassification improvement (NRI) of 1.314 (p<0.001). CONCLUSIONS: Non-α frequency on non-infarct side and seizure activity were reliable indicators for death prediction. 6-14 days after onset was the better time window for death evaluation of LHI patients through EEG.

16.
Chem Sci ; 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39328193

RESUMO

The oxygen level in a tumor typically exhibits complex characteristics, ranging from mild hypoxia to moderate and even severe hypoxia. This poses significant challenges for the efficacy of photodynamic therapy, where oxygen is an essential element. Herein, we propose a novel therapeutic strategy and develop a series of lipid droplet-targeting photosensitive dyes (Ser-TPAs), i.e., in situ synergistic activation of two different electron transfer-type reactions. Based on this strategy, Ser-TPAs can synergistically generate O2˙- and nitrogen radicals regardless of the oxygen content, which results in a sustained high concentration of strongly oxidizing substances in the lipid droplets of cancer cells. As such, Ser-TPAs exhibited inhibitory activity against tumor growth in vivo, resulting in a significant reduction in tumor volume (V experimental group : V control group ≈ 0.07). This strategy offers a conceptual framework for the design of innovative photosensitive dyes that are suitable for cancer therapy in complex oxygen environments.

17.
bioRxiv ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39345364

RESUMO

Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegeneration, such as Alzheimer's disease (AD) remain elusive. Bioinformatic analysis of the published single-cell RNA-seq data collected from AD patient cohorts indicates that the Trpc3 gene is uniquely upregulated in excitatory neurons. TRPC3 expression is also upregulated in post-mortem AD brains, and in both acute and chronic mouse models of AD. Functional screening of TRPC3 antagonists resulted in a lead inhibitor JW-65, which completely rescued Aß-induced neurotoxicity, impaired synaptic plasticity (e.g., LTP), and learning memory in acute and chronic experimental AD models. In cultured rat hippocampal neurons, we found that treatment with soluble ß-amyloid oligomers (AßOs) induces rapid and sustained upregulation of the TRPC3 expression selectively in excitatory neurons. This aberrantly upregulated TRPC3 contributes to AßOs-induced Ca 2+ overload through the calcium entry and store-release mechanisms. The neuroprotective action of JW-65 is primarily mediated via restoring AßOs-impaired Ca 2+ /calmodulin-mediated signaling pathways, including calmodulin kinases CaMKII/IV and calcineurin (CaN). The synaptic protective mechanism via TRPC3 inhibition was further supported by hippocampal RNA-seq data from the symptomatic 5xFAD mice after chronic treatment with JW-65. Overall, these findings not only validate TRPC3 as a novel therapeutic target for treating synaptic dysfunction of AD but most importantly, disclose a distinct role of upregulated TRPC3 in AD pathogenesis in mediating Ca 2+ dyshomeostasis.

18.
Mar Drugs ; 22(9)2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39330272

RESUMO

Glioblastoma represents the predominant and a highly aggressive primary neoplasm of the central nervous system that has an abnormal metabolism. Our previous study showed that chrysomycin A (Chr-A) curbed glioblastoma progression in vitro and in vivo. However, whether Chr-A could inhibit orthotopic glioblastoma and how it reshapes metabolism are still unclear. In this study, Chr-A markedly suppressed the development of intracranial U87 gliomas. The results from airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) indicated that Chr-A improved the abnormal metabolism of mice with glioblastoma. Key enzymes including glutaminase (GLS), glutamate dehydrogenases 1 (GDH1), hexokinase 2 (HK2) and glucose-6-phosphate dehydrogenase (G6PD) were regulated by Chr-A. Chr-A further altered the level of nicotinamide adenine dinucleotide phosphate (NADPH), thus causing oxidative stress with the downregulation of Nrf-2 to inhibit glioblastoma. Our study offers a novel perspective for comprehending the anti-glioma mechanism of Chr-A, highlighting its potential as a promising chemotherapeutic agent for glioblastoma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Estresse Oxidativo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Antraquinonas/farmacologia , Glutaminase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Progressão da Doença , Glutamato Desidrogenase/metabolismo , NADP/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Camundongos Nus
19.
Metabolites ; 14(9)2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39330502

RESUMO

Drylands cover more than 40% of global land surface and will continue to expand by 10% at the end of this century. Understanding the resistance mechanisms of native species is of particular importance for vegetation restoration and management in drylands. In the present study, metabolome of a dominant shrub Campylotropis polyantha in a dry-hot valley were investigated. Compared to plants grown at the wetter site, C. polyantha tended to slow down carbon (C) assimilation to prevent water loss concurrent with low foliar reactive oxygen species and sugar concentrations at the drier and hotter site. Nitrogen (N) assimilation and turn over were stimulated under stressful conditions and higher leaf N content was kept at the expense of root N pools. At the drier site, roots contained more water but less N compounds derived from the citric acid cycle. The site had little effect on metabolites partitioning between leaves and roots. Generally, roots contained more C but less N. Aromatic compounds were differently impacted by site conditions. The present study, for the first time, uncovers the apparent metabolic adaptations of C. polyantha to hostile dryland conditions. However, due to the limited number of samples, we are cautious about drawing general conclusions regarding the resistance mechanisms. Further studies with a broader spatial range and larger time scale are therefore recommended to provide more robust information for vegetation restoration and management in dryland areas under a changing climate.

20.
Front Neurosci ; 18: 1326572, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39268033

RESUMO

The benefits of femtosecond laser-assisted in situ keratomileusis (FS-LASIK) for correcting vision, particularly in terms of spherical equivalent (SE) and visual acuity (VA), have gained broad recognition. Nevertheless, it has remained uncertain whether FS-LASIK has a positive impact on contrast sensitivity (CS). In this study, we measured CS on seven participants by the quick contrast sensitivity function (qCSF) and compared CS before and after the surgery at two time points (1 day and 7 days after) by the repeated measures analysis of variance (ANOVA). Then, we clarified the underlying mechanisms using the perceptual template model (PTM). Furthermore, we investigated the relationship among SE, VA, and CS employing the Pearson correlation test. We found that (1) CS exhibited significant improvements on postoperative day 1, with further enhancements observed up to postoperative day 7, (2) CS improvements were dependent on spatial frequency (SF) and external noise, (3) CS improvements were attributed to the reduction of internal noise and the enhancement of the perceptual template, (4) VA and SE demonstrated significant improvement post-surgery, and (5) no significant correlations were observed among SE, VA, and CS, possibly due to limitations in sample size and lighting conditions. These findings contribute to our comprehension of FS-LASIK and provide a great indicator for assessing the outcomes of visual surgery.

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