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1.
Cell Death Discov ; 10(1): 177, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627379

RESUMO

Osteosarcoma (OS) is the most prevalent primary malignancy of bone in children and adolescents. It is extremely urgent to develop a new therapy for OS. In this study, the GSE14359 chip from the GEO database was used to screen differentially expressed genes in OS. DNA polymerase epsilon 2 (POLE2) was confirmed to overexpress in OS tissues and cell lines by immunohistochemical staining, qPCR and Western blot. Knockdown of POLE2 inhibited the proliferation and migration of OS cells in vitro, as well as the growth of tumors in vivo, while the apoptosis rate was increased. Bioinformatics analysis revealed that CD44 and Rac signaling pathway were the downstream molecule and pathway of POLE2, which were inhibited by knockdown of POLE2. POLE2 reduced the ubiquitination degradation of CD44 by acting on MDM2. Moreover, knockdown of CD44 inhibited the tumor-promoting effects of POLE2 overexpression on OS cells. In conclusion, POLE2 augmented the expression of CD44 via inhibiting MDM2-mediated ubiquitination, and then activated Rac signaling pathway to influence the progression of OS, indicating that POLE2/CD44 might be potential targets for OS treatment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38597324

RESUMO

Purpose: The study aims to explore the roles and underlying mechanisms of long noncoding RNAs endogenous bornavirus-like nucleoprotein (lncRNA EBLN3P) in colon cancer, emphasizing the potential impact of these insights on advancing colon cancer treatment strategies. By shedding light on lncRNA EBLN3P's involvement, this research could contribute to the development of novel therapeutic approaches, enhancing the efficacy of interventions for colon cancer patients. Methods: We employed quantitative reverse transcription polymerase chain reaction to assess the levels of lncRNA EBLN3P, zinc finger protein (ZFP91), and miR-519d-3p, alongside CCK-8 and EdU assays for cell proliferation, flow cytometry for apoptosis, and Transwell and wound healing assays for migration and invasion. The in vivo function of lncRNA EBLN3P was investigated through a xenograft model, and protein levels were evaluated via Western blot analysis. Results: LncRNA EBLN3P was found to be upregulated in colon cancer tissues and cells, promoting cell proliferation and metastasis while inhibiting apoptosis. Downregulation of lncRNA EBLN3P reduced tumor size, volume, and weight in a mouse model. MiR-519d-3p, which negatively interacts with lncRNA EBLN3P, was found to be downregulated in colon cancer tissues and cell lines. Its upregulation hindered cancer cell proliferation and metastasis while enhancing apoptosis. ZFP91, a binding partner of miR-519d-3p, was upregulated in colon cancer and inversely related to miR-519d-3p levels. Rescue experiments indicated that the effects of lncRNA EBLN3P silencing could be reversed by miR-519d-3p suppression, but were mitigated by ZFP91 downregulation. Conclusion: LncRNA EBLN3P facilitates colon cancer progression via the miR-519d-3p/ZFP91 axis, presenting a novel understanding of lncRNA EBLN3P's role and offering potential therapeutic insights for colon cancer treatment. This study fills a critical gap by linking lncRNA EBLN3P with the miR-519d-3p/ZFP91 axis in the context of colon cancer, thereby broadening our understanding of the molecular mechanisms underlying colon cancer progression.

4.
Medicine (Baltimore) ; 103(14): e37684, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38579032

RESUMO

BACKGROUND: Wrist arthroscopy technology is a surgical technology invented in recent years and widely used in clinical treatment of various wrist diseases. This study uses the methods of bibliometrics and visual analysis to understand the global research status, research hotspots, and future development trends of wrist arthroscopy. METHODS: The relevant literature of global publications on wrist arthroscopy from 2013 to 2023 was extracted from the Web of Science Core Collection database, and the annual output, cooperation, hot spots, research status, and development trend of this field were analyzed by using the bibliometric software (VOSviewers, CiteSpace, and the R package "Bibliometrix"). RESULTS: A total of 635 articles were included, from 2013 to 2023, the number of publications related to wrist arthroscopy showed an overall upward trend, the USA, France, and China are the top 3 countries in terms of the number of publications, whereas Mayo Clinic is the institution with the highest number of publications, Ho PC holds a core position in this field, keyword analysis indicates that the research hotspots are the applications of wrist arthroscopy in triangular fibrocartilage complex injuries, scaphoid nonunion, and avascular necrosis of the lunate. CONCLUSION SUBSECTIONS: Wrist arthroscopy has shown tremendous potential in treating various wrist diseases. However, there are still some challenges in its research domain. With continuous deep research, strengthened international collaboration, and ongoing technological advancements, wrist arthroscopy has the potential to become the standard treatment in hand surgery, offering more efficient and safer treatment options for patients worldwide.


Assuntos
Artroscopia , Punho , Humanos , Instituições de Assistência Ambulatorial , Bibliometria , China
5.
J Clin Epidemiol ; : 111356, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38604271

RESUMO

OBJECTIVE: To investigate the frequency, determinants, stages, and barriers of patient and public involvement (PPI) in systematic reviews, and to explore its association with the dissemination of reviews. STUDY DESIGN AND SETTING: We examined systematic reviews that required the inclusion of a PPI declaration, published in The BMJ between January 1, 2015, and December 31, 2022. Multivariable analysis was used to assess the association between PPI and key variables. We investigated the association between PPI and the dissemination of reviews using Altmetric scores, citations, and full-text views. RESULTS: A total of 217 systematic reviews were included, of which 56 (25.8%, 95% CI 20.0% to 31.6%) included PPI, with a steady increase from 5.9% (1/17) in 2015 to 44.4% (4/35) in 2022. Of the 217 systematic reviews, 160 (73.7%) involved methodologists as co-authors. Factors significantly associated with a higher proportion of PPI included the publication year after 2019 (adjusted odds ratio [aOR] 2.46, 95% confidence interval [CI] 1.26 to 4.83), the involvement of methodologists (aOR 3.08; 95% CI 1.27 to 7.47), and being led by researchers from high-income countries (aOR 5.47; 95% CI 1.23 to 24.30). Reviews that included PPI had higher Altmetric scores per month (6.6 vs. 3.4, P=0.002) and more monthly full-text (1048.6 vs. 636.5, P<0.001) and PDF (217.7 vs. 129.0, P<0.001) views than reviews without PPI. However, there was no difference in the monthly citations (2.2 vs. 2.0, P=0.365) between reviews with and without PPI. CONCLUSION: The proportion of systematic reviews reporting PPI in The BMJ has increased over time, possibly due to journal policies, but it still remains at a low level. Reviews led by researchers from high-income countries or involving methodologists are associated with a higher frequency of PPI within The BMJ. Furthermore, reviews incorporating PPI within The BMJ have a higher potential for broad dissemination.

6.
Nat Plants ; 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570642

RESUMO

Plant high-affinity K+ transporters (HKTs) play a pivotal role in maintaining the balance of Na+ and K+ ions in plants, thereby influencing plant growth under K+-depleted conditions and enhancing tolerance to salinity stress. Here we report the cryo-electron microscopy structures of Oryza sativa HKT2;1 and HKT2;2/1 at overall resolutions of 2.5 Å and 2.3 Å, respectively. Both transporters adopt a dimeric assembly, with each protomer enclosing an ion permeation pathway. Comparison between the selectivity filters of the two transporters reveals the critical roles of Ser88/Gly88 and Val243/Gly243 in determining ion selectivity. A constriction site along the ion permeation pathway is identified, consisting of Glu114, Asn273, Pro392, Pro393, Arg525, Lys517 and the carboxy-terminal Trp530 from the neighbouring protomer. The linker between domains II and III adopts a stable loop structure oriented towards the constriction site, potentially participating in the gating process. Electrophysiological recordings, yeast complementation assays and molecular dynamics simulations corroborate the functional importance of these structural features. Our findings provide crucial insights into the ion selectivity and transport mechanisms of plant HKTs, offering valuable structural templates for developing new salinity-tolerant cultivars and strategies to increase crop yields.

7.
Int J Biol Macromol ; 266(Pt 2): 131283, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38561119

RESUMO

Glycosaminoglycan (GAG) lyases are important tools for investigating the structure of GAGs and preparing low-molecular-weight GAGs. The PL35 family, a recently established polysaccharide lyase family, should be further investigated. In this study, we discovered a new GAG lyase, CHa1, which belongs to the PL35 family. When expressed heterologously in Escherichia coli (BL21), CHa1 exhibited high expression levels and solubility. The optimal activity was observed in Tris-HCl buffer (pH 7.0) or sodium phosphate buffer (pH 8.0) at 30 °C. The specific activities towards HA, CSA, CSC, CSD, CSE, and HS were 3.81, 13.03, 36.47, 18.46, 6.46, and 0.50 U/mg protein, respectively. CHa1 digests substrate chains randomly that acting as an endolytic lyase and shows a significant preference for GlcA-containing structures, prefers larger oligosaccharides (≥UDP8) and can generate a series of oligosaccharides composed mainly of the A unit when digesting CSA. These oligosaccharides include ΔC-A, ΔC-A-A, ΔC-A-A-A, ΔC-A-A-A-A, and ΔC-A-A-A-A-A. The residues Tyr257 and His421 play crucial roles in the catalytic process, and Ser211, Asn212, Asn213, Trp214, Gln216, Lys360, Arg460 and Gln462 may participate in the binding process of CHa1. This study on CHa1 contributes to our understanding of the PL35 family and provides valuable tools for investigating the structure of GAGs.

8.
Small ; : e2311914, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566542

RESUMO

The high-performance hole transporting material (HTM) is one of the most important components for the perovskite solar cells (PSCs) in promoting power conversion efficiency (PCE). However, the low conductivity of HTMs and their additional requirements for doping and post-oxidation greatly limits the device performance. In this work, three novel pyrene-based derivatives containing methoxy-substituted triphenylamines units (PyTPA, PyTPA-OH and PyTPA-2OH) are designed and synthesized, where different numbers of hydroxyl groups are connected at the 2- or 2,7-positions of the pyrene core. These hydroxyl groups at the 2- or 2,7-positions of pyrene play a significantly role to enhance the intermolecular interactions that are able to generate in situ radicals with the assistance of visible light irradiation, resulting in enhanced hole transferring ability, as well as an enhanced conductivity and suppressed recombination. These pyrene-core based HTMs exhibit excellent performance in PSCs, which possess a higher PCE than those control devices using the traditional spiro-OMeTAD as the HTM. The best performance can be found in the devices with PyTPA-2OH. It has an average PCE of 23.44% (PCEmax = 23.50%), which is the highest PCE among the reported PSCs with the pyrene-core based HTMs up to date. This research offers a novel avenue to design a dopant-free HTM by the combination of the pyrene core, methoxy triphenylamines, and hydroxy groups.

9.
Clin Pharmacokinet ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578394

RESUMO

BACKGROUND AND OBJECTIVE: Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an antibody with affinity for Trop-2 coupled to SN-38 via hydrolyzable linker. SG is approved for patients with metastatic triple-negative breast cancer (mTNBC) who have received two or more prior chemotherapies (at least one in a metastatic setting) and for patients with pretreated hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. METHODS: In these analyses, the pharmacokinetics of SG, free SN-38, and total antibody (tAB) were characterized using data from 529 patients with mTNBC or other solid tumors across two large clinical trials (NCT01631552; ASCENT, NCT02574455). Three population pharmacokinetic models were constructed using non-linear mixed-effects modeling; clinically relevant covariates were evaluated to assess their impact on exposure. Models for SG and tAB were developed independently whereas free SN-38 was sequentially generated via a first-order release process from SG. RESULTS: Pharmacokinetics of the three analytes were each described by a two-compartment model with estimated body weight-based scaling exponents for clearance and volume. Typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/h and 3.68 L for SG and 0.0164 L/h and 4.26 L for tAB, respectively. Mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, UGT1A1 genotype, or Trop-2 expression did not have a clinically relevant impact on exposure for any of the three analytes. CONCLUSIONS: These analyses support the approved SG dosing regimen of 10 mg/kg as intravenous infusion on days 1 and 8 of 21-day cycles and did not identify a need for dose adjustment based on evaluated covariates or disease characteristics.

10.
Phytomedicine ; 127: 155476, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38430586

RESUMO

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. PURPOSE: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. METHODS: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90ß) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. RESULTS: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90ß, thus disrupting the HSP90ß-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. CONCLUSION: Resveratrol acted as a non-classical HSP90ß inhibitor, binding to the STING-HSP90ß interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90ß and resveratrol-mediated inhibition of HSP90ß as a potential antiviral approach.


Assuntos
Encefalite por Herpes Simples , Herpes Simples , Herpesvirus Humano 1 , Animais , Camundongos , Humanos , Encefalite por Herpes Simples/tratamento farmacológico , Encefalite por Herpes Simples/diagnóstico , Antivirais/farmacologia , Antivirais/uso terapêutico , Resveratrol/farmacologia , Resveratrol/uso terapêutico , NF-kappa B/metabolismo , Doenças Neuroinflamatórias , Herpes Simples/tratamento farmacológico
11.
Front Public Health ; 12: 1358290, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38525328

RESUMO

Purpose: The detrimental effects of environmental tobacco smoke (ETS) on women's reproductive health have been widely recognized. However, the detailed association between exposure to environmental tobacco smoke and the incidence of infertility remains under-explored. This investigation focuses on exploring this potential connection. Methods: For this analysis, we extracted data from the US National Health and Nutrition Examination Survey (NHANES) database, covering the years 2013 to 2018, focusing on individuals with recorded serum cotinine levels and infertility information. ETS exposure and fertility status were analyzed as independent and dependent variables, respectively. We applied weighted multivariate logistic regression method to evaluate the impact of ETS on infertility, including subgroup analyses for more detailed insights. Results: The study encompassed 3,343 participants. Logistic regression analysis revealed a notable positive correlation between ETS exposure and infertility, with an odds ratio (OR) of 1.64 (95% Confidence Interval [CI]: 1.14-2.36). We observed a non-linear relationship between ETS exposure and infertility risk. Notably, infertility risk increased by 64% in serum cotinine levels above 0.136 compared to that in serum cotinine levels below 0.011. Further, subgroup analysis and interaction tests showed consistent results across different segments, underscoring the robustness of the ETS-infertility link. Conclusion: Our findings suggest that environmental tobacco smoke exposure may be a contributing factor to infertility. These results reinforce the recommendation for women in their reproductive years to avoid ETS exposure, especially when planning for pregnancy.


Assuntos
Infertilidade , Poluição por Fumaça de Tabaco , Gravidez , Humanos , Feminino , Estados Unidos/epidemiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/análise , Inquéritos Nutricionais , Cotinina/análise
12.
Phys Chem Chem Phys ; 26(12): 9309-9316, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38426248

RESUMO

Toll-like receptor 4 (TLR4) is a pivotal innate immune recognition receptor that regulates intricate signaling pathways within the immune system. Neoseptin-3 (Neo-3), a recently identified small-molecule agonist for mouse TLR4/MD2, exhibits chiral recognition properties. Specifically, the L-enantiomer of Neo-3 (L-Neo-3) effectively activates the TLR4 signaling pathway, while D-Neo-3 fails to induce TLR4 activation. However, the underlying mechanism by which TLR4 enantioselectively recognizes Neo-3 enantiomers remains poorly understood. In this study, in silico simulations were performed to investigate the mechanism of chiral recognition of Neo-3 enantiomers by TLR4/MD2. Two L-Neo-3 molecules stably resided within the cavity of MD2 as a dimer, and the L-Neo-3 binding stabilized the (TLR4/MD2)2 dimerization state. However, the strong electrostatic repulsion between the hydrogen atoms on the chiral carbon of D-Neo-3 molecules caused the relative positions of two D-Neo-3 molecules to continuously shift during the simulation process, thus preventing the formation of D-Neo-3 dimer as well as their stable interactions with the surrounding residues in (TLR4/MD2)2. Considering that L-Neo-3 could not sustain a stable dimeric state in the bulk aqueous environment, it is unlikely that L-Neo-3 entered the cavity of MD2 as a dimeric unit. Umbrella sampling simulations revealed that the second L-Neo-3 molecule entering the cavity of MD2 exhibited a lower binding energy (-25.75 kcal mol-1) than that of the first L-Neo-3 molecule (-14.31 kcal mol-1). These results imply that two L-Neo-3 molecules enter the cavity of MD2 sequentially, with the binding of the first L-Neo-3 molecule facilitating the entry of the second one. This study dissects the binding process of Neo-3 enantiomers, offering a comprehensive understanding of the atomic-level mechanism underlying TLR4's chiral recognition of Neo-3 molecules.


Assuntos
Simulação de Dinâmica Molecular , Receptor 4 Toll-Like , Camundongos , Animais , Antígeno 96 de Linfócito , Transdução de Sinais
13.
J Cancer Res Clin Oncol ; 150(3): 124, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478111

RESUMO

BACKGROUND: Cancer-associated fibroblasts (CAF) play a critical role in promoting tumor growth, metastasis, and immune evasion. While numerous studies have investigated CAF, there remains a paucity of research on their clinical application in colorectal cancer (CRC). METHODS: In this study, we collected differentially expressed genes between CAF and normal fibroblasts (NF) from previous CRC studies, and utilized machine learning analysis to differentiate two distinct subtypes of CAF in CRC. To enable practical application, a CAF-related genes (CAFGs) scoring system was developed based on multivariate Cox regression. We then conducted functional enrichment analysis, Kaplan-Meier plot, consensus molecular subtypes (CMS) classification, and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to investigate the relationship between the CAFGs scoring system and various biological mechanisms, prognostic value, tumor microenvironment, and response to immune checkpoint blockade (ICB) therapy. Moreover, single-cell transcriptomics and proteomics analyses have been employed to validate the significance of scoring system-related molecules in the identity and function of CAF. RESULTS: We unveiled significant distinctions in tumor immune status and prognosis not only between the CAF clusters, but also across high and low CAFGs groups. Specifically, patients in CAF cluster 2 or with high CAFGs scores exhibited higher CAF markers and were enriched for CAF-related biological pathways such as epithelial-mesenchymal transition (EMT) and angiogenesis. In addition, CAFGs score was identified as a risk index and correlated with poor overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and recurrence-free survival (RFS). High CAFGs scores were observed in patients with advanced stages, CMS4, as well as lymphatic invasion. Furthermore, elevated CAFG scores in patients signified a suppressive tumor microenvironment characterized by the upregulation of programmed death-ligand 1 (PD-L1), T-cell dysfunction, exclusion, and TIDE score. And high CAFGs scores can differentiate patients with lower response rates and poor prognosis under ICB therapy. Notably, single-cell transcriptomics and proteomics analyses identified several molecules related to CAF identity and function, such as FSTL1, IGFBP7, and FBN1. CONCLUSION: We constructed a robust CAFGs score system with clinical significance using multiple CRC cohorts. In addition, we identified several molecules related to CAF identity and function that could be potential intervention targets for CRC patients.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Proteínas Relacionadas à Folistatina , Humanos , Multiômica , Fibroblastos , Algoritmos , Neoplasias Colorretais/genética , Microambiente Tumoral/genética , Prognóstico
14.
J Affect Disord ; 354: 627-633, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38522815

RESUMO

BACKGROUND: Elevated Depressive symptoms (DS) and low back pain (LBP) pose significant and growing public health challenges, and China is no exception. This study innovatively examined the relationship between specific DS and distinct patterns of DS and incident LBP. METHODS: This study extracted data from 4713 participants aged 45+ years from the China and Health Retirement Longitudinal Study (CHARLS), followed-up for incidence LBP (June 2011-September 2020). DS was assessed by the 10-item Center for Epidemiological Studies Depression Scale (CESD-10). The incident LBP was determined by self-reported. Latent class analysis (LCA) was employed to categorize patterns of DS. Cox proportional hazards regression models were used to examine the association between DS and incident LBP. RESULTS: Over the 9.25-year follow-up period, 2234 incident LBP cases were identified. There was a significant independent association between positive DS and incident LBP with an HR of 1.73 (95 % CI = 1.55-1.94). Of the 10-item DS, difficulty concentrating (adjusted HR = 1.16, 95 % CI = 1.03-1.31), effortfulness (adjusted HR = 1.32, 95 % CI = 1.18-1.49), hopelessness (adjusted HR = 1.13, 95 % CI = 1.02-1.25), restless sleep (adjusted HR = 1.17, 95 % CI = 1.06-1.30), and loneliness (adjusted HR = 1.18, 95 % CI = 1.02-1.36), each independently associated with incident LBP. Regarding patterns of DS, compared to the "healthy" pattern of DS, four patterns showed significant association with incident LBP, especially the cumulative pattern of DS. LIMITATIONS: DS and LBP were assessed based on self-reported. CONCLUSIONS: In middle-aged and older Chinese adults, 5 specific DS (difficulty concentrating, effortfulness, hopelessness, restless sleep, and loneliness) and distinct patterns of DS indicate varied risks of developing LBP.


Assuntos
Depressão , Dor Lombar , Adulto , Pessoa de Meia-Idade , Humanos , Idoso , Depressão/epidemiologia , Depressão/complicações , Estudos Longitudinais , Incidência , Dor Lombar/epidemiologia , China/epidemiologia
15.
Physiol Behav ; 279: 114523, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38492912

RESUMO

Melatonin is a neurohormone synthesized by the pineal gland to regulate the circadian rhythms and has proven to be effective in treating drug addiction and dependence. However, the effects of melatonin to modulate the drug-seeking behavior of fentanyl and its underlying molecular mechanism is elusive. This study was designed to investigate the effects of melatonin on fentanyl - induced behavioral sensitization and circadian rhythm disorders in mice. The accompanying changes in the expression of Brain and Muscle Arnt-Like (BMAL1), tyrosine hydroxylase (TH), and monoamine oxidase A (MAO-A) in relevant brain regions including the suprachiasmatic nucleus (SCN), nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus (Hip) were investigated by western blot assays to dissect the mechanism by which melatonin modulates fentanyl - induced behavioral sensitization and circadian rhythm disorders. The present study suggest that fentanyl (0.05, 0.1 and 0.2 mg/kg) could induce behavioral sensitization and melatonin (30.0 mg/kg) could attenuate the behavioral sensitization and circadian rhythm disorders in mice. Fentanyl treatment reduced the expression of BMAL1 and MAO-A and increased that of TH in relevant brain regions. Furthermore, melatonin treatment could reverse the expression levels of BMAL1, MAO-A, and TH. In conclusion, our study demonstrate for the first time that melatonin has therapeutic potential for fentanyl addiction.

16.
Transl Vis Sci Technol ; 13(3): 24, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38546981

RESUMO

Purpose: To investigate the potential effects and mechanism of nicotinamide riboside (NR) on the oxidative stress and fibrosis model of human trabecular meshwork (HTM) cell line cells. Methods: HTM cells were pretreated with NR, followed by the induction of oxidative injury and fibrosis by hydrogen peroxide (H2O2) and TGF-ß2, respectively. Cell viability was tested using Hoechst staining and MTT assays, cell proliferation was assessed by EdU assay, and cell apoptosis was detected by flow cytometry and western blotting. DCFH-DA and DHE probes were used to measure the level of reactive oxygen species (ROS), and MitoTracker staining was used to measure the mitochondrial membrane potential (MMP). Fibrotic responses, including cell migration and deposition of extracellular matrix (ECM) proteins, were detected via Transwell assays, qRT-PCR, and immunoblotting. Results: NR pretreatment improved the viability, proliferation, and MMP of H2O2-treated HTM cells. Compared to cells treated solely with H2O2, HTM cells treated with both NR and H2O2, exhibited a reduced rate of apoptosis and generation of ROS. Compared with H2O2 pretreatment, NR pretreatment upregulated expression of the JAK2/Stat3 pathway but inhibited mitogen-activated protein kinase (MAPK) pathway expression. Moreover, 10-ng/mL TGF-ß2 promoted cell proliferation and migration, which were inhibited by NR pretreatment. Both qRT-PCR and immunoblotting showed that NR inhibited the expression of fibronectin in a TGF-ß2-induced fibrosis model. Conclusions: NR has a protective effect on oxidative stress and fibrosis in HTM cells, which may be related to the JAK2/Stat3 pathway and MAPK pathway. Translational Relevance: Our research provides the ongoing data for potential therapy of NAD+ precursors in glaucoma.


Assuntos
Niacinamida/análogos & derivados , Compostos de Piridínio , Malha Trabecular , Fator de Crescimento Transformador beta2 , Humanos , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/farmacologia , Malha Trabecular/metabolismo , Malha Trabecular/patologia , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/fisiologia , Fibrose
17.
Artigo em Inglês | MEDLINE | ID: mdl-38462073

RESUMO

BACKGROUND: . Nocardia gipuzkoensis was first described as a novel and distinct species in 2020 by Imen Nouioui and pulmonary nocardiosis associated with Nocardia gipuzkoensis was once reported in two bronchiectasis patients. Noteworthy, both reported Nocardia gipuzkoensis cases showed sensitivity to Trimethoprim/Sulfamethoxazol (TMP-SMZ), which are usually recommended for empirical therapy. METHODS: We reported the third case of Nocardia gipuzkoensis infection in a 16-year-old girl with chief complaints of cough, persistent chest and back pain. No underlying immuno-suppressive conditions and glucocorticoid use was revealed. Patchy lesions next to spine and located in the posterior basal segment of lower lobes of left lung were seen in thorax computed tomography (CT), but no pathogenic bacteria was detected according to routine laboratory testings. RESULTS: Metagenomic next-generation sequencing (mNGS) combined with Whole Genome Sequencing (WGS) was used to classified our isolate from bronchoalveolar lavage fluid (BALF) as a Nocardia gipuzkoensis. It is worth mentioning that drug susceptibility testing of our isolate showed resistance to TMP-SMZ, which was never reported before. The patient improved remarkably both clinically and radiographically according to the treatment with Imipenem-cilastatin infusion alone. CONCLUSION: mNGS and WGS showed excellent performance in identifying Nocardia genus to the species level and improving detection rate of Nocardia gipuzkoensis ignored by traditional culture. Different from previously reported cases, Nocardia gipuzkoensis infection case showed resistance to TMP-SMZ, which is an unprecedented finding and a crucial addition to our understanding of the antibacterial spectrum of Nocardia gipuzkoensis. The successful treatment with Imipenem-cilastatin infusion alone in this case is a testament to the importance of precise identification and tailored antibiotic therapy.

18.
Brain Stimul ; 17(2): 245-257, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38428583

RESUMO

Temporal interference (TI) electric field brain stimulation is a novel neuromodulation technique that enables the non-invasive modulation of deep brain regions, but few advances about TI stimulation effectiveness and mechanisms have been reported. Conventional transcranial alternating current stimulation (tACS) can enhance motor skills, whether TI stimulation has an effect on motor skills in mice has not been elucidated. In the present study, TI stimulation was proved to stimulating noninvasively primary motor cortex (M1) of mice, and that TI stimulation with an envelope wave frequency of 20 Hz (Δ f = 20 Hz) once a day for 20 min for 7 consecutive days significantly improved the motor skills of mice. The mechanism of action may be related to regulating of neurotransmitter metabolism, increasing the expression of synapse-related proteins, promoting neurotransmitter release, increasing dendritic spine density, enhancing the number of synaptic vesicles and the thickness of postsynaptic dense material, and ultimately enhance neuronal excitability and plasticity. It is the first report about TI stimulation promoting motor skills of mice and describing its mechanisms.

19.
Medicine (Baltimore) ; 103(9): e37326, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38428856

RESUMO

BACKGROUND: Hashimoto thyroiditis (HT) is a common autoimmune thyroid disease for which there is no specific treatment. Oral levothyroxine sodium tablets significantly improved thyroid function but did not promote a reduction in thyroid-related antibody concentrations. Acupuncture can improve clinical symptoms and thyroid function in HT patients, reduce serum TPOAb and TGAb levels in HT patients, and improve patients' quality of life. METHODS: We conducted a systematic review and meta-analysis to evaluate the effect of acupuncture versus levothyroxine sodium tablets on Hashimoto thyroiditis. We searched Web of Science, Embase, China National Knowledge Infrastructure, WanFang, VIP, SinoMed and the Cochrane Central Registry of Controlled Trials to identify candidate randomized controlled trials (RCTs). RESULTS: A total of 1020 patients participated in 14 randomized controlled trials. The results of meta-analysis showed that acupuncture regulated TPOAb content (mean difference [MD] = -63.18, 95%CI = -91.73 to -34.62, P < .00001), TGAb content (MD = -68.56, 95%CI = -101.55 to -35.57, P < .00001), serum free triiodothyronine (FT3) content (MD = 0.74, 95%CI = 0.20 to 1.27, P < .00001), serum free thyroxine (FT4) content (MD = 1.10, 95%CI = 0.29 to 1.92, P < .00001), TSH content (MD = -2.16, 95%CI = -3.14 to -1.19, P < .00001) had a significant effect. CONCLUSION: Compared with levothyroxine sodium tablets alone, acupuncture can significantly regulate the contents of TPOAb, TGAb, FT3, FT4 and TSH.


Assuntos
Terapia por Acupuntura , Doença de Hashimoto , Humanos , Doença de Hashimoto/tratamento farmacológico , Tiroxina/uso terapêutico , Hormônios Tireóideos , Tireotropina
20.
Eur J Med Res ; 29(1): 149, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429764

RESUMO

BACKGROUND: As a traditional Mongolian medicine, Zhenzhu Tongluo pills has played a good neuroprotective function in clinic. However, the key mechanisms by which it works are poorly studied. OBJECTIVES: To study the effect and mechanism of Zhenzhu Tongluo pills in treating diabetic peripheral neuropathy injury. METHODS: Diabetic peripheral neuropathy model was established by injecting STZ into rats. Physiological, behavioral, morphological and functional analyses were used to evaluate that the overall therapeutic effect of rats, ELISA, qRT-PCR, Western blot, immunohistochemical staining, HE staining and TUNEL staining were used to further study the related mechanism. RESULTS: Zhenzhu Tongluo pills can significantly improve the physiological changes, behavioral abnormalities, structural and functional damage in diabetic peripheral neuropathy rats, which may be related to the anti-inflammatory and anti-apoptotic effects that realized by regulating PI3K/AKT, MAPK, NF-κB signaling pathways. CONCLUSIONS: Zhenzhu Tongluo pills has neuroprotective effect, and anti-inflammatory and anti-apoptosis may be the important way of its function.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Medicamentos de Ervas Chinesas , Ratos , Animais , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Fosfatidilinositol 3-Quinases , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , NF-kappa B/metabolismo , Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus/tratamento farmacológico
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