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1.
Nature ; 630(8016): 484-492, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38811729

RESUMO

The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.


Assuntos
Bactérias , Bacteriófagos , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Bactérias/virologia , Bactérias/genética , Bactérias/imunologia , Bacteriófagos/genética , Bacteriófagos/imunologia , Chryseobacterium/genética , Chryseobacterium/imunologia , Chryseobacterium/virologia , Proteína 9 Associada à CRISPR/química , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/imunologia , Clivagem do DNA , Loci Gênicos/genética , Modelos Moleculares , Domínios Proteicos
2.
Proc Natl Acad Sci U S A ; 121(11): e2312136121, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38446848

RESUMO

Anxiety is a remarkably common condition among patients with pharyngitis, but the relationship between these disorders has received little research attention, and the underlying neural mechanisms remain unknown. Here, we show that the densely innervated pharynx transmits signals induced by pharyngeal inflammation to glossopharyngeal and vagal sensory neurons of the nodose/jugular/petrosal (NJP) superganglia in mice. Specifically, the NJP superganglia project to norepinephrinergic neurons in the nucleus of the solitary tract (NTSNE). These NTSNE neurons project to the ventral bed nucleus of the stria terminalis (vBNST) that induces anxiety-like behaviors in a murine model of pharyngeal inflammation. Inhibiting this pharynx→NJP→NTSNE→vBNST circuit can alleviate anxiety-like behaviors associated with pharyngeal inflammation. This study thus defines a pharynx-to-brain axis that mechanistically links pharyngeal inflammation and emotional response.


Assuntos
Faringite , Faringe , Humanos , Animais , Camundongos , Ansiedade , Encéfalo , Células Receptoras Sensoriais , Inflamação
3.
Proc Natl Acad Sci U S A ; 121(22): e2402764121, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38771879

RESUMO

Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.


Assuntos
Proteínas de Bactérias , Macrófagos , Proteínas de Membrana , Infecções Estafilocócicas , Staphylococcus aureus , Sistemas de Secreção Tipo VII , Ubiquitinação , Staphylococcus aureus/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/imunologia , Humanos , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Animais , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/metabolismo , Sistemas de Secreção Tipo VII/metabolismo , Sistemas de Secreção Tipo VII/imunologia , Sistemas de Secreção Tipo VII/genética , Camundongos , Evasão da Resposta Imune , Interações Hospedeiro-Patógeno/imunologia
4.
Int J Cancer ; 155(8): 1400-1408, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-38822730

RESUMO

Nasopharyngeal carcinoma (NPC) risk prediction models based on Epstein-Barr virus (EBV)-antibody testing have shown potential for screening of NPC; however, the long-term stability is unclear. Here, we investigated the kinetics of two EBV-antibody NPC risk scores within the Taiwan NPC Multiplex Family Study. Among 545 participants with multiple blood samples, we evaluated the stability of a 2-marker enzyme-linked immunosorbent assay score and 13-marker multiplex serology score using the intra-class correlation coefficient (ICC) by fitting a linear mixed model that accounted for the clustering effect of multiple measurements per subject and age. We also estimated the clustering of positive tests using Fleiss's kappa statistic. Over an average 20-year follow-up, the 2-marker score showed high stability over time, whereas the 13-marker score was more variable (p < .05). Case-control status is associated with the kinetics of the antibody response, with higher ICCs among cases. Positive tests were more likely to cluster within the same individual for the 2-marker score than the 13-marker score (p < .05). The 2-marker score had an increase in specificity from ~90% for single measurement to ~96% with repeat testing. The 13-marker score had a specificity of ~73% for a single measurement that increased to ~92% with repeat testing. Among individuals who developed NPC, none experienced score reversion. Our findings suggest that repeated testing could improve the specificity of NPC screening in high-risk NPC multiplex families. Further studies are required to determine the impact on sensitivity, establish optimal screening intervals, and generalize these findings to general population settings in high-risk regions.


Assuntos
Anticorpos Antivirais , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Taiwan/epidemiologia , Herpesvirus Humano 4/imunologia , Anticorpos Antivirais/sangue , Masculino , Feminino , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/virologia , Adulto , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/virologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/epidemiologia , Carcinoma Nasofaríngeo/virologia , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/epidemiologia , Cinética , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Adulto Jovem , Fatores de Risco , Idoso
5.
Kidney Int ; 105(3): 562-581, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38142040

RESUMO

The parathyroid gland is one of the main organs that regulate calcium and phosphorus metabolism. It is mainly composed of chief cells and oxyphil cells. Oxyphil cell counts are low in the parathyroid glands of healthy adults but are dramatically increased in patients with uremia and secondary hyperparathyroidism (SHPT). Increased oxyphil cell counts are related to drug treatment resistance, but the origin of oxyphil cells and the mechanism of proliferation remain unknown. Herein, three types of parathyroid nodules (chief cell nodules, oxyphil cell nodules and mixed nodules, respectively) excised from parathyroid glands of uremic SHPT patients were used for single-cell RNA sequencing (scRNA-seq), other molecular biology studies, and transplantation into nude mice. Through scRNA-seq of parathyroid mixed nodules from three patients with uremic SHPT, we established the first transcriptomic map of the human parathyroid and found a chief-to-oxyphil cell transdifferentiation characterized by gradual mitochondrial enrichment associated with the uremic milieu. Notably, the mitochondrial enrichment and cellular proliferation of chief cell and oxyphil cell nodules decreased significantly after leaving the uremic milieu via transplantation into nude mice. Remarkably, the phenotype of oxyphil cell nodules improved significantly in the nude mice as characterized by decreased mitochondrial content and the proportion of oxyphil cells to chief cells. Thus, our study provides a comprehensive single-cell transcriptome atlas of the human parathyroid and elucidates the origin of parathyroid oxyphil cells and their underlying transdifferentiating mechanism. These findings enhance our understanding of parathyroid disease and may open new treatment perspectives for patients with chronic kidney disease.


Assuntos
Hiperparatireoidismo Secundário , Glândulas Paratireoides , Adulto , Animais , Camundongos , Humanos , Glândulas Paratireoides/metabolismo , Células Oxífilas , Camundongos Nus , Transdiferenciação Celular , Hiperparatireoidismo Secundário/genética , Hiperparatireoidismo Secundário/terapia , Análise de Sequência de RNA
6.
Mol Carcinog ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39150155

RESUMO

Proliferation is a critical characteristic of the progression of gastric cancer (GC). Receptor tyrosine kinase-like orphan receptor 2 (ROR2), the orphan receptor tyrosine kinase-like receptor, exhibits effects on tumor growth due to its abnormal expression in cancer. The goal of our study was to assess the potential regulatory role exerted by the ROR2 on GC cells. Through previous bioinformatics analysis, we discovered an association between ROR2 and the G2/M phase of the GC cell cycle. However, little is known about the link between ROR2 and the G2/M phase cell cycle in GC. Here, the findings of our study indicate that ROR2, after transcribed expression by Twist1, activates the PI3K/AKT/mTOR/S6K signal transduction pathway, thus leading to the acceleration of the G2/M phase and subsequent promotion of cell proliferation in GC. Furthermore, the functional link among ROR2, Twist1, and G2/M phase of cell cycle was also confirmed in mouse xenograft tissues and human tissues. ROR2 expression was correlated with Twist expression and lower survival in vivo. Notably, our suggestion is that focusing on ROR2 as a potential therapeutic approach could show potential for the management of GC.

7.
J Transl Med ; 22(1): 345, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600566

RESUMO

BACKGROUND: Hearing loss has been shown to be a risk factor for psychiatric disorders. In addition, long-term hearing loss is associated with increased hospitalization and mortality rates; however, the increased risk and duration of effect of hearing loss in combination with other chronic diseases on each psychiatric disorder are still not clearly defined. The purpose of this article is to clarify the risk of hearing loss for each disorder over time. METHODS: This was a retrospective cohort study, and a national health insurance research database in Taiwan was utilized. All (n = 1,949,101) Taiwanese residents who had a medical visit between 2000 and 2015 were included. Patients with hearing loss and a comparative retrospective cohort were analyzed. Every subject was tracked individually from their index date to identify the subjects who later received a diagnosis of a psychiatric disorder. The Kaplan‒Meier method was used to analyze the cumulative incidence of psychiatric disorders. Cox regression analysis was performed to identify the risk of psychiatric disorders. RESULTS: A total of 13,341 (15.42%) and 31,250 (9.03%) patients with and without hearing loss, respectively, were diagnosed with psychiatric disorders (P < 0.001). Multivariate analysis indicated that hearing loss significantly elevated the risk of psychiatric disorders (adjusted HR = 2.587, 95% CI 1.723-3.346, p < 0.001). CONCLUSION: Our findings indicate that patients with hearing loss are more likely to develop psychiatric disorders. Furthermore, the various psychiatric disorders are more likely to occur at different times. Our findings have important clinical implications, including a need for clinicians to implement early intervention for hearing loss and to pay close attention to patients' psychological status. Trial registration TSGHIRB No. E202216036.


Assuntos
Perda Auditiva , Transtornos Mentais , Humanos , Estudos de Coortes , Perda Auditiva/complicações , Perda Auditiva/epidemiologia , Incidência , Transtornos Mentais/complicações , Transtornos Mentais/epidemiologia , Fatores de Risco , Taiwan/epidemiologia
8.
Ann Surg Oncol ; 2024 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-39154160

RESUMO

BACKGROUND: Human papillomavirus (HPV) is a crucial prognostic factor in oropharyngeal cancer (OPC). p16 is a surrogate marker for diagnosing HPV+ OPC, however it is not direct evidence of HPV existence. OBJECTIVE: The purpose of our study was to evaluate an HPV DNA test-Cobas HPV assay-in diagnosing HPV+ OPC through neck lymph node aspiration. METHODS: Patients with suspected neck mass who received fine needle aspiration (FNA) or core needle biopsy (CNB) at the National Taiwan University Hospital between January 2018 and December 2022 were reviewed. Besides routine cytology and pathology study, needle rinse fluid was collected for the Cobas HPV assay to detect high-risk HPV. RESULTS: We analyzed 137 patients with suspected lymph nodes, 32 (23.4%) of whom were HPV+ OPC patients and 105 (76.6%) of whom had non-HPV-related disease. FNA was performed in 31 patients and CNB was performed in 106 patients, according to the size and necrosis status of the lymph nodes. For diagnosing HPV+ OPC, CNB combined with p16 immunohistochemistry staining showed sensitivity of 93.3%, specificity of 97.8%, positive predictive value (PPV) of 87.5%, negative predictive value (NPV) of 98.9%, and accuracy of 97.2%. On the other hand, for the needle rinse Roche Cobas HPV assay, the test showed sensitivity of 96.9%, specificity of 100%, PPV of 100%, NPV of 99.1%, and accuracy of 99.3%. Compared with p16 IHC staining, the Cobas HPV test showed better PPV with statistical significance (p = 0.04). CONCLUSION: The Cobas HPV assay is a US FDA-approved, highly automated, and readily used technique to directly detect the presence of high-risk HPV. We recommend utilizing the Cobas HPV assay in combination with routine cytology or histopathology examination in the work-up of neck lymphadenopathy.

9.
Opt Lett ; 49(4): 862-865, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38359201

RESUMO

A diode-pumped wavelength switchable passively Q-switched 2.3 µm Tm:YVO4 laser was demonstrated in this work. A Cr:ZnS saturable absorber was introduced into the cavity for initiating passive Q-switching. With the increase of the absorbed pump power, the passively Q-switched laser could be switched from the single wavelength of 2366 nm to the dual wavelength of 2290 and 2360 nm. The pulse duration and pulse repetition frequency could be tuned in the ranges of 0.745-1.782 µs and 2.9-43.4 kHz, respectively. The pulse energy and peak power were estimated to be 7.5 µJ and 10 W, respectively, at an absorbed pump power of 12 W.

10.
J Org Chem ; 89(3): 1633-1647, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38235569

RESUMO

A metal-free and atom-economic route for the synthesis of naphtho[1,2-b]furan-3-ones has been realized via p-TsOH·H2O-catalyzed intramolecular tandem double cyclization of γ-hydroxy acetylenic ketones with alkynes in formic acid. The benzene-linked furanonyl-ynes are the key intermediates obtained by the scission/recombination of C-O double bonds. Further, the structural modifications of the representative product were implemented by reduction, demethylation, substitution, and [5 + 2]-cycloaddition.

11.
Phys Chem Chem Phys ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158723

RESUMO

Although Mo2C and earth-abundant 3d transition metals are regarded as potential catalysts to replace noble metal catalysts for effective hydrogen evolution reaction, their large-scale application is still inhibited by their own defects. Here, a facile thermal treatment method for nonprecious metal catalysts is developed to prepare a porous Ni/Mo2C composite catalyst. The loading density of Ni nanoparticles on the Mo2C surface has an important effect on the activity of the catalyst. By optimizing the Ni doping ratio, the Ni-40/Mo2C-17 sample exhibits the lowest onset overpotential and lowest overpotential at 10 mA cm-2 in both acidic and alkaline electrolytes, compared to other reported Ni- and Mo2C-based catalysts. In addition, theoretical calculations have also confirmed the synergistic effect between Ni nanoparticles and Mo2C, which can balance the thermodynamics between H adsorption and desorption of H2. This work provides an avenue for designing high-performance water-splitting catalytic materials using low-cost species, which exhibit excellent HER activity in a wide pH range.

12.
Surg Endosc ; 38(4): 2106-2115, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38438672

RESUMO

BACKGROUND: This study aimed to compare postoperative complications in patients with esophagogastric variceal bleeding (EVB) who underwent laparoscopic splenectomy combined with pericardial devascularization (LSPD) versus transjugular intrahepatic portosystemic shunt (TIPS) procedures. METHODS: A retrospective collection of medical records was conducted from January 2014 to May 2020 at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The study included patients from the departments of trauma surgery, interventional radiology, and general surgery who were diagnosed with EVB caused by portal hypertension and treated with LSPD or TIPS. Follow-up data were obtained to assess the occurrence of postoperative complications in both groups. RESULTS: A total of 201 patients were included in the study, with 104 cases in the LSPD group and 97 cases in the TIPS group. There was no significant difference in the 1-year and 3-year post-surgery survival rates between the TIPS and LSPD groups (P = 0.669, 0.066). The 3-year survival rate of Child-Pugh B patients in the LSPD group was higher than TIPS group (P = 0.041). The LSPD group also had a significantly higher rate of freedom from rebleeding at 3-year post-surgery compared to the TIPS group (P = 0.038). Stratified analysis showed no statistically significant difference in the rebleeding rate between the two groups. Furthermore, the LSPD group had a higher rate of freedom from overt hepatic encephalopathy at 1-year and 3-year post-surgery compared to the TIPS group (P = 0.007, < 0.001). The LSPD group also had a lower rate of severe complications at 3-year post-surgery compared to the TIPS group (P = 0.020). CONCLUSION: Compared to TIPS, LSPD does not increase the risk of mortality and rebleeding, while demonstrating fewer complications. In patients classified as Child-Pugh A and B, the use of LSPD for treating EVB is both safe and effective.


Assuntos
Varizes Esofágicas e Gástricas , Laparoscopia , Derivação Portossistêmica Transjugular Intra-Hepática , Humanos , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Esplenectomia/efeitos adversos , Estudos Retrospectivos , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Cirrose Hepática/cirurgia , Laparoscopia/efeitos adversos , Prognóstico , Resultado do Tratamento , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia
13.
Am J Otolaryngol ; 45(5): 104420, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39067090

RESUMO

BACKGROUND: Head and neck surgical simulation training (SST) is an important part in otolaryngology head and neck surgical education. In this study, we provide a live porcine model for SST in recurrent laryngeal nerve (RLN) and facial nerve (FN) dissection for otolaryngology head and neck residents. METHODS: A lecture with surgical manual is provided to illustrate the surgical landmarks of pig, and step-by-step procedures for thyroid and parotid surgery, as well as neck dissection. We used 4-month-old pig weighting 32 kg for the SST. The mentor demonstrated result of RLN injury with continuous nerve monitoring. Participants used monopolar stimulation probe (4 pulse/s, 100 µs, 3-8 mA; Medtronic) to identify and intermittent monitor the RLN and FN during the SST. After the dissection course, we conducted a questionnaire survey to check the effectiveness of this training model. RESULTS: Total 30 participants were recruited, including 16 female and 14 male resident doctors. There were 1, 4 and 25 learners for 3rd year, 4th and 5th years residents, respectively. Before this training course, 53 % (16/30) and 63 % (19/30) had successful experience in finding the RLN and FN, respectively. After the SST, all of our participants had successful identify the RLN and FN (p-value <0.01); all had positive response to stimulation and familiar with the procedure. CONCLUSIONS: The live porcine model is effectiveness in SST for RLN and FN dissection. Live porcine model with real-time RLN and FN monitoring should be provided for otolaryngology head and neck resident training.


Assuntos
Nervo Facial , Internato e Residência , Otolaringologia , Nervo Laríngeo Recorrente , Treinamento por Simulação , Animais , Suínos , Treinamento por Simulação/métodos , Otolaringologia/educação , Internato e Residência/métodos , Nervo Facial/cirurgia , Feminino , Humanos , Masculino , Nervo Laríngeo Recorrente/cirurgia , Dissecação/educação , Modelos Animais , Competência Clínica , Traumatismos do Nervo Laríngeo Recorrente/prevenção & controle , Esvaziamento Cervical/educação
14.
Int J Mol Sci ; 25(10)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38791192

RESUMO

The synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) are the most vulnerable structures in the noise-exposed cochlea. Cochlear synaptopathy results from the disruption of these synapses following noise exposure and is considered the main cause of poor speech understanding in noisy environments, even when audiogram results are normal. Cochlear synaptopathy leads to the degeneration of SGNs if damaged IHC-SGN synapses are not promptly recovered. Oxidative stress plays a central role in the pathogenesis of cochlear synaptopathy. C-Phycocyanin (C-PC) has antioxidant and anti-inflammatory activities and is widely utilized in the food and drug industry. However, the effect of the C-PC on noise-induced cochlear damage is unknown. We first investigated the therapeutic effect of C-PC on noise-induced cochlear synaptopathy. In vitro experiments revealed that C-PC reduced the H2O2-induced generation of reactive oxygen species in HEI-OC1 auditory cells. H2O2-induced cytotoxicity in HEI-OC1 cells was reduced with C-PC treatment. After white noise exposure for 3 h at a sound pressure of 118 dB, the guinea pigs intratympanically administered 5 µg/mL C-PC exhibited greater wave I amplitudes in the auditory brainstem response, more IHC synaptic ribbons and more IHC-SGN synapses according to microscopic analysis than the saline-treated guinea pigs. Furthermore, the group treated with C-PC had less intense 4-hydroxynonenal and intercellular adhesion molecule-1 staining in the cochlea compared with the saline group. Our results suggest that C-PC improves cochlear synaptopathy by inhibiting noise-induced oxidative stress and the inflammatory response in the cochlea.


Assuntos
Cóclea , Molécula 1 de Adesão Intercelular , Ruído , Estresse Oxidativo , Ficocianina , Sinapses , Animais , Estresse Oxidativo/efeitos dos fármacos , Cobaias , Ficocianina/farmacologia , Ficocianina/uso terapêutico , Cóclea/metabolismo , Cóclea/efeitos dos fármacos , Cóclea/patologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Ruído/efeitos adversos , Molécula 1 de Adesão Intercelular/metabolismo , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Perda Auditiva Provocada por Ruído/metabolismo , Perda Auditiva Provocada por Ruído/patologia , Espécies Reativas de Oxigênio/metabolismo , Masculino , Gânglio Espiral da Cóclea/efeitos dos fármacos , Gânglio Espiral da Cóclea/metabolismo , Gânglio Espiral da Cóclea/patologia , Peróxido de Hidrogênio/metabolismo , Células Ciliadas Auditivas Internas/efeitos dos fármacos , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patologia , Antioxidantes/farmacologia , Linhagem Celular , Perda Auditiva Oculta
15.
Int J Mol Sci ; 25(13)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-39000202

RESUMO

The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) protein plays an essential role in the cisplatin (CDDP)-induced generation of reactive oxygen species (ROS). In this study, we evaluated the suitability of ultrasound-mediated lysozyme microbubble (USMB) cavitation to enhance NOX4 siRNA transfection in vitro and ex vivo. Lysozyme-shelled microbubbles (LyzMBs) were constructed and designed for siNOX4 loading as siNOX4/LyzMBs. We investigated different siNOX4-based cell transfection approaches, including naked siNOX4, LyzMB-mixed siNOX4, and siNOX4-loaded LyzMBs, and compared their silencing effects in CDDP-treated HEI-OC1 cells and mouse organ of Corti explants. Transfection efficiencies were evaluated by quantifying the cellular uptake of cyanine 3 (Cy3) fluorescein-labeled siRNA. In vitro experiments showed that the high transfection efficacy (48.18%) of siNOX4 to HEI-OC1 cells mediated by US and siNOX4-loaded LyzMBs significantly inhibited CDDP-induced ROS generation to almost the basal level. The ex vivo CDDP-treated organ of Corti explants of mice showed an even more robust silencing effect of the NOX4 gene in the siNOX4/LyzMB groups treated with US sonication than without US sonication, with a marked abolition of CDDP-induced ROS generation and cytotoxicity. Loading of siNOX4 on LyzMBs can stabilize siNOX4 and prevent its degradation, thereby enhancing the transfection and silencing effects when combined with US sonication. This USMB-derived therapy modality for alleviating CDDP-induced ototoxicity may be suitable for future clinical applications.


Assuntos
Cisplatino , Células Ciliadas Auditivas , Microbolhas , Muramidase , NADPH Oxidase 4 , Ototoxicidade , Espécies Reativas de Oxigênio , Cisplatino/farmacologia , Animais , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Camundongos , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ototoxicidade/genética , Muramidase/genética , RNA Interferente Pequeno/genética , Ondas Ultrassônicas , Técnicas de Silenciamento de Genes , Linhagem Celular
16.
Zhonghua Nan Ke Xue ; 29(5): 450-454, 2023 May.
Artigo em Zh | MEDLINE | ID: mdl-38602764

RESUMO

Male infertility is one of the serious problems currently affecting human reproduction and health. Healthy gut microbiota is involved in the development of the immune system and protection against pathogen invasion, and it maintain normal metabolism and improve reproductive potential by secreting a variety of substances. The imbalance of gut microbiota can promote the local and systemic immune inflammatory response, induce chronic metabolic diseases, affect the synthesis of sex hormones, cause abnormal spermatogenesis, maturation or activation, and it is closely related to the decline of male fertility. By exploring the correlation between gut microbiota and male infertility, this paper aims to provide new clues and directions for the clinical diagnosis and treatment of male infertility.


Assuntos
Microbioma Gastrointestinal , Infertilidade Masculina , Humanos , Masculino , Transporte Biológico , Reprodução
17.
Transl Cancer Res ; 13(6): 3126-3141, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38988939

RESUMO

Background and Objective: This review aims to investigate the ferroptosis mechanism of fumarate hydratase (FH)-related tumors for the purpose of possible treatment of tumors. Ferroptosis is an iron (Fe)-dependent form of regulated cell death caused by lipid peroxidation on the cell membrane. Studies have implicated FH in tumorigenesis. As mutations in the FH gene alter cellular metabolism and increase tumorigenesis risk, particularly in the kidneys. As most tumor cells require higher amounts of ferrous ions (Fe2+) than normal cells, they are more susceptible to ferroptosis. Recent studies have indicated that ferroptosis is inhibited the pathogenesis and progression of FH-deficient tumors by regulating lipid and iron metabolism, glutathione-glutathione peroxidase 4 (GSH-GPX4), nuclear factor-erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathways. While the Fe2+ content is significantly lower in FH-deficient tumor cells, than that in normal cells. It is promising to promote ferroptosis by increasing the concentration of Fe2+ in cells to achieve the purpose of tumor treatment. Methods: In this study, we searched for relevant articles on ferroptosis and FH-deficient tumors using PubMed database. Key Content and Findings: FH is a tumor suppressor. A number of basic studies have shown that the loss of FH plays an important role in hereditary leiomyomas and tumors such as renal cell carcinoma, ovarian cancer, and other tumors. This type of tumor cells can through induce ferroptosis, inhibit proliferation, migration and invasion of tumor cells, increase the sensitivity of tumor cells to chemotherapy, and reverse the drug resistance through various molecular mechanisms. At present, the research on ferroptosis in FH-related tumors is still in the basic experimental stage. Conclusions: This article reviews the anti-tumor effects and mechanisms of FH and ferroptosis, in order to further explore the medical value of ferroptosis in FH-related tumor therapy.

18.
Curr Neuropharmacol ; 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38288836

RESUMO

Memory refers to the imprint accumulated in the brain by life experiences and represents the basis for humans to engage in advanced psychological activities such as thinking and imagination. Previously, research activities focused on memory have always targeted neurons. However, in addition to neurons, astrocytes are also involved in the encoding, consolidation, and extinction of memory. In particular, astrocytes are known to affect the recruitment and function of neurons at the level of local synapses and brain networks. Moreover, the involvement of astrocytes in memory and memory-related disorders, especially in Alzheimer's disease (AD) and post-traumatic stress disorder (PTSD), has been investigated extensively. In this review, we describe the unique contributions of astrocytes to synaptic plasticity and neuronal networks and discuss the role of astrocytes in different types of memory processing. In addition, we also explore the roles of astrocytes in the pathogenesis of memory-related disorders, such as AD, brain aging, PTSD and addiction, thus suggesting that targeting astrocytes may represent a potential strategy to treat memory-related neurological diseases. In conclusion, this review emphasizes that thinking from the perspective of astrocytes will provide new ideas for the diagnosis and therapy of memory-related neurological disorders.

19.
Environ Sci Pollut Res Int ; 31(15): 22847-22857, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38411908

RESUMO

Plastic aging can cause alterations in the physical and chemical characteristics of plastics, as well as their behavior in the environment. Due to the extremely slow natural aging process, laboratory simulated aging methods have to be used. In this study, non-thermal plasma (NTP) was adopted to investigate the aging process of polypropylene (PP) and polyethylene terephthalate (PET) microplastics. Various analytical instruments, including proton transfer reaction mass spectrometry and single-particle aerosol mass spectrometry, were employed to examine and identify the organic constituents of the gas, liquid, and particle phase degradation products, as well as to monitor the degradation process. The results showed that after 90 min of aging, both PP and PET surfaces showed yellowing, and the carbonyl index of PP increased while that of PET decreased, with an increase in crystallinity. The organic components of reaction products, such as ketones, esters, acids, and alcohols, increased with longer aging times. Gas products mainly contain aromatic hydrocarbons, while particles from aged PET contain compounds with benzene rings and metal elements. Liquid products from aged PP show a significant presence of branched alkanes. Based on this analysis, degradation mechanisms of PP and PET by NTP were proposed. This investigation represents the initial systematically exploration of the release of organic substances during the degradation of microplastics mediated by NTP. It provides significant insights into the detrimental organic compounds emitted during this process, thereby offering valuable information for understanding the environmental and human health implications of natural microplastic degradation. Furthermore, it addressed the requirements for increased attention to the potential environmental risks associated with these harmful components.


Assuntos
Polipropilenos , Poluentes Químicos da Água , Humanos , Idoso , Polipropilenos/química , Plásticos/análise , Microplásticos , Poluentes Químicos da Água/análise , Envelhecimento , Polietilenotereftalatos , Monitoramento Ambiental/métodos
20.
Anal Chim Acta ; 1304: 342531, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38637047

RESUMO

BACKGROUND: The global release of organic and heavy metal components into natural water bodies is a major concern for the environment and human health. The assessment of water quality relies on analyzing organic and heavy metal components qualitatively and quantitatively. Real-time identification of organic and metal components in water systems requires different analytical techniques due to varying measurement requirements. Thus, on-line detecting both organic compounds and heavy metals in ambient water systems simultaneously using a single instrumentation setup presents a significant challenge. RESULTS: In this study, an analytical technique of nebulization-assisted injection plasma ionization mass spectrometry (NI-PIMS) was developed. This novel method enables the simultaneous detection of heavy metals and organic compounds in water system with high sensitivity, which has been demonstrated by the limit of quantification (LOQ) values below 1.0 µg/L for the three sterols (Enrofloxacin, ciprofloxacin, and clenbuterol) and three heavy metals (Pb, Ba, and Cd). Moreover, the method was successfully applied to rapidly analyze real water samples from urban and rural areas in China. The analytical results are available in less than 0.5 min, and only a few microliters of sample are required for each analysis. SIGNIFICANCE AND NOVELTY: As far as we know, this is the first report of on-line simultaneous analysis of organic compounds and heavy metals in a water system using a single mass spectrometry instrument. Compared to traditional methods, NI-PIMS demonstrates higher efficiency, sensitivity, no or lower sample preparation, and less sample consumption. The advancement and widespread use of this technology are expected to enhance the effectiveness of mass spectrometers, broaden the applications, and play an important role in complex sample analysis in fields such as atmospheric science, environmental science, and earth science.

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