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The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.
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Understanding the distribution of halogenated organic compounds (HOCs) in marine sediments is essential for understanding the marine carbon and halogen cycling, and also important for assessing the ecosystem health. In this study, a method based on combustion-ion chromatography was developed for determination of the composition and abundance of HOCs in marine sediments. The method showed high accuracy, precision and reproducibility in determining the content of adsorbable organic halogens (AOX), including fluorine, chlorine and bromine (AOF, AOCl, AOBr) and the corresponding insoluble organic halogens (IOF, IOCl, IOBr, IOX), as well as total organic halogen contents (TOX). Application of the method in coastal and deep-sea sediments revealed high ratios of organic halogens in the organic carbon pool of marine sediments, suggesting that organic halogen compounds represent an important yet previously overlooked stock of carbon and energy in marine sediments. Both the TOX and the proportion of organohalogens in organic carbon (X:C ratio) showed an increasing trend from the coast to the deep-sea sediments, indicating an increased significance of HOCs in deep-sea environments. The developed method and the findings of this study lay the foundation for further studies on biogeochemical cycling of HOCs in the ocean.
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Monitoreo del Ambiente , Sedimentos Geológicos , Contaminantes Químicos del Agua , Sedimentos Geológicos/química , Sedimentos Geológicos/análisis , Monitoreo del Ambiente/métodos , Contaminantes Químicos del Agua/análisis , Halógenos/análisis , Halógenos/química , Hidrocarburos Halogenados/análisis , Cromatografía/métodosRESUMEN
In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework.
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Neoplasias del Colon , Regulación Neoplásica de la Expresión Génica , Receptores Acoplados a Proteínas G , Humanos , Neoplasias del Colon/genética , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Pronóstico , Receptores Acoplados a Proteínas G/genética , Biomarcadores de Tumor/genética , Femenino , Aprendizaje Automático , Perfilación de la Expresión Génica , MasculinoRESUMEN
Vaginitis, characterized by pathogenic invasion and a deficiency in beneficial lactobacilli, has recognized lactobacilli supplementation as a novel therapeutic strategy. However, due to individual differences in vaginal microbiota, identifying universally effective Lactobacillus strains is challenging. Traditional methodologies for probiotic selection, which heavily depend on extensive in vitro experiments, are both time-intensive and laborious. The aim of this study was to pinpoint possible vaginal probiotic candidates based on whole-genome screening. We sequenced the genomes of 98 previously isolated Lactobacillus strains, annotating their genes involved in probiotic metabolite biosynthesis, adherence, acid/bile tolerance, and antibiotic resistance. A scoring system was used to assess the strains based on their genomic profiles. The highest-scoring strains underwent further in vitro evaluation. Consequently, two strains, Lactobacillus crispatus LG55-27 and Lactobacillus gasseri TM13-16, displayed an outstanding ability to produce d-lactate and adhere to human vaginal epithelial cells. They also showed higher antimicrobial activity against Gardnerella vaginalis, Escherichia coli, Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa compared to reference Lactobacillus strains. Their resilience to acid and bile environments highlights the potential for oral supplementation. Oral and vaginal administration of these two strains were tested in a bacterial vaginosis (BV) rat model at various doses. Results indicated that combined vaginal administration of these strains at 1 × 106 CFU/day significantly mitigated BV in rats. This research offers a probiotic dosage guideline for vaginitis therapy, underscoring an efficient screening process for probiotics using genome sequencing, in vitro testing, and in vivo BV model experimentation.
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Long term stability, high responsivity, and fast response speed are essential for the commercialization of graphene photodetectors (GPDs). In this work, a parylene/graphene UV photodetector with long term stability, ultrahigh responsivity and fast response speed, is demonstrated. Parylene as a stable physical and chemical insulating layer reduces the environmental sensitivity of graphene, and enhances the performances of GPDs. In addition, utilizing bilayer electrodes reduces the buckling and damage of graphene after transferring. The parylene/graphene UV photodetector exhibits an ultrahigh responsivity of 5.82 × 105AW-1under 325 nm light irradiation at 1 V bias. Additionally, it shows a fast response speed with a rise time of 80µs and a fall time of 17µs, and a long term stability at 405 nm wavelength which is absent in the device without parylene. The parylene/graphene UV photodetector possesses superior performances. This paves the way for the commercial application of the high-performance graphene hybrid photodetectors, and provides a practical method for maintaining the long term stability of two dimensional (2D) materials.
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BACKGROUND: Myocardial ischemia/reperfusion injury (MIRI) is an important complication of reperfusion therapy, and has a lack of effective prevention and treatment methods. Oleuropein (OP) is a natural strong antioxidant with many protective effects on cardiovascular diseases, but its protective effect on MIRI has not yet been studied in depth. METHODS: Tert-Butyl hydroperoxide (tBHP) was used to establish an in vitro oxidative stress model. Cell viability was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and lactate dehydrogenase (LDH). Flow cytometry and fluorescence assays were performed for evaluating the ROS levels and mitochondrial membrane potential (MMP). Immunofluorescence analysis detected the NRF2 nuclear translocation and autophagy indicators. Further, Western blotting and quantitative real-time PCR were performed to evaluate the expression levels of proteins and mRNAs. Molecular docking, CETSA, and molecular interaction analysis explored the binding between OP and TLR4. The protective effects of OP in vivo were determined using a preclinical MIRI rat model. RESULTS: OP protected against tBHP-treated injury, reduced ROS levels and reversed the damaged MMP. Mechanistically, OP activated NRF2-related antioxidant pathways, inhibited autophagy and attenuated the TLR4/MAPK signaling pathway in tBHP-treated H9C2 cells with a high binding affinity to TLR4 (KD = 37.5 µM). The TLR4 inhibitor TAK242 showed a similar effect as OP. In vivo, OP could alleviate cardiac ischemia/reperfusion injury and it ameliorated adverse cardiac remodeling. Consistent with in vitro studies, OP inhibited TLR4/MAPK and autophagy pathway and activated NRF2-dependent antioxidant pathways in vivo. CONCLUSION: This study shows that OP binds to TLR4 to regulate oxidative stress and autophagy for protecting damaged cardiomyocytes, supporting that OP can be a potential therapeutic agent for MIRI.
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Geminiviruses are an important group of viruses that infect a variety of plants and result in heavy agricultural losses worldwide. The homologs of C4 (or L4) in monopartite geminiviruses and AC4 (or AL4) in bipartite geminiviruses are critical viral proteins. The C4 proteins from several geminiviruses are the substrates of S-acylation, a dynamic post-translational modification, for the maintenance of their membrane localization and function in virus infection. Here we initiated a screening and identified a plant protein ABAPT3 (Alpha/Beta Hydrolase Domain-containing Protein 17-like Acyl Protein Thioesterase 3) as the de-S-acylation enzyme of C4 encoded by BSCTV (Beet severe curly top virus). Overexpression of ABAPT3 reduced the S-acylation of BSCTV C4, disrupted its plasma membrane localization, inhibited its function in pathogenesis, and suppressed BSCTV infection. Because the S-acylation motifs are conserved among C4 from different geminiviruses, we tested the effect of ABAPT3 on the C4 protein of ToLCGdV (Tomato leaf curl Guangdong virus) from another geminivirus genus. Consistently, ABAPT3 overexpression also disrupted the S-acylation, subcellular localization, and function of ToLCGdV C4, and inhibited ToLCGdV infection. In summary, we provided a new approach to globally improve the resistance to different types of geminiviruses in plants via de-S-acylation of the viral C4 proteins and it can be extendedly used for suppression of geminivirus infection in crops.
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Developing new antimicrobials to combat drug-resistant bacterial infections is necessary due to the increasing problem of bacterial resistance. In this study, four metallic ruthenium complexes modified with benzothiazoles were designed, synthesized and subjected to bio-evaluated. Among them, Ru-2 displayed remarkable inhibitory activity against Staphylococcus aureus (S. aureus) with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. Additionally, it showcased low hemolytic toxicity (HC50 > 200 µg/mL) and the ability to effectively eradicate S. aureus without fostering drug resistance. Further investigation into the antibacterial mechanism suggested that Ru-2 may target the phospholipid component of S. aureus, leading to the disruption of the bacterial cell membrane and subsequent leakage of cell contents (nucleic acid, protein, and ONPG), ultimately resulting in the death of the bacterial cell. In vivo studies, both the G. mellonella larvae and the mouse skin infection models were conducted, indicated that Ru-2 could potentially serve as a viable candidate for the treatment of S. aureus infection. It exhibited no toxic or side effects on normal tissues. The results suggest that benzothiazole-modified ruthenium complexes may have potential as membrane-active antimicrobials against drug-resistant bacterial infections.
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Antiinfecciosos , Infecciones Bacterianas , Complejos de Coordinación , Staphylococcus aureus Resistente a Meticilina , Rutenio , Animales , Ratones , Staphylococcus aureus , Rutenio/farmacología , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Benzotiazoles/farmacología , Complejos de Coordinación/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
B0 field inhomogeneity is a long-lasting issue for Cardiac MRI (CMR) in high-field (3T and above) scanners. The inhomogeneous B0 fields can lead to corrupted image quality, prolonged scan time, and false diagnosis. B0 shimming is the most straightforward way to improve the B0 homogeneity. However, today's standard cardiac shimming protocol requires manual selection of a shim volume, which often falsely includes regions with large B0 deviation (e.g., liver, fat, and chest wall). The flawed shim field compromises the reliability of high-field CMR protocols, which significantly reduces the scan efficiency and hinders its wider clinical adoption. This study aims to develop a dual-channel deep learning model that can reliably contour the cardiac region for B0 shim without human interaction and under variable imaging protocols. By utilizing both the magnitude and phase information, the model achieved a high segmentation accuracy in the B0 field maps compared to the conventional single-channel methods (Dice score: 2D-mag = 0.866, 3D-mag = 0.907, and 3D-mag-phase = 0.938, all p < 0.05). Furthermore, it shows better generalizability against the common variations in MRI imaging parameters and enables significantly improved B0 shim compared to the standard method (SD(B0Shim): Proposed = 15 ± 11% vs. Standard = 6 ± 12%, p < 0.05). The proposed autonomous model can boost the reliability of cardiac shimming at 3T and serve as the foundation for more reliable and efficient high-field CMR imaging in clinical routines.
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Tracheopathia osteochondroplastica (TO) is a rare and benign condition. It typically manifests as multiple osteocartilaginous nodules in the submucosa of the central airway. TO-related clinical symptoms and physical signs are nonspecific. The bronchoscopic examination is helpful in establishing the diagnosis. Treatment for TO is mostly conservative and symptom-oriented. The prognosis of TO is generally good, although cases of associated airway stenosis have been reported. In this case report, we describe the clinical, imaging, and histological features, and videoed bronchoscopic findings, of a middle-aged male patient with incidentally diagnosed TO.
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Aerobic composting stands as a widely-adopted method for treating organic solid waste (OSW), simultaneously producing organic fertilizers and soil amendments. This biologically-driven biochemical reaction process, however, presents challenges due to its complex non-linear metabolism and the heterogeneous nature of the solid medium. These characteristics inherently limit the simulation accuracy and efficiency optimization in aerobic composting. Recently, significant efforts have been made to simulate and control composting process parameters, as well as predicting and optimizing composting product quality. Notably, the integration of machine learning (ML) in aerobic composting of organic waste has garnered considerable attention for its applicability and predictive capability in exploring the complex non-linear relationships of organic waste composting parameters. Despite numerous studies on ML applications in OSW composting, a systematic review of research findings in this field is lacking. This study offers a systematic overview of the application level, current status, and versatility of ML in OSW composting. It spans various aspects, such as compost maturity, environmental pollutants, nutrients, moisture, heat loss, and microbial metabolism. The survey reveals that ML-intervention predominantly focuses on compost maturity and environmental pollutants, followed by nutrients, moisture, heat loss, and microbial activity. The most commonly employed predictive models and optimization algorithms are artificial neural networks (47%) and genetic algorithms (10%). These demonstrate high prediction accuracy and maximize composting efficiency in the simulation and prediction of organic waste composting, alongside regulation of key parameters. Deep neural networks and ensemble learning models prove effective in achieving superior predictive performance by selecting feature variables in compost maturity and pollutant residue prediction of organic waste composting in a simpler and more objective manner.
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Compostaje , Aprendizaje Automático , Compostaje/métodos , Residuos Sólidos/análisis , Eliminación de Residuos/métodos , Redes Neurales de la Computación , Suelo/química , Fertilizantes/análisis , Administración de Residuos/métodosRESUMEN
Electrochemical biosensors have emerged as one of the promising tools for tracking human body physiological dynamics via non-invasive perspiration analysis. However, it remains a key challenge to integrate multiplexed sensors in a highly controllable and reproducible manner to achieve long-term reliable biosensing, especially on flexible platforms. Herein, a fully inkjet printed and integrated multiplexed biosensing patch with remarkably high stability and sensitivity is reported for the first time. These desirable characteristics are enabled by the unique interpenetrating interface design and precise control over active materials mass loading, owing to the optimized ink formulations and droplet-assisted printing processes. The sensors deliver sensitivities of 313.28 µA mm-1 cm-2 for glucose and 0.87 µA mm-1 cm-2 for alcohol sensing with minimal drift over 30 h, which are among the best in the literature. The integrated patch can be used for reliable and wireless diet monitoring or medical intervention via epidermal analysis and would inspire the advances of wearable devices for intelligent healthcare applications.
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Técnicas Biosensibles , Glucosa , Dispositivos Electrónicos Vestibles , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Glucosa/análisis , Humanos , Sudor/química , Sudor/metabolismo , Impresión , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Etanol/análisisRESUMEN
Small peptides modulate multiple processes in plant cells, but their regulation by post-translational modification remains unclear. ROT4 (ROTUNDIFOLIA4) belongs to a family of Arabidopsis non-secreted small peptides, but knowledge on its molecular function and how it is regulated is limited. Here, we find that ROT4 is S-acylated in plant cells. S-acylation is an important form of protein lipidation, yet so far it has not been reported to regulate small peptides in plants. We show that this modification is essential for the plasma membrane association of ROT4. Overexpression of S-acylated ROT4 results in a dramatic increase in immune gene expression. S-acylation of ROT4 enhances its interaction with BSK5 (BRASSINOSTEROID-SIGNALING KINASE 5) to block the association between BSK5 and PEPR1 (PEP RECEPTOR1), a receptor kinase for secreted plant elicitor peptides (PEPs), thereby activating immune signaling. Phenotype analysis indicates that S-acylation is necessary for ROT4 functions in pathogen resistance, PEP response, and the regulation of development. Collectively, our work reveals an important role for S-acylation in the cross-talk of non-secreted and secreted peptide signaling in plant immunity.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Plantas/metabolismo , Péptidos/metabolismo , Acilación , Inmunidad de la Planta , Proteínas Quinasas/metabolismoRESUMEN
Cardiac fibrosis (CF) in response to persistent exogenous stimuli or myocardial injury results in cardiovascular diseases (CVDs). Protein tyrosine phosphatase 1B (PTP1B) can promote collagen deposition through regulating AMPK/TGF-ß/Smads signaling pathway, and PTP1B knockout improves cardiac dysfunction against overload-induced heart failure. Oleanolic acid (OA) has been proven to be an inhibitor of PTP1B, and its anti-cardiac remodeling effects have been validated in different mouse models. To improve the bioactivity of OA and to clarify whether OA derivatives with stronger inhibition of PTP1B activity have greater prevention of cardiac remodeling than OA, four new OA derivatives were synthesized and among them, we found that compound B had better effects than OA in inhibiting cardiac fibrosis both in vivo in the isoproterenol (ISO)-induced mouse cardiac fibrosis and in vitro in the TGF-ß/ISO-induced 3T3 cells. Combining with the results of molecular docking, surface plasmon resonance and PTP1B activity assay, we reported that OA and compound B directly bound to PTP1B and inhibited its activity, and that compound B showed comparable binding capability but stronger inhibitory effect on PTP1B activity than OA. Moreover, compound B presented much greater effects on AMPK activation and TGF-ß/Smads inhibition than OA. Taken together, OA derivative compound B more significantly alleviated cardiac fibrosis than OA through much greater inhibition of PTP1B activity and thus much stronger regulation of AMPK/TGF-ß/Smads signaling pathway.
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Ácido Oleanólico , Factor de Crecimiento Transformador beta , Animales , Ratones , Factor de Crecimiento Transformador beta/metabolismo , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Transducción de Señal , Simulación del Acoplamiento Molecular , Fibrosis , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Textile bioelectronics that allow comfortable epidermal contact hold great promise in noninvasive biosensing. However, their applications are limited mainly because of the large intrinsic electrical resistance and low compatibility for electronics integration. We report an integrated wristband that consists of multifunctional modules in a single piece of textile to realize wireless epidermal biosensing. The in-textile metallic patterning and reliable interconnect encapsulation contribute to the excellent electrical conductivity, mechanical robustness, and waterproofness that are competitive with conventional flexible devices. Moreover, the well-maintained porous textile architectures deliver air permeability of 79 mm s-1 and moisture permeability of 270 g m-2 day-1, which are more than one order of magnitude higher than medical tapes, thus ensuring superior wearing comfort. The integrated in-textile wristband performed continuous sweat potassium monitoring in the range of 0.3 to 40 mM with long-term stability, demonstrating its great potential for wearable fitness monitoring and point-of-care testing.
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Técnicas Biosensibles , Dispositivos Electrónicos Vestibles , Epidermis , Sudor , TextilesRESUMEN
Background: Although percutaneous transthoracic catheter drainage (PCD) has been proven effective in lung abscesses, the optimal timing of PCD is still unclear. The study aimed to evaluate the safety and efficacy of early versus delayed drainage in patients with lung abscesses. Methods: This retrospective study included 103 consecutive patients with liquefied lung abscesses more than 3 cm confirmed by a CT scan received CT-guided PCD over 16 years, from July 2005 to September 2021, in a single institution were reviewed. Early drainage was defined as PCD within one week after a lung abscess was diagnosed. The primary outcome was 90-day mortality. The secondary outcomes included perioperative complications and patients' length of hospital stay (LoS). Factors associated with 90-day mortality and LoS were also analyzed. The key statistical methods were Chi-square test, Fisher's exact test, Student t-test, and Pearson correlation. Results: Amount the 103 patients, there were 64 patients who received early PCD, and 39 patients received delayed PCD. Between the two groups, there were no significant differences in clinical characteristics, 90-day mortality, or perioperative complications. The LoS was significantly shortened in early PCD group (28.6 ± 25.5 vs. 39.3 ± 26.8 (days), p = 0.045). Higher Charlson comorbidity index, secondary lung abscess, and liver cirrhosis were associated with higher mortality (all p < 0.05). Positive sputum culture significantly increased the LoS (coefficient 19.35 (10.19, 28.50), p < 0.001). Conclusion: The 90-day mortality and complications were similar for early PCD and delayed PCD patients, but LoS was significantly shortened in early PCD patient.
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Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy of the digestive system with increasing incidence and mortality rates. The biological roles of microRNA (miR)-378a-3p in tumor cells remain contested, and the mechanisms underlying the functions, energy metabolism, and cell survival mechanisms in ESCC cells are yet to be fully elucidated. In the present study, miR-378a-3p overexpression and negative control plasmids were transfected into ECA-109 cells using electroporation. Western blotting was used to detect the relative expression of proteins, and flow cytometry was used to detect cell apoptosis. Subsequently, ELISA assays were performed to determine enzyme activity, and an ATP detection kit was used to measure ATP content. Dual-luciferase reporter assays were performed to identify the target genes of miR-378a-3p. The results of the present study demonstrated that miR-378a-3p inhibited the gene expression and enzyme activities of glucose transporter protein 1 (GLUT-1), Aldolase A (ALDOA), and pyruvate kinase M2 (PKM2), all of which are involved in the glycolytic pathway of cells. Energy metabolism was suppressed by miR-378a-3p by reducing ATP content, and this downregulated the expression of Bcl-2 and Survivin. Moreover, increased miR-378a-3p expression promoted cell apoptosis in the early stages by increasing the expression levels and the activity of Bad and Caspase-3, while inhibiting the expression levels of Bcl-2 and Survivin. The results of the present study also demonstrated that GLUT-1/ALDOA/PKM2 were target genes of miR-378a-3p. Notably, miR-378a-3p blocked energy production and promoted the apoptosis of tumor cells via the downregulation of glycolytic enzyme expression and by reducing the mitochondrial membrane potential in ESCC. Bad, Caspase-3, Survivin, and Bcl-2 may be associated with blocking energy production and promoting apoptosis via miR-378a-3p in ESCC cells.
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Bacterial vaginosis (BV) is a common infection of the lower genital tract with a vaginal microbiome dysbiosis caused by decreasing of lactobacilli. Previous studies suggested that supplementation with live Lactobacillus may benefit the recovery of BV, however, the outcomes vary in people from different regions. Herein, we aim to evaluate the effectiveness of oral Chinese-origin Lactobacillus with adjuvant metronidazole (MET) on treating Chinese BV patients. In total, 67 Chinese women with BV were enrolled in this parallel controlled trial and randomly assigned to two study groups: a control group treated with MET vaginal suppositories for 7 days and a probiotic group treated with oral Lactobacillus gasseri TM13 and Lactobacillus crispatus LG55 as an adjuvant to MET for 30 days. By comparing the participants with Nugent Scores ≥ 7 and < 7 on days 14, 30, and 90, we found that oral administration of probiotics did not improve BV cure rates (72.73% and 84.00% at day 14, 57.14% and 60.00% at day 30, 32.14% and 48.39% at day 90 for probiotic and control group respectively). However, the probiotics were effective in restoring vaginal health after cure by showing higher proportion of participants with Nugent Scores < 4 in the probiotic group compared to the control group (87.50% and 71.43% on day 14, 93.75% and 88.89% on day 30, and 77.78% and 66.67% on day 90). The relative abundance of the probiotic strains was significantly increased in the intestinal microbiome of the probiotic group compared to the control group at day 14, but no significance was detected after 30 and 90 days. Also, the probiotics were not detected in vaginal microbiome, suggesting that L. gasseri TM13 and L. crispatus LG55 mainly acted through the intestine. A higher abundance of Prevotella timonensis at baseline was significantly associated with long-term cure failure of BV and greatly contributed to the enrichment of the lipid IVA synthesis pathway, which could aggravate inflammation response. To sum up, L. gasseri TM13 and L. crispatus LG55 can restore the vaginal health of patients recovering from BV, and individualized intervention mode should be developed to restore the vaginal health of patients recovering from BV. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/, identifier NCT04771728.
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Lactobacillus crispatus , Lactobacillus gasseri , Vaginosis Bacteriana , Femenino , Humanos , Adyuvantes Inmunológicos/uso terapéutico , Adyuvantes Farmacéuticos , Lactobacillus/fisiología , Metronidazol/uso terapéutico , Resultado del Tratamiento , Vagina/microbiología , Vaginosis Bacteriana/microbiologíaRESUMEN
Accumulating evidence has shown that the quality of proteins must be tightly monitored and controlled to maintain cellular proteostasis. Misfolded proteins and protein aggregates are targeted for degradation through the ubiquitin proteasome (UPS) and autophagy-lysosome systems. The ubiquitination and deubiquitinating enzymes (DUBs) have been reported to play pivotal roles in the regulation of the UPS system. However, the function of DUBs in the regulation of autophagy remain to be elucidated. In this study, we found that knockdown of Leon/USP5 caused a marked increase in the formation of autophagosomes and autophagic flux under well-fed conditions. Genetic analysis revealed that overexpression of Leon suppressed Atg1-induced cell death in Drosophila. Immunoblotting assays further showed a strong interaction between Leon/USP5 and the autophagy initiating kinase Atg1/ULK1. Depletion of Leon/USP5 led to increased levels of Atg1/ULK1. Our findings indicate that Leon/USP5 is an autophagic DUB that interacts with Atg1/ULK1, negatively regulating the autophagic process.