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Zn(OTf)2-catalyzed intra- and intermolecular selenofunctionalization of alkenes was achieved with electrophilic N-phenylselenophthalimide. This method provides straightforward and efficient access to various seleno-substituted heterocycles and vicinal Se heteroatom-disubstituted molecules under mild conditions. This reaction is compatible with various substrates/functional groups, and preliminary studies on the reaction mechanistic were also conducted.
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Chrysin is a flavonoid with various biological activities. However, its low water solubility and strong metabolism render its oral bioavailability rather poor. This study aimed to develop a stable solid dispersion formulation of chrysin to improve the dissolution of chrysin, so as to increase its oral bioavailability and improve its antihyperlipidemic activities. A solid dispersion of chrysin was prepared using a solvent evaporation method, with Plasdone® S630 as the hydrophilic carrier. The formulations were characterized via X-ray diffraction, in vitro dissolution studies, and stability studies. An in-situ perfusion model was used to evaluate the absorption rates. Plasma pharmacokinetics and antihyperlipidemic performance after the oral administration of the chrysin formulations were investigated in rats. It was found that the solid dispersion of chrysin prepared using the drug-polymer mass ratio of 1:6 can form the optimized formulation. X-ray diffraction results showed that the chrysin was in an amorphous state in this optimized formulation. The cumulative release percentage of the optimized solid dispersion of chrysin at pH 1.2 and pH 6.8 was elevated to above 90% within 24 h, indicating that the formulation could enhance the dissolution rates of chrysin. Stability studies showed that the optimized formulation presented acceptable long-term storage stability, but it was susceptible to high temperature and humidity. The solid dispersion of chrysin showed higher absorption rates in the in-situ perfusion model. Pharmacokinetic studies revealed that Cmax and AUC after the intragastric administration of solid dispersion of chrysin were appreciably higher than those resulting from chrysin suspension. The oral bioavailability of the solid dispersion of chrysin was 41 times higher than that of chrysin suspension. Pharmacological studies suggested that the solid dispersion of chrysin was more powerful than chrysin raw material in improving biochemical indicators in the hyperlipidemic model in rats. This study reveals the potential use of a novel oral formulation of chrysin to reduce the currently required high dose.
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The detergency of motor gasoline is closely related to vehicle exhaust emissions and fuel economy. This paper proposed an improved method for the rapid detection of gasoline detergency based on the deposit images of test gasoline on aluminum plates produced by a multichannel gasoline detergency simulation test (MGST). The detection algorithm system was structured to recognize the deposit plate images by computer vision based on the convolutional neural networks (CNNs). Compared with the traditional simulation test, the improved MGST method resulted in significant reductions in fuel consumption, cost, and test time. The performance of three transfer learning models (Inception-ResNet-V2, Inception-V3, and ResNet50-V2) and a customized CNN was evaluated in the detection algorithm system, and their detection accuracies reached 94, 94, 88, and 82%. Inception-RsNet-V2 was selected due to its higher accuracy and better robustness. Based on the model interpretation, it is evident that the model undergoes feature extraction from the sediment deposits on the deposit plate. Subsequently, it employed the acquired deposit features to accurately detect gasoline samples that failed to meet detergency standards. This approach was proved to be effective in enhancing the detection process and ensuring reliable results for gasoline detergency evaluation. It is beneficial to environmental protection regulators for managing market gasoline detergency and urban mobile source pollution. In addition, a deposit plate image database should be established to further improve the detection model performance during the environmental regulation.
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Cellular senescence is an irreversible state of cell cycle arrest, characterized by a gradual decline in cell proliferation, differentiation, and biological functions. Cellular senescence is double-edged for that it can provoke organ repair and regeneration in physiological conditions but contribute to organ and tissue dysfunction and prime multiple chronic diseases in pathological conditions. The liver has a strong regenerative capacity, where cellular senescence and regeneration are closely involved. Herein, this review firstly introduces the morphological manifestations of senescent cells, the major regulators (p53, p21, and p16), and the core pathophysiologic mechanisms underlying senescence process, and then specifically generalizes the role and interventions of cellular senescence in multiple liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. In conclusion, this review focuses on interpreting the importance of cellular senescence in liver diseases and summarizes potential senescence-related regulatory targets, aiming to provide new insights for further researches on cellular senescence regulation and therapeutic developments for liver diseases.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Senescencia Celular , Neoplasias Hepáticas/patologíaRESUMEN
Sestrin2 (SESN2), a highly conserved stress-responsive protein, can be triggered by various noxious stimuli, such as hypoxia, DNA damage, oxidative stress, endoplasmic reticulum (ER) stress, and inflammation. Multiple transcription factors regulate SESN2 expression, including hypoxia-inducible factor 1 (HIF-1), p53, nuclear factor E2-related factor 2 (Nrf2), activating transcription factor 4 (ATF4), ATF6, etc. Upon induction, SESN2 generally leads to activation of adenosine monophosphate-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). To maintain cellular homeostasis, SESN2 and its downstream molecules directly scavenge reactive oxygen species or indirectly influence the expression patterns of key genes associated with redox, macroautophagy, mitophagy, ER stress, apoptosis, protein synthesis, and inflammation. In liver diseases including acute liver injury, fatty liver diseases, hepatic fibrosis, and hepatocellular carcinoma (HCC), SESN2 is abnormally expressed and correlated with disease progression. In NAFLD, SESN2 helps with postponing disease progression through balancing glycolipid metabolism and macroautophagy (lipophagy), and rectifying oxidative damage and ER stress. During hepatic fibrosis, SESN2 represses HSCs activation and intrahepatic inflammation, hindering the occurrence and progress of fibrogenesis. However, the role of SESN2 in HCC is controversial due to its paradoxical pro-autophagic and anti-apoptotic effects. In conclusion, this review summarizes the biological functions of SESN2 in hypoxia, genotoxic stress, oxidative stress, ER stress, and inflammation, and specifically emphasizes the pathophysiological significance of SESN2 in liver diseases, aiming to providing a comprehensive understanding for SESN2 as a potential therapeutic target in liver diseases.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Inflamación , Hipoxia , Cirrosis Hepática , SestrinasRESUMEN
We investigated the role of zinc-finger protein 281 (ZNF281), a novel molecule, in ethanol-induced hepatocyte senescence and uncovered the potential mechanism. Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of ZNF281 in hepatocyte senescence. ZNF281 expression was upregulated in both alcohol-fed mice livers and ethanol-treated hepatocytes. Silence of ZNF281 in hepatocytes using siRNA mitigated ethanol-caused decrease in cell viability and increased release of aspartate aminotransferase, alanine transaminase, and lactate dehydrogenase. ZNF281 siRNA reduced senescence-associated ß-galactosidase-positive cells under ethanol exposure, abolished cell cycle arrest at G0/G1 phase, and diminished senescence-associated secretory phenotype and proinflammatory cytokines (IL-1ß and IL-6) release. At molecular level, ZNF281 deficiency altered the expression profile of senescence-associated proteins including p53, p21, p16, high mobility group AT-hook 1, and phospho-histone H2A.X and telomerase-associated regulatory factors including telomerase reverse transcriptase, telomeric repeat binding factor 1 (TRF1), and TRF2. ZNF281 knockdown promoted hepatocyte recovery from ethanol-induced mitochondrial dysfunction and ROS production, which was correlated with rescuing HK2-PINK1/Parkin signalling-mediated mitophagy. Mechanistically, ZNF281 directly bound to 5'-GGCGGCGGGCGG-3' motif within HK2 promoter region and transcriptionally repressed HK2 expression. Systematic ZNF281 knockdown by adeno-associated virus encoding ZNF281 shRNA protected mice from alcohol feeding-caused hepatocyte injury and senescence. This study provides a novel factor ZNF281 as a driver of hepatocyte senescence during alcoholic liver disease.
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Hepatopatías Alcohólicas , Mitofagia , Ratones , Animales , Hepatocitos/metabolismo , Hepatopatías Alcohólicas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Etanol , Proteínas Quinasas/metabolismo , ARN Interferente Pequeño/metabolismo , Senescencia CelularRESUMEN
Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism.
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Etanol , Hepatocitos , Ratones , Animales , Etanol/metabolismo , Etanol/farmacología , Hepatocitos/metabolismo , Hígado , AutofagiaRESUMEN
The objective of this study was to investigate the feasibility of the bolus administration of PLS via skin by using dissolving microneedles of palonosetron hydrochloride (PLS-DMNs). Tip-loaded PLS-DMNs were fabricated by a casting method using sodium hyaluronate (HA) as DMNs-forming polymer. PLS-DMNs were shown to have a content of 118.5 ± 8.7 µg per piece with sufficient mechanical strength for insertion into pig skin ex vivo. In situ dissolution of PLS-DMNs was achieved within 5 min and 83.2 % of PLS was delivered. In vitro studies showed that PLS-DMNs provided much higher PLS permeation than that after passive permeation using a PLS hydrogel. Moreover, the application of 30 min-iontophoresis at the beginning of PLS-DMNs administration further enhanced PLS delivery. In vivo pharmacokinetic studies were carried out in rats. The area under the curve (AUC) and the time to reach the peak (Tmax) after application of PLS-DMNs was not significantly different compared to those after subcutaneous (S.C.) injection. PLS-DMNs plus 30 min-iontophoresis enabled the pharmacokinetic profile to be even closer to that seen after S.C. administration. These results suggest that application of PLS-DMNs with short-duration iontophoresis exhibits promise as an alternative PLS delivery method that can be painlessly self-administered with rapid onset.
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Iontoforesis , Agujas , Ratas , Porcinos , Animales , Microinyecciones , Administración Cutánea , Palonosetrón , Piel , Sistemas de Liberación de Medicamentos/métodos , VómitosRESUMEN
Diphyllin and its natural derivatives were identified as potent vacuolar H+ -ATPase (V-ATPase) inhibitors. In this study, twelve 2, 4, 5-trideoxyhexopyranosides derivatives of diphyllin were synthesized. Most of these compounds showed potent abilities to inhibit the growth of HT-29, MCF-7, HepG2 cancer cells with IC50 values at submicromolar concentration. The compounds 5c3 and 5c4 showed the best inhibitory activity on breast cancer cell lines MCF-7 with IC50 values of 0.09 and 0.10 µM. Compounds 5c3 and 5c4 showed similar V-ATPase inhibitory potency to diphyllin. Molecular docking showed that a hydrogen bond was found between the hydroxyl of 5c3 and SerA534 in the pocket of the V-ATPase receptor.
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Antineoplásicos , Lignanos , ATPasas de Translocación de Protón Vacuolares , Antineoplásicos/química , Antineoplásicos/farmacología , Benzodioxoles/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Lignanos/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
Background: Functional constipation (FC) is a common gastrointestinal (GI) disorder characterized by symptoms of constipation without a clear physiologic or anatomic cause. Gut microbiome dysbiosis has been postulated to be a factor in the development of FC, and treatment with probiotic regimens, including strains of Lactobacillus plantarum (L. plantarum), has demonstrated efficacy in managing symptoms. To further understand the role of L. plantarum in GI health, we conducted an animal study and a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of a specific sub-strain, Lp3a, on FC. Methods: For the animal study, male Kunming mice were treated with doses of L. plantarum Lp3a ranging from 0.67 to 2.00 g/kg or an equivalent amount of placebo for 15 days prior to the induction of constipation via 20 mL/kg of 25% diphenoxylate solution. GI motility parameters including intestinal motion and stool amount were then assessed. In the human study, 120 patients with FC were randomized to treatment [L. plantarum Lp3a; 2×1.0×1010 (colony forming units; CFU) ×7 days] or control groups (n=60 each). The primary endpoint was survey information on FC signs/symptoms. Participants and observers were blinded to group allocation. A subset of 20 Lp3a treated patients underwent pre- and post-treatment 16 s ribosomal ribonucleic acid (rRNA) gene sequencing. Whole genome sequencing (WGS) of L. plantarum Lp3a was also performed. Results: Lp3a-treated mice showed significantly improved intestinal motion, reduced time to first defecation, and increased stool amounts. Similarly, patients in the treatment group (n=59) reported significant improvements in FC signs/symptoms compared to controls (n=58; all P<0.05). Although 16 s rRNA sequencing revealed no significant variations between pre- and post-treatment samples, WGS of Lp3a itself revealed several biological pathways that may underlie the relief of FC symptoms in animals and humans, including methane and fatty acid metabolism and bile acid biosynthesis. Conclusions: We found that the use of the novel probiotic sub-strain, L. plantarum Lp3a, led to clinically significant improvements in FC in both mice and humans, and identified the potential biological mechanisms underlying this activity.
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Atypical protein kinase C (aPKCs) serve key functions in embryonic development by regulating apicalbasal polarity. Previous studies have shed light on their roles during adulthood, especially in the development of Alzheimer's disease (AD). Although the crystal structure of PKCι has been resolved, an agonist of aPKCs remains to be discovered. In the present study, by using the Discovery Studio program and LibDock methodology, a small molecule library (K66X4436 KINA Set) of compounds were screened for potential binding to PKCι. Subsequently, the computational docking results were validated using affinity selectionmass spectrometry, before in vitro kinase activity was used to determine the function of the hit compounds. A cellbased model assay that can mimic the pathology of AD was then established and used to assess the function of these hit compounds. As a result, the aPKC agonist Z640 was identified, which could bind to PKCι in silico, in vitro and in this cellbased model. Z640 was further confirmed as a nonselective aPKC agonist that can activate the kinase activity of both PKCι and PKCζ. In the cellbased assay, Z640 was found to protect neuronal cell lines from amyloidß (Aß) oligomerinduced cell death by reducing reactive oxygen species production and restore mitochondrial function. In addition, Z640 could reduce Aß40 generation in a dosedependent manner and shift amyloid precursor protein processing towards the nonamyloid pathway. To conclude, the present study is the first, to the best of the authors' knowledge to identify an aPKC agonist by combining computerassisted drug discovery and cellbased assays. The present study also revealed that aPKC agonists have therapeutic potential for the treatment of AD.
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Péptidos beta-Amiloides , Isoenzimas , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Línea Celular , Isoenzimas/metabolismo , FosforilaciónRESUMEN
Chronic alcohol consumption can cause alcoholic liver disease (ALD), leading to morbidity and mortality worldwide. Complex disease progression of ALD varies from alcoholic fatty liver to alcoholic steatohepatitis, eventually contributing to fibrosis and cirrhosis. Accumulating evidence revealed that necroptosis, a way of programmed cell death different from apoptosis and traditional necrosis, is involved in the underlying pathogenic molecular mechanism of ALD. Receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like pseudokinase have been implicated as key mediators to execute necroptosis. Also, necroptosis has gained increasing attention due to its potential association with primary pathological hallmarks of ALD, including oxidative stress, hepatic steatosis and inflammation. This review summarizes the recent progress on the roles and mechanisms of necroptosis and focuses on the crosstalk between necroptosis and the other pathogenesis of ALD, providing a theoretical basis for targeting necroptosis as a novel treatment for ALD.
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Hepatocitos/patología , Hepatopatías Alcohólicas/patología , Hígado/patología , Necroptosis/fisiología , Animales , Hepatocitos/metabolismo , Humanos , Hepatopatías Alcohólicas/metabolismo , Necrosis/metabolismo , Estrés Oxidativo/fisiologíaRESUMEN
Hepatocyte necroptosis is a core pathogenetic event during alcoholic liver disease. This study was aimed to explore the potential of tetramethylpyrazine (TMP), an active hepatoprotective ingredient extracted from Ligusticum Wallichii Franch, in limiting alcohol-triggered hepatocyte necroptosis and further specify the molecular mechanism. Results revealed that TMP reduced activation of receptor-interacting protein kinase 1 (RIPK1)/RIPK3 necrosome in ethanol-exposed hepatocytes and phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which thereby diminished necroptosis and leakage of damage-associated molecular patterns. Suppression on mitochondrial translocation of p-MLKL by TMP contributed to recovery of mitochondrial function in ethanol-damaged hepatocytes. TMP also disrupted necroptotic signal loop by interrupting mitochondrial reactive oxygen species (ROS)-dependent positive feedback between p-MLKL and RIPK1/RIPK3 necrosome. Further, TMP promoted clearance of impaired mitochondria in ethanol-incubated hepatocytes via restoring PINK1/parkin-mediated mitophagy. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) was downregulated in ethanol-exposed hepatocytes, which was restored after TMP treatment. In vitro UQCRC2 knockdown lowered the capacities of TMP in reducing mitochondrial ROS accumulation, relieving mitochondria damage, and enhancing PINK1/parkin-mediated mitophagy in ethanol-exposed hepatocytes. Analogously, systematic UQCRC2 knockdown interrupted the actions of TMP to trigger autophagic signal, repress necroptotic signal, and protect against alcoholic liver injury, inflammation, and ROS overproduction. In conclusion, this work concluded that TMP rescued UQCRC2 expression in ethanol-challenged hepatocytes, which contributed to necroptosis inhibition by facilitating PINK1/parkin-mediated mitophagy. These findings uncovered a potential molecular pharmacological mechanism underlying the hepatoprotective action of TMP and suggested TMP as a promising therapeutic candidate for alcoholic liver disease.
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Complejo III de Transporte de Electrones/metabolismo , Hepatopatías Alcohólicas , Mitofagia , Necroptosis , Hepatocitos/enzimología , Humanos , Hepatopatías Alcohólicas/tratamiento farmacológico , Proteínas Quinasas/genética , PirazinasRESUMEN
A novel series of 1-substituted phenazines 4a-4l were designed and synthesized via Palladium-catalyzed reactions from 1-phenazine trifluoromethanesulfonate. These phenazines showed antichlamydial activity with IC50 values from 1 to 10 µM. Among them, compounds 4c and 4i exhibited the best antichlamydial activity with IC50 values from 2.06 to 2.74 µM without apparent cytotoxicity to host cells.
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Paladio , Fenazinas , Estructura Molecular , Fenazinas/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: The brain-gut-microbiome axis has emerged as an important pathway through which perturbations in the gut and/or microbial microenvironment can impact neurological function. Such alterations have been implicated in a variety of neuropsychiatric disorders, including depression, anxiety, and Alzheimer's Disease (AD) and the use of probiotics as therapy for these diseases remains promising. However, the mechanisms underlying the gut microenvironment's influence on disease pathogenesis and therapy remain unclear. OBJECTIVE: The objective of this study is to investigate the effect of a novel probiotic formula, BIOCG, on cognitive function and pathobiological mechanisms, including amyloid processing and dendritic spine dynamics, in a mouse model of AD. METHODS: BIOCG was administered for 3 months to 3xTg or 3xTg; Thy1-YFP AD mice and functional outcomes were assessed via behavioral testing and electrophysiology. Mechanisms relevant to AD pathogenesis including dendritic spine morphology and turnover, Amyloid Precursor Protein (APP) processing and microglial phenotype were also evaluated. Finally, we sequenced fecal samples following probiotic treatment to assess the impact on gut microbial composition and correlate the changes with the above described measures. RESULTS: Mice treated with BIOCG demonstrated preserved cognitive abilities and stronger Long- Term Potentiation (LTP), spontaneous Excitatory Postsynaptic Currents (sEPSC), and glutamate-induced LTPs, indicative of functional and electrophysiological effects. Moreover, we observed attenuated AD pathogenesis, including reduced Amyloid Beta (Aß) burden, as well as more mature dendritic spines in the BIOCG-treated. Our finding of changes in microglial number and phenotype in the treatment group suggests that this formulation may mediate its effects via attenuation of neuroinflammation. Sequencing data confirmed that the gut microbiome in treated mice was more varied and harbored a greater proportion of "beneficial" bacteria. CONCLUSION: Overall, our results indicate that treatment with BIOCG enhances microbial diversity and, through gut-brain axis interactions, attenuates neuroinflammation to produce histologic and functional improvement in AD pathogenesis.
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Enfermedad de Alzheimer , Probióticos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Cognición/fisiología , Espinas Dendríticas , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Probióticos/farmacología , Probióticos/uso terapéuticoRESUMEN
Chlamydia trachomatis is an obligate intracellular bacterium whose unique developmental cycle consists of an infectious elementary body and a replicative reticulate body. Progression of this developmental cycle requires temporal control of the transcriptome. In addition to the three chlamydial sigma factors (σ66, σ28, and σ54) that recognize promoter sequences of genes, chlamydial transcription factors are expected to play crucial roles in transcriptional regulation. Here, we investigate the function of GrgA, a Chlamydia-specific transcription factor, in C. trachomatis transcriptomic expression. We show that 10 to 30 min of GrgA overexpression induces 13 genes, which likely comprise the direct regulon of GrgA. Significantly, σ66-dependent genes that code for two important transcription repressors are components of the direct regulon. One of these repressors is Euo, which prevents the expression of late genes during early phases. The other is HrcA, which regulates molecular chaperone expression and controls stress response. The direct regulon also includes a σ28-dependent gene that codes for the putative virulence factor PmpI. Furthermore, overexpression of GrgA leads to decreased expression of almost all tRNAs. Transcriptomic studies suggest that GrgA, Euo, and HrcA have distinct but overlapping indirect regulons. These findings, together with temporal expression patterns of grgA, euo, and hrcA, indicate that a transcriptional regulatory network of these three transcription factors plays critical roles in C. trachomatis growth and development. IMPORTANCE Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen worldwide and is a leading cause of preventable blindness in underdeveloped areas as well as some developed countries. Chlamydia carries genes that encode a limited number of known transcription factors. While Euo is thought to be critical for early chlamydial development, the functions of GrgA and HrcA in the developmental cycle are unclear. Activation of euo and hrcA immediately following GrgA overexpression indicates that GrgA functions as a master transcriptional regulator. In addition, by broadly inhibiting tRNA expression, GrgA serves as a key regulator of chlamydial protein synthesis. Furthermore, by upregulating pmpI, GrgA may act as an upstream virulence determinant. Finally, genes coregulated by GrgA, Euo, and HrcA likely play critical roles in chlamydial growth and developmental control.
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The Chinese government has developed an ambitious project to promote the application of ethanol gasoline (E10) on a national scale since 2017. Given the difference in fuel properties between E10 and traditional gasoline, it is necessary to evaluate the volatile organic compound (VOC) emissions from E10-fuelled vehicles. In this study, a two-week sampling campaign was conducted in an urban tunnel, in which E10-fuelled vehicles were dominant, to evaluate the characteristics of VOC emissions from the mixed fleet. In total, 105 VOC species were identified, and the ozone formation potential (OFP) and secondary organic aerosol formation potential (SOAFP) were estimated. The results showed that for vehicular VOC concentrations in the tunnel, alkanes, oxygenated VOCs (OVOCs) and alkenes were the most abundant VOC groups, with the average proportion being more than 80% of the total VOCs. The fleet-average VOC emission factor (EF) was 14.8 mg/km/veh, which was much lower than that from traditional gasoline-fuelled vehicle fleets, and alkanes, OVOCs, alkenes and aromatics were the major VOC groups. Because of the large number of E10-fuelled vehicles in the mixed fleet, a high proportion of OVOCs among the vehicular VOC emissions was observed. Ethane, acrolein, ethanol, ethylene and toluene were the top five VOC species with the largest EF in VOC emissions from the fleet. Alkenes were the main contributors with an average contribution of 43.9% of the total OFP, whereas aromatics dominated the total SOAFP by 95.8% on average. These results may provide a reference for the extensive application of ethanol gasoline and the development of vehicular emission models.
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Contaminantes Atmosféricos , Ozono , Compuestos Orgánicos Volátiles , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , China , Monitoreo del Ambiente , Ozono/análisis , Emisiones de Vehículos/análisis , Compuestos Orgánicos Volátiles/análisisRESUMEN
Vehicular emissions have become a primary anthropogenic source of urban atmospheric volatile halogenated hydrocarbons (VHCs) with the rapid increase of vehicle population, while characteristics of the VHC emissions from different vehicles were rarely systematically investigated. In this study, the on-road tailpipe emissions were sampled from seven in-use vehicles, including two light-duty gasoline vehicles (LDGV), three light-duty diesel trucks (LDDT), one heavy-duty diesel truck (HDDT), and a liquefied petroleum gas-electric hybrid bus (LPGB), using a portable emission measurement system (PEMS) combined with summa canisters, and 35 individual VHC species were identified by a gas chromatography mass spectrometry detector (GC-MSD). Results showed that VHC emissions under urban driving conditions were much higher than those on the suburban roads and highways. The VHC emission factors of LDGV were 1.2 ± 0.34 mg/km and 3.6 ± 1.5, 6.8 ± 0.89, and 1.6 ± 0.28 mg/km for LDDT, HDDT, and LPGB, respectively. For the LDGV, chlorobenzene, 1,2-dichloroethane, and hexachlorobutadiene were the top three VHC species. 1,2-Dichloroethane, trichloromethane, and methyl chloride were the main VHC constituents in the LDDT. Chlorobenzene was the most abundant VOC species for the HDDT, followed by 1,2-dichloroethane and 1,4-dichlorobenzene. The major species for LPGB were 1,2,4-trichlorobenzene, carbon tetrachloride, and benzyl chloride. The major tailpipe VHC species obtained in this study were partial consistent with previous studies with different test methods. The results provide an initial evaluation of the tailpipe VHC emissions, which may provide experimental data support for the refined source apportionment of atmospheric VHCs and the control of vehicular VHCs.
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Contaminantes Atmosféricos , Hidrocarburos Halogenados , Contaminantes Atmosféricos/análisis , Monitoreo del Ambiente , Gasolina/análisis , Vehículos a Motor , Emisiones de Vehículos/análisisRESUMEN
Oxidative stress plays an important role in the pathogenesis of human retinal diseases. Ginkgo biloba products are widely consumed herbal supplements that contain ingredients with anti-oxidant potentials. However, the active agents in ginkgo biloba extracts (GBE) are unclear. This study assessed the anti-oxidant effects of 19 natural compounds isolated from GBE to provide a rational basis for their use in preventing retinal diseases. The compounds were tested in retinal pigment epithelial (RPE) cells subjected to tert-butyl hydroperoxide (t-BHP)-induced oxidative stress. Cell viability and intracellular reactive oxygen species (ROS) were assessed and flow cytometry was used to delineate the cell death profile. The expression of nuclear factor erythroid 2-related factor-2 (Nrf2) was activated in RPE cells by t-BHP accompanied with an activation of Erk1/2 signaling. GBE-derived rutin and procyanidin B2 ameliorated t-BHP-induced cell death and promoted cell viability by suppressing intracellular ROS generation. These agents also enhanced Nrf2 expression with activating Erk1/2 signaling in RPE cells. In contrast, the other compounds tested were minimally active and did not prevent the loss of cell viability elicited by t-BHP. The present findings suggest that rutin and procyanidin B2 may have potential therapeutic values in the prevention of retinal diseases induced by oxidative damage.
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Biflavonoides/farmacología , Catequina/farmacología , Ginkgo biloba/química , Sistema de Señalización de MAP Quinasas/fisiología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Proantocianidinas/farmacología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Rutina/farmacología , Antioxidantes/farmacología , Western Blotting , Supervivencia Celular , Células Cultivadas , Citometría de Flujo , Humanos , Potencial de la Membrana Mitocondrial , Especies Reactivas de Oxígeno/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , terc-Butilhidroperóxido/toxicidadRESUMEN
The obligate intracellular bacterium Chlamydia trachomatis is a group of worldwide human pathogens that can lead to serious reproductive problems. The frequent clinical treatment failure promoted the development of novel antichlamydial agents. Here, we firstly reported a group of pyrroloisoxazolidine-inhibited C. trachomatis in a dose-dependent manner in vitro. Among them, compounds 1 and 2 exhibited the strongest inhibitory activity with IC50 values from 7.25 to 9.73 µM. The compounds disturbed the whole intracellular life cycle of C. trachomatis, mainly targeting the middle reticulate body proliferation stages. Besides, the compounds partially inhibited the chlamydial infection by reducing elementary body infectivity at high concentration. Our findings suggest the potential of pyrroloisoxazolidine derivatives as promising lead molecules for the development of antichlamydial agents.