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1.
J Hazard Mater ; 423(Pt B): 127163, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34530275

RESUMO

Antibiotics are inevitably entered into anaerobic co-digestion (AcoD) system of food waste (FW) and sludge along with the addition of abundant antibiotic-containing activated sludge. However, the in-depth insights into antibiotics affecting AcoD performance have not comprehensively studied. In present study, the results showed that tetracycline (TC), sulfamethoxazole (SMZ) and erythromycin (ERY) inhibited and delayed methane production except for 5 mg/L ERY. By comparison, TC and SMZ significantly inhibited the cumulative methane yields (one-way ANOVA, p < 0.01), and the inhibition effects were magnified as the antibiotic level increased. Physicochemical and methane yield analysis indicated antibiotics inhibited hydrolysis process and delayed methanogenesis process, which was in line with the declined abundance of acetogenic Proteiniphilum and hydrogenotrophic Methanobacterium during AcoD. Furthermore, metatranscriptomic analysis demonstrated the microbial activities of major organic and energy metabolism were down-regulated under antibiotics exposure, thereby down-regulating the expressions of key coenzymes (coenzymes M, F420, methanofuran) biosynthesis for methanogenesis and methane metabolism. The declined methanogenesis activity was completely consistent with the inhibited activity of dominant Methanosarcina and methane production, proving the importance of Methanosarcina on methane production. This study provides new metatranscriptomic evidence into the effects of antibiotics on methanogenesis during AcoD.

2.
Sci Total Environ ; 805: 150158, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34537708

RESUMO

Using current wastewater treatment technologies, it can be challenging to remove the emerging contaminants (ECs) present in kitchen wastewater (KW) of complex compositions and high organic content. In this study, biochar, derived from straw, was modified as an adsorbent to remove ECs such as bisphenol A (BPA), tetracycline (TC) and ofloxacin (OFL) from a complex KW system. An alkali-modified biochar, having larger specific surface areas and stronger hydrophobicity, was found to exhibit a higher adsorption capacity, with more than 95% of the target ECs being removed. Indeed, in a static operation mode, the alkali-modified biochar had maximum adsorption capacities of 71.43, 101.01 and 54.05 mg/g for BPA, TC, and OFL, respectively. The adsorption kinetics and isotherms models indicated that the adsorption process was controlled by chemisorption, as well as the monolayer adsorption of contaminants onto the external and internal surfaces of the alkali-modified biochar. The adsorption of TC and OFL was significantly affected by the initial pH values of KW. However, the presence of different environmental factors (COD, NH4+ and PO43-) had little effects on the adsorption of the contaminants. The alkali-modified biochar was further tested in a fixed-bed column where the maximum dynamic adsorption capacities for BPA and OFL were 55 and 45 mg/g, representing about 75% and 83% of the static saturated adsorption capacities. These findings can be of major significance for the application of alkali-modified biochar in the removal of ECs from complex KW systems.


Assuntos
Águas Residuárias , Poluentes Químicos da Água , Adsorção , Álcalis , Antibacterianos , Compostos Benzidrílicos , Carvão Vegetal , Cinética , Fenóis
3.
Bioresour Technol ; 344(Pt B): 126257, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34752891

RESUMO

This study revealed the effects and regulation mechanisms on antibiotic resistance genes (ARGs) dissemination during anaerobic co-digestion (AcoD) of food waste and sludge under the exposure of tetracycline, sulfamethoxazole (SMZ) and erythromycin (ERY). Results indicated antibiotics significantly increased the abundance of ARGs, and selectively enriched integron gene, suggesting antibiotics promoted the dissemination of ARGs. Procrustes analysis indicated that bacterial community, integrons and physicochemical properties displayed significant correlations with ARGs, and they respectively contributed 10.61%, 6.94% and 2.97% of explanations on ARGs variation. Especially, the maximum combined contribution (48.6%) of bacterial community and integrons, implying their significances on ARGs alteration. Metatranscriptomic analysis further demonstrated antibiotics upregulated the expressions of total ARGs and virulence factors, raising potential risks. The proposed mechanisms for ARGs dissemination facilitated by antibiotics might be attributed to the changes of ARGs-regulated functions for inducing DNA/cell damage and DNA conjugation during AcoD.

4.
Cardiovasc Res ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528077

RESUMO

The Hippo pathway is an evolutionarily and functionally conserved signaling pathway that controls organ size by regulating cell proliferation, apoptosis, and differentiation. Emerging evidence has shown that the Hippo pathway plays critical roles in cardiac development, homeostasis, disease, and regeneration. Targeting the Hippo pathway has tremendous potential as a therapeutic strategy for treating intractable cardiovascular diseases such as heart failure. In this review, we summarize the function of the Hippo pathway in the heart. Particularly, we highlight the posttranslational modification of Hippo pathway components, including the core kinases LATS1/2 and their downstream effectors YAP/TAZ, in different contexts, which has provided new insights and avenues in cardiac research.

5.
Microorganisms ; 9(9)2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34576777

RESUMO

Pochonia chlamydosporia is a fungal parasite of nematode eggs. Studies have shown that some strains of Pochonia chlamydosporia can promote plant growth and induce plants' systemic resistance to root-knot nematodes by colonizing in their roots. This study aimed to verify the effect of the PC-170 strain on tomato growth and systemic resistance. Split-root experiments were conducted to observe the systemic resistance induced by PC-170. To explore the defense pathway that was excited due to the colonization by PC-170, we tested the expression of marker genes for defense pathways, and used mutant lines to verify the role of plant defense pathways. Our results showed that PC-170 can colonize roots, and promotes growth. We found a role for jasmonic acid (JA) in modulating tomato colonization by PC-170. PC-170 can activate tomato defense responses to reduce susceptibility to infection by the root-knot nematode Meloidogyne incognita, and induced resistance to some pathogens in tomatoes. The marker genes of the defense pathway were significantly induced after PC-170 colonization. However, salicylic acid (SA)- and jasmonic acid (JA)-dependent defenses in roots were variable with the invasion of different pathogens. Defense pathways play different roles at different points in time. SA- and JA-dependent defense pathways were shown to cross-communicate. Different phytohormones have been involved in tomato plants' responses against different pathogens. Our study confirmed that adaptive JA signaling is necessary to regulate PC-170 colonization and induce systemic resistance in tomatoes.

6.
Int J Clin Pract ; : e14900, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34546617

RESUMO

AIM: This meta-analysis aimed to explore potential risk factors for severe Covid-19. METHODS: We systemically and comprehensively retrieved the eligible study evaluating clinical differences between severe vs non-severe Covid-19. Main effect sizes were demographic characteristics, comorbidities, signs and symptoms, laboratory findings as well as radiological features of chest CT. RESULTS: A total of 2566 Covid-19 people (771 in the severe group and 1795 in the non-severe group) from 14 studies were eligible for this meta-analysis. It was demonstrated that older age and males were more likely to have severe Covid-19. Patients with underlying comorbidities, such as hypertension, diabetes, heart disease and COPD were significantly more susceptible to severe Covid-19. Patients with dyspnoea were more likely to be severely ill. Depressed total lymphocytes were observed in this article. Meanwhile, although reticulation (30.8%), intrathoracic lymph node enlargement (20.5%) and pleural effusions (30.8%) were relatively infrequent, meta-analysis revealed that patients with these presentations in chest CT were associated with increased risk of severe Covid-19. CONCLUSIONS: There are significant differences in clinical characteristics between the severe and non-severe Covid-19 patients. Many factors are related to the severity of the disease, which can help clinicians to differentiate severe patients from non-severe patients.

7.
Neurourol Urodyn ; 40(8): 1989-1998, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34487577

RESUMO

AIMS: The aim of this study was to develop and test the feasibility of a magnetic resonance imaging (MRI)-based measurement strategy to evaluate the effectiveness of surgical procedures in restoring normal anatomy in all three systems of pelvic floor support and quantify the structural changes induced by prolapse surgery. METHODS: Patients underwent clinical examination and stress MRI preoperatively and again 3 months postoperatively. Preoperative and postoperative measures of three MRI-based structural support systems were made: (1) vaginal wall, (2) apical and paravaginal support, and (3) hiatal closure system. Preoperative to postoperative structural changes were calculated and compared to normal values, and bivariate associations were determined. RESULTS: The three structural support systems were successfully quantified for both preoperative and postoperative MRIs regardless of operative approaches in all 15 women in the pilot group. Apical support was restored to normal in 11 of 12 patients who underwent an apical suspension procedure and 9 of 14 patients with a posterior repair had normalization of genital hiatus size. Mid-vaginal paravaginal location was elevated an average of 2.5 ± 2.0 cm despite no paravaginal repairs being performed. Paravaginal location improvements were also significantly correlated with apical elevation (r values 0.99-0.87, p < 0.001). CONCLUSIONS: A strategy that quantifies structural-specific preoperative impairments and improvements after prolapse surgery was successfully developed. Early findings reveal that prolapse surgery is more successful in restoring normal anatomy at Level I than Level III. Improvement in paravaginal location is significantly correlated with apical elevation.


Assuntos
Prolapso de Órgão Pélvico , Procedimentos Cirúrgicos Reconstrutivos , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Imageamento por Ressonância Magnética , Diafragma da Pelve/diagnóstico por imagem , Diafragma da Pelve/cirurgia , Prolapso de Órgão Pélvico/diagnóstico por imagem , Prolapso de Órgão Pélvico/cirurgia , Prolapso , Resultado do Tratamento , Vagina/diagnóstico por imagem , Vagina/cirurgia
8.
Mol Pharmacol ; 100(4): 372-387, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34353882

RESUMO

ONC201 is a first-in-class imipridone compound that is in clinical trials for the treatment of high-grade gliomas and other advanced cancers. Recent studies identified that ONC201 antagonizes D2-like dopamine receptors at therapeutically relevant concentrations. In the current study, characterization of ONC201 using radioligand binding and multiple functional assays revealed that it was a full antagonist of the D2 and D3 receptors (D2R and D3R) with low micromolar potencies, similar to its potency for antiproliferative effects. Curve-shift experiments using D2R-mediated ß-arrestin recruitment and cAMP assays revealed that ONC201 exhibited a mixed form of antagonism. An operational model of allostery was used to analyze these data, which suggested that the predominant modulatory effect of ONC201 was on dopamine efficacy with little to no effect on dopamine affinity. To investigate how ONC201 binds to the D2R, we employed scanning mutagenesis coupled with a D2R-mediated calcium efflux assay. Eight residues were identified as being important for ONC201's functional antagonism of the D2R. Mutation of these residues followed by assessing ONC201 antagonism in multiple signaling assays highlighted specific residues involved in ONC201 binding. Together with computational modeling and simulation studies, our results suggest that ONC201 interacts with the D2R in a bitopic manner where the imipridone core of the molecule protrudes into the orthosteric binding site, but does not compete with dopamine, whereas a secondary phenyl ring engages an allosteric binding pocket that may be associated with negative modulation of receptor activity. SIGNIFICANCE STATEMENT: ONC201 is a novel antagonist of the D2 dopamine receptor with demonstrated efficacy in the treatment of various cancers, especially high-grade glioma. This study demonstrates that ONC201 antagonizes the D2 receptor with novel bitopic and negative allosteric mechanisms of action, which may explain its high selectivity and some of its clinical anticancer properties that are distinct from other D2 receptor antagonists widely used for the treatment of schizophrenia and other neuropsychiatric disorders.


Assuntos
Antineoplásicos/metabolismo , Antagonistas dos Receptores de Dopamina D2/metabolismo , Imidazóis/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismo , Receptores de Dopamina D2/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CHO , Cricetinae , Cricetulus , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Dopamina D2/química
9.
Immunology ; 164(4): 803-816, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34396536

RESUMO

Retinal neovascularization (RNV), a pathological process shared among diabetic retinopathy, retinopathy of prematurity and other retinopathies, has been widely studied, but the mechanism remains unclear. In this study, the mechanism by which the interleukin (IL)-23/IL-17 axis regulates RNV in oxygen-induced retinopathy (OIR) model mice and in cell experiments in vitro was characterized. In the retinas of OIR mice, IL-23/IL-17 axis activation was increased and regulated RNV formation, and this effect was accompanied by increased macrophage recruitment and nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome activation. Moreover, inhibiting the IL-23/IL-17 axis reduced the number of macrophage and the expression and activation of NLRP3 inflammasome. On the other hand, recombinant (r) IL-23p19 and rIL-17A promoted the expression and activation of NLRP3 inflammasome, and the proliferation and migration of macrophages. Furthermore, macrophage elimination decreased the activation of IL-23/IL-17 axis and the expression and activation of NLRP3 inflammasome. In summary, our experiments showed that the IL-23/IL-17 axis promoted the formation of RNV by activating the NLRP3 inflammasome in retinal macrophages of an OIR mouse model.

10.
Front Chem ; 9: 689608, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34268295

RESUMO

The lumen of the endoplasmic reticulum (ER) has resident proteins that are critical to perform the various tasks of the ER such as protein maturation and lipid metabolism. These ER resident proteins typically have a carboxy-terminal ER retention/retrieval sequence (ERS). The canonical ERS that promotes ER retrieval is Lys-Asp-Glu-Leu (KDEL) and when an ER resident protein moves from the ER to the Golgi, KDEL receptors (KDELRs) in the Golgi recognize the ERS and return the protein to the ER lumen. Depletion of ER calcium leads to the mass departure of ER resident proteins in a process termed exodosis, which is regulated by KDELRs. Here, by combining computational prediction with machine learning-based models and experimental validation, we identify carboxy tail sequences of ER resident proteins divergent from the canonical "KDEL" ERS. Using molecular modeling and simulations, we demonstrated that two representative non-canonical ERS can stably bind to the KDELR. Collectively, we developed a method to predict whether a carboxy-terminal sequence acts as a putative ERS that would undergo secretion in response to ER calcium depletion and interacts with the KDELRs. The interaction between the ERS and the KDELR extends beyond the final four carboxy terminal residues of the ERS. Identification of proteins that undergo exodosis will further our understanding of changes in ER proteostasis under physiological and pathological conditions where ER calcium is depleted.

11.
Front Med (Lausanne) ; 8: 656615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34109195

RESUMO

Sleep plays an important role in immune function. However, the effects of very-short-term sleep deprivation on the early recovery of immune function after sepsis remain unclear. This study was conducted in the intensive care unit to investigate the effects of 2 consecutive days of sleep deprivation (SD) on lymphocyte recovery over the following few days in septic patients who were recovering from a critical illness. The patients' self-reports of sleep quality was assessed using the Richards-Campbell Sleep Questionnaire at 0 and 24 h after inclusion. The demographic, clinical, laboratory, treatment, and outcome data were collected and compared between the good sleep group and poor sleep group. We found that 2 consecutive days of SD decreased the absolute lymphocyte count (ALC) and ALC recovery at 3 days after SD. Furthermore, post-septic poor sleep decreased the plasma levels of atrial natriuretic peptide (ANP) immediately after 2 consecutive days of SD. The ANP levels at 24 h after inclusion were positively correlated with ALC recovery, the number of CD3+ T cells, or the number of CD3+ CD4+ cells in the peripheral blood on day 5 after inclusion. Our data suggested that very-short-term poor sleep quality could slow down lymphocyte recovery over the following few days in septic patients who were recovering from a critical illness. Our results underscore the significance of very-short-term SD on serious negative effects on the immune function. Therefore, it is suggested that continuous SD or several short-term SD with short intervals should be avoided in septic patients.

12.
ACS Appl Mater Interfaces ; 13(23): 27382-27391, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34081431

RESUMO

To overcome the inherent high hysteresis loss of ferroelectric polymer-based nanocomposites, non-ferroelectric linear dielectric poly(methyl methacrylate) (PMMA) is adopted as the polymer matrix for high discharge efficiency. At the same time, slender ferroelectric BaTiO3 nanowires (BT NWs) with a high dielectric constant are selected as the nanofiller for high energy density. To avoid the agglomeration of BT NWs and enhance the strength of interfaces, dopamine is used as organic coatings to tailor the interface. The BT@dopa NWs/PMMA nanocomposites exhibit excellent interface compatibility between the BT NWs and PMMA matrix and a very good microstructure uniformity. Based on this, hierarchically structured BT@SiO2@dopa NWs are designed and prepared to overcome the uneven electric field distribution at the interface, resulting from the dielectric constant mismatch. The discharged energy density (Ue) can be largely enhanced from 3.76 J/cm3 for pure PMMA films to 11.78 J/cm3 for PMMA-based nanocomposites by incorporating 5.0 wt % BT@SiO2@dopa NWs. In addition, a high discharging efficiency (η) of 91% is obtained simultaneously in the nanocomposites. Both experimental and theoretical simulations demonstrate that the double core-shell structure nanowire fillers can effectively alleviate the local field distortion, inhibit leakage current, and suppress remnant electric displacement, leading to the high Ue and η. These findings are significant in facilitating the development of high-performance film dielectric capacitor materials using PMMA-based nanocomposites toward high energy storage density.

13.
Chem Pharm Bull (Tokyo) ; 69(6): 529-536, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34078799

RESUMO

Emerging evidence highlights the importance of microRNAs (miRNAs) as functional regulators in cardiovascular disease. This study aimed to investigate the functional significance of miR-135a in the regulation of cardiac injury after isoprenaline (ISO) stimulation and the underlying mechanisms of its effects. Murine models with cardiac-specific overexpression of miR-135a were constructed with an adeno-associated virus expression system. The cardiac injury model was induced by ISO injection (60 mg/kg per day for 14 d). In vitro, we used H9c2 cells to establish a cell injury model by ISO stimulation (10 µM). The results indicated that miR-135a was increased during days 0-6 of ISO injection and was then downregulated during days 8-14 of ISO injection. The expression of miR-135a was consistent with the in vivo findings. Moreover, mice with cardiac overexpression of miR-135a exhibited reduced cardiac fibrosis, lactate dehydrogenase levels, Troponin I, inflammatory response and apoptosis. Overexpression of miR-135a also ameliorated cardiac dysfunction induced by ISO. MiR-135 overexpression in H9c2 cells increased cell viability and decreased cell apoptosis and inflammation in response to ISO. Conversely, miR-135 silencing in H9c2 cells decreased cell viability and increased cell apoptosis and inflammation in response to ISO. Mechanistically, we found that miR-135a negatively regulated toll-like receptor 4 (TLR4), which was confirmed by luciferase assay. Furthermore, the TLR4 inhibitor eritoran abolished the adverse effect of miR-135 silencing. Overall, miR-135a promotes ISO-induced cardiac injury by inhibiting the TLR4 pathway. MiR-135a may be a therapeutic agent for cardiac injury.


Assuntos
MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Células Cultivadas , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/patologia
14.
Mol Biol Evol ; 38(10): 4222-4237, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34164688

RESUMO

The frameshift hypothesis is a widely accepted model of bird wing evolution. This hypothesis postulates a shift in positional values, or molecular-developmental identity, that caused a change in digit phenotype. The hypothesis synthesized developmental and paleontological data on wing digit homology. The "most anterior digit" (MAD) hypothesis presents an alternative view based on changes in transcriptional regulation in the limb. The molecular evidence for both hypotheses is that the MAD expresses Hoxd13 but not Hoxd11 and Hoxd12. This digit I "signature" is thought to characterize all amniotes. Here, we studied Hoxd expression patterns in a phylogenetic sample of 18 amniotes. Instead of a conserved molecular signature in digit I, we find wide variation of Hoxd11, Hoxd12, and Hoxd13 expression in digit I. Patterns of apoptosis, and Sox9 expression, a marker of the phalanx-forming region, suggest that phalanges were lost from wing digit IV because of early arrest of the phalanx-forming region followed by cell death. Finally, we show that multiple amniote lineages lost phalanges with no frameshift. Our findings suggest that the bird wing evolved by targeted loss of phalanges under selection. Consistent with our view, some recent phylogenies based on dinosaur fossils eliminate the need to postulate a frameshift in the first place. We suggest that the phenotype of the Archaeopteryx lithographica wing is also consistent with phalanx loss. More broadly, our results support a gradualist model of evolution based on tinkering with developmental gene expression.

15.
Pharmacol Res ; 170: 105722, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34116208

RESUMO

A progressive increase in drug craving following drug exposure is an important trigger of relapse. CircularRNAs (CircRNAs), key regulators of gene expression, play an important role in neurological diseases. However, the role of circRNAs in drug craving is unclear. In the present study, we trained mice to morphine conditioned place preference (CPP) and collected the nucleus accumbens (NAc) sections on abstinence day 1 (AD1) and day 14 (AD14) for RNA-sequencing. CircTmeff-1, which was highly expressed in the NAc core, was associated with incubation of context-induced morphine craving. The gain- and loss- of function showed that circTmeff-1 was a positive regulator of incubation. Simultaneously, the expression of miR-541-5p and miR-6934-3p were down-regulated in the NAc core during the incubation period. The dual luciferase reporter, RNA pulldown, and fluorescence insitu hybridization assays confirmed that miR-541-5p and miR-6934-3p bind to circTmeff-1 selectively. Furthermore, bioinformatics and western blot analysis suggested that vesicle-associated membrane protein 1 (VAMP1) and neurofascin (NFASC), both overlapping targets of miR-541-5p and miR-6934-3p, were highly expressed during incubation. Lastly, AAV-induced down-regulation of circTmeff-1 decreased VAMP1 and NFASC expression and incubation of morphine craving. These findings suggested that circTmeff-1, a novel circRNA, promotes incubation of context-induced morphine craving by sponging miR-541/miR-6934 in the NAc core. Thus, circTmeff-1 represents a potential therapeutic target for context-induced opioid craving, following prolonged abstinence.

16.
Cell Biosci ; 11(1): 82, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933165

RESUMO

BACKGROUND: Neovascularization is a leading cause of visual loss typically associated with diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Interleukin-17A (IL-17A) and endoplasmic reticulum (ER) stress both have been demonstrated to play a proangiogenic role in ischemic retinopathies. However, the relationship between IL-17A and ER stress in retinal neovascularization (RNV) under hypoxic conditions and its underlying mechanisms remain unclear. METHODS: In this study, oxygen-induced retinopathy (OIR) mice model was established and intravitreal injections were conducted. Changes of IL-17A and ER stress markers in retinas and cultured primary bone marrow derived macrophage (BMDM) under normoxic or hypoxic conditions were detected. Western blotting, Real-Time RT-PCR, Immunofluorescence assays were conducted to explore the roles and relationship of IL-17A and ER stress in RNV, as well as its underlying mechanisms. RESULTS: Compared to that in normal controls, IL-17A and ER stress markers were all remarkably increased under hypoxic conditions both in vivo and in vitro. Neutralization or knock out of IL-17A decreased ER stress. ER stress inhibitor 4-phenylbutyrate (4-PBA), attenuated the production of IL-17A, suggesting a positive feedback loop between IL-17A and ER stress. Inhibition of IL-17A or ER stress decreased areas of nonperfusion and neovascularization in OIR retinas. As TXNIP/NLRP3 pathway activation has been demonstrated to be involved in increased retinal vascular permeability of ischemic retinopathy, we observed that TXNIP/NLRP3 pathway mediated in the interaction between IL-17A and ER stress under hypoxic conditions. CONCLUSION: The interplay between IL-17A and ER stress contributes to RNV in macrophages via modulation of TXNIP/NLRP3 signaling pathway under hypoxic conditions. The feedback loops may become an innovative and multiple pharmacological therapeutic target for ischemic retinopathy.

17.
Acta Pharmacol Sin ; 42(12): 2144-2154, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34017067

RESUMO

Mitochondria are essential organelles that provide energy for mammalian cells and participate in multiple functions, such as signal transduction, cellular differentiation, and regulation of apoptosis. Compared with the mitochondria in somatic cells, oocyte mitochondria have an additional level of importance since they are required for germ cell maturation, dysfunction in which can lead to severe inherited disorders. Thus, a systematic proteomic profile of oocyte mitochondria is urgently needed to support the basic and clinical research, but the acquisition of such a profile has been hindered by the rarity of oocyte samples and technical challenges associated with capturing mitochondrial proteins from live oocytes. Here, in this work, using proximity labeling proteomics, we established a mitochondria-specific ascorbate peroxidase (APEX2) reaction in live GV-stage mouse oocytes and identified a total of 158 proteins in oocyte mitochondria. This proteome includes intrinsic mitochondrial structural and functional components involved in processes associated with "cellular respiration", "ATP metabolism", "mitochondrial transport", etc. In addition, mitochondrial proteome capture after oocyte exposure to the antitumor chemotherapeutic cisplatin revealed differential changes in the abundance of several oocyte-specific mitochondrial proteins. Our study provides the first description of a mammalian oocyte mitochondrial proteome of which we are aware, and further illustrates the dynamic shifts in protein abundance associated with chemotherapeutic agents.

18.
J Hazard Mater ; 416: 125744, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862482

RESUMO

The prevalence of antibiotic resistance genes (ARGs) has been widely reported in various environments. However, little is known of them in food waste (FW) leachate with high organic content and how their distribution is influenced by biotreatment processes. Here, twelve ARGs, two integrase genes and bacterial communities were investigated during two full-scale FW biotreatment processes. High ARGs abundances (absolute: 1.03 × 107-2.82 × 109copies/mL; relative: 0.076-2.778copies/16S rRNA) were observed across all samples. Although biotreatment effectively reduced absolute abundance of ARGs, additional bacteria acquiring ARGs caused an increase in their relative abundance, which further increased the transmission risk of ARGs. mexF, blaCTX-M, sul1 played crucial roles and sul1 might be considered as an indicator for the prediction of total ARGs. It is worrying that the discharge (effluent and sludge) included highly abundant ARGs (5.09 × 1014-4.83 × 1015copies/d), integrons (1.11 × 1014-6.04 × 1014copies/d) and potential pathogens (such as Pseudomonas and Streptococcus), which should be given more attentions. blaCTX-M and tetQ possessed most potential hosts, Proteobacteria-L and Firmicutes-W were predominant contributors of ARGs-hosts at genus level. This study suggested FW leachate biotreatment systems could be reservoirs of ARGs and facilitated the proliferation of them. The exploration of effective removal methods and formulation of emission standard are necessary for future ARGs mitigation.


Assuntos
Microbiota , Eliminação de Resíduos , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/genética , Alimentos , Genes Bacterianos , RNA Ribossômico 16S , Águas Residuárias
19.
Huan Jing Ke Xue ; 42(5): 2413-2421, 2021 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-33884812

RESUMO

The organic fraction of municipal solid waste (OFMSW) has become one of the sources and reservoirs of antibiotic resistance genes (ARGs). It is essential to explore the fate of ARGs during biological treatment of OFMSW. Therefore, the changes in several types of ARGs and integron genes during anaerobic digestion of the OFMSW were analyzed by quantitative PCR. Furthermore, the effects of different particle sizes of activated carbon on the behaviors of the target genes and the potential microbial mechanisms of ARGs dynamics were investigated. The results showed that the total ARGs in the initial system were reduced after anaerobic digestion with or without the presence of activated carbon. The removal rate of the absolute abundance of total ARGs was 29.95%-63.40%. In the final system of anaerobic digestion of the OFMSW, the abundance of total ARGs in powdered activated carbon (PAC) groups was significantly higher than that in the control group (P<0.05). The supplementation of PAC inhibited the reduction of ARGs, and the supplementation of granular activated carbon had no significant effect on the change in ARGs. The potential host bacteria of ARGs were mainly Clostridia, Bacteroidia, and Synergistia during anaerobic digestion. The enrichment of host bacteria caused by PAC addition was the main reason for the increase in the target genes. Moreover, Clostridia might have been the main driving factor for the growth and decline of ARGs. These results will help us to understand the dissemination of ARGs and the impacts of activated carbon addition on ARGs during anaerobic digestion of the OFMSW.


Assuntos
Antibacterianos , Resíduos Sólidos , Anaerobiose , Antibacterianos/farmacologia , Carvão Vegetal , Resistência Microbiana a Medicamentos , Genes Bacterianos/genética
20.
Biomolecules ; 11(4)2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924613

RESUMO

The dopamine D2/D3 receptor (D2R/D3R) agonists are used as therapeutics for Parkinson's disease (PD) and other motor disorders. Selective targeting of D3R over D2R is attractive because of D3R's restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D2R and D3R poses a challenge in the development of D3R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D3R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D3R and D2R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D3R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D3R over D2R selectivity, and G protein bias at D3R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D3R and support further evaluation of functionally biased D3R agonists for their therapeutic potential.


Assuntos
Agonistas de Dopamina/farmacologia , Receptores de Dopamina D3/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacologia , Sítios de Ligação , Agonistas de Dopamina/síntese química , Transferência de Energia , Células HEK293 , Humanos , Luminescência , Morfolinas/química , Morfolinas/farmacologia , Ligação Proteica , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/química , Estereoisomerismo , Relação Estrutura-Atividade
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