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1.
Bioact Mater ; 7: 324-332, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34466735

RESUMO

Formation of graded biomaterials to render shape-morphing scaffolds for 4D biofabrication holds great promise in fabrication of complex structures and the recapitulation of critical dynamics for tissue/organ regeneration. Here we describe a facile generation of an adjustable and robust gradient using a single- or multi-material one-step fabrication strategy for 4D biofabrication. By simply photocrosslinking a mixed solution of a photocrosslinkable polymer macromer, photoinitiator (PI), UV absorber and live cells, a cell-laden gradient hydrogel with pre-programmable deformation can be generated. Gradient formation was demonstrated in various polymers including poly(ethylene glycol) (PEG), alginate, and gelatin derivatives using various UV absorbers that present overlap in UV spectrum with that of the PI UV absorbance spectrum. Moreover, this simple and effective method was used as a universal platform to integrate with other hydrogel-engineering techniques such as photomask-aided microfabrication, photo-patterning, ion-transfer printing, and 3D bioprinting to fabricate more advanced cell-laden scaffold structures. Lastly, proof-of-concept 4D tissue engineering was demonstrated in a study of 4D bone-like tissue formation. The strategy's simplicity along with its versatility paves a new way in solving the hurdle of achieving temporal shape changes in cell-laden single-component hydrogel scaffolds and may expedite the development of 4D biofabricated constructs for biological applications.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34637590

RESUMO

Engineering of cell plasma membrane using functional DNA is important for study and control of cellular behaviors. However, most efforts limit to apply artificial DNA interactions on external cell membrane due to the lack of suitable synthetic tools to engineer intracellular side, which impedes many applications in cell biology. Inspired by natural extracellular vesicle-cell fusion process, we introduce a fusogenic spherical nucleic acid construct to realize robust DNA functionalization on both external and internal cell surfaces via liposome fusion-based transport (LiFT), enabling applications including construction of heterotypic cell assembly for programmed signaling pathway and detection of intracellular metabolites. This approach can engineer cell membrane in a highly efficient and spatially-controlled manner, allowing for building anisotropic membrane structure with two orthogonal DNA functionalities.

3.
Lab Chip ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34608465

RESUMO

Microfluidic paper-based analytical devices (µPADs) are foundational devices for point-of-care testing, yet suffer from limitations in regards to their sensitivity and capability in handling complex assays. Here, we demonstrate an airflow-based, evaporative method that is capable of manipulating fluid flows within paper membranes to offer new functionalities for multistep delivery of reagents and improve the sensitivity of µPADs by 100-1000 times. This method applies an air-jet to a pre-wetted membrane, generating an evaporative gradient such that any solutes become enriched underneath the air-jet spot. By controlling the lateral position of this spot, the solutes in the paper strip are enriched and follow the air jet trajectory, driving the reactions and enhancing visualization for colorimetric readout in multistep assays. The technique has been successfully applied to drive the sequential delivery in multistep immunoassays as well as improve sensitivity for colorimetric detection assays for nucleic acids and proteins via loop-mediated isothermal amplification (LAMP) and ELISA. For colorimetric LAMP detection of the COVID-19 genome, enrichment of the solution on paper could enhance the contrast of the dye in order to more clearly distinguish between the positive and negative results to achieve a sensitivity of 3 copies of SARS-Cov-2 RNAs. For ELISA, enrichment of the oxidized TMB substrate yielded a sensitivity increase of two-to-three orders of magnitude when compared to non-enriched samples - having a limit of detection of around 200 fM for IgG. Therefore, this enrichment method represents a simple process that can be easily integrated into existing detection assays for controlling fluid flows and improving detection of biomarkers on paper.

4.
Pharm Stat ; 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34605168

RESUMO

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross-industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34626041

RESUMO

Surface terminations of two-dimensional MXene (Ti 3 C 2 T x ) considerably impact its physicochemical properties. Commonly used etching methods usually introduce -F surface terminations or metallic impurities in MXene. We present a new molten-salt-assisted electrochemical etching method to synthesize fluorine-free Ti 3 C 2 Cl 2 . Using electrons as reaction agents, cathode reduction and anode etching can be spatially isolated; thus,  no metallics are present in the Ti 3 C 2 Cl 2 product. The surface terminations can be in situ modified from -Cl to -O and/or -S, which considerably shortens the modification steps and enriches the the variety of surface terminations. The obtained -O-terminated Ti 3 C 2 T x are excellent electrode materials for supercapacitors, exhibiting capacitances of 225 F g -1 at 1.0 A g -1 , good rate performance (91.1% at 10 A g -1 ) and excellent capacitance retention (100 % after 10000 charging-discharging cycles at 10 A g -1 ), which is superior to multi-layered Ti 3 C 2 T x prepared by other etching methods.

6.
J Cell Physiol ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34676546

RESUMO

Circular RNAs (circRNAs) are closed back-splicing products of precursor mRNA in eukaryotes. Compared with linear mRNAs, circRNAs have a special structure and stable expression. A large number of studies have provided different regulatory mechanisms of circRNAs in tumors. Challenges exist in understanding the control of circRNAs because of their sequence overlap with linear mRNA. Here, we survey the most recent progress regarding the regulation of circRNA biogenesis by RNA-binding proteins, one of the vital functional proteins. Furthermore, substantial circRNAs exert compelling biological roles by acting as protein sponges, by being translated themselves or regulating posttranslational modifications of proteins. This review will help further explore more types of functional proteins that interact with circRNA in cancer and reveal other unknown mechanisms of circRNA regulation.

7.
Bioconjug Chem ; 32(10): 2173-2183, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34606715

RESUMO

Stapled α-helical peptides emerge as one of the attractive peptidomimetics which can efficiently penetrate the cell membrane to access intracellular targets. However, the incorporation of a highly lipophilic cross-link may lead to nonspecific membrane toxicity in certain cases. Here, we report a new class of thioether-tethered bicyclic α-helical peptide to mimic the highly constrained loop-helix structure of natural toxins with the dual-targeting ability for both cell-surface receptors and intracellular targets. The thioether cross-links are introduced to replace the redox-sensitive disulfide bonds in natural toxins via a photoinduced thiol-yne reaction followed by macrolactamization. As a proof of concept, αVß3 integrin targeting ligand was grafted into one of the macrocycles in the bicyclic scaffold, while a mitochondria-targeting proapoptotic motif was introduced into the other macrocycle stabilized by an i, i + 7 alkyl thioether cross-link to recapitulate its α-helical conformation. The obtained dual-targeting bicyclic α-helical BIRK peptides showed highly stable α-helical conformation in the presence of denaturants or under high temperature. Notably, BIRK peptides could induce selective cell death in αVß3 integrin-positive B16F10 cells by interfering with the bioenergetic functions of mitochondria. This work provides a new avenue to design and stabilize α-helical peptides in a highly constrained bicyclic loop-helix scaffold with dual functionality.

8.
Sci Total Environ ; 807(Pt 1): 150775, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34619187

RESUMO

An unprecedented devastating forest fire occurred in Australia from September 2019 to March 2020. Satellite observations revealed that this rare fire event in Australia destroyed a record amount of more than 202,387 km2 of forest, including 56,471 km2 in eastern Australia, which is mostly composed of evergreen forest. The released aerosols contained essential nutrients for the growth of marine phytoplankton and were transported by westerly winds over the Southern Ocean, with rainfall-induced deposition to the ocean beneath. Here, we show that a prominent oceanic bloom, indicated by the rapid growth of phytoplankton, took place in the Southern Ocean along the trajectory of fire-born aerosols in response to atmospheric deposition. Calculations of carbon released during the fire versus carbon absorbed by the oceanic phytoplankton bloom suggest that they were nearly equal. This finding illustrates the critical role of the oceans in mitigating natural and anthropogenic carbon dioxide releases to the atmosphere, which are a primary driver of climate change.

9.
Water Res ; 204: 117599, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34481285

RESUMO

Extensive use of organoarsenic feed additives such as roxarsone has caused organoarsenicals to occur in livestock wastewater and further within anaerobic wastewater treatment systems. Currently, information on the long-term impacts of roxarsone on anaerobic granular sludge (AGS) activity and the underlying mechanisms is very limited. In this study, the response of AGS to long-term loading of roxarsone was investigated using a laboratory up-flow anaerobic sludge blanket reactor spiked with 5.0 mg L-1 of roxarsone. Under the effect of roxarsone, methane production decreased by ∼40% due to the complete inhibition on acetoclastic methanogenic activity on day 260, before being restored eventually. Over 30% of the influent arsenic was accumulated in the AGS and the capability of AGS to prevent intracellular As(III) accumulation increased with time. The AGS size was reduced by ∼30% to 1.20‒1.26 mm. Based on morphology and confocal laser scanning microscopy analysis, roxarsone exposure stimulated the excretion of extracellular polymeric substances and the surface spalling of AGS. High-throughput sequencing analysis further indicated roxarsone initially altered the acidogenic pathway and severely inhibited the acetoclastic methanogen Methanothrix. Acetogenic bacteria and Methanothrix were finally enriched and became the main contributor for a full restoration of the initial methane production. These findings provide a deeper understanding on the effect of organoarsenicals on AGS, which is highly beneficial for the effective anaerobic treatment of organoarsenic-bearing wastewater.


Assuntos
Roxarsona , Esgotos , Anaerobiose , Reatores Biológicos , Eliminação de Resíduos Líquidos , Águas Residuárias
10.
J Clin Lab Anal ; : e24006, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545630

RESUMO

PURPOSE: The purpose of this study was to construct and validate a simple model for the prediction of survival in patients with trauma-related ARDS. METHODS: This is a single-center, retrospective cohort study using MIMIC-III Clinical Database. RESULTS: 842 patients were included in this study. 175 (20.8%) died in-hospital, whereas 215 (25.5%) died within 90 days. The deceased group had higher Acute Physiology Score (APS III), Sequential Organ Failure Assessment (SOFA), and Simplified Acute Physiology Score II (SAPS II). In multivariate logistic regression model, independent risk factors for mortality in ARDS patients included age ([odds ratio] OR, 1.035; 95% confidence interval [CI], 1.020-1.049), body mass index (OR, 0.957; 95% CI, 0.926-0.989), red blood cell distribution width (OR, 1.283; 95% CI, 1.141-1.443), hematocrit (OR, 1.055; 95% CI, 1.017-1.095), lactate (OR, 1.226; 95% CI, 1.127-1.334), blood urea nitrogen (OR, 1.025; 95% CI, 1.007-1.044), acute kidney failure (OR, 1.875; 95% CI, 1.188-2.959), sepsis (OR, 1.917; 95% CI, 1.165-3.153), type of admission (emergency vs. elective [OR, 2.822; 95% CI, 1.647-4.837], and urgent vs. elective [OR, 5.156; 95% CI, 1.896-14.027]). The area under the curve (AUC) of the model was 0.826, which was superior than the SAPS II (0.776), APS III (0.718), and SOFA (0.692). In the cross-validation model, the accuracy of the test set was 0.823, the precision was 0.643, and the AUC was 0.813. CONCLUSIONS: We established a prediction model using data commonly used in the clinic, which has high accuracy and precision and is worthy of use in clinical practice.

11.
Chem Commun (Camb) ; 57(77): 9898-9901, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34494624

RESUMO

A Z-scheme system was successfully constructed for visible-light-driven photocatalytic H2 production from lignocelluloses, the highest H2 evolution rate of this Z-scheme system is 5.3 and 1.6 µmol h-1 in α-cellulose and poplar wood chip aqueous solutions, respectively, under visible light irradiation.

12.
Appl Environ Microbiol ; : AEM0032121, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586911

RESUMO

Steroidal 17-carbonyl reduction is crucial to the production of natural bioactive steroid medicines, boldenone (BD) is one of the important C17-hydroxylated steroids. Although efforts have been made to produce BD through biotransformation, the challenge of complex transformation process, high substrates cost, and low catalytic efficiencies have yet to be mastered. Phytosterol (PS) is the most widely accepted substrate for the production of steroid medicines due to its similar foundational structure and ubiquitous sources. 17ß-Hydroxysteroid dehydrogenase (17ßHSD) and its native electron donor play significant roles in the 17ß-carbonyl reduction reaction of steroids. In this study, we bridged 17ßHSD with a cofactor regeneration strategy in Mycobacterium neoaurum to establish a one-step biocatalytic carbonyl reduction strategy for efficient biosynthesis of BD from PS for the first time. After investigating different intracellular electron transfer strategies, we rationally designed the engineered strain with co-expression of 17ßhsd and glucose-6-phosphate dehydrogenase (G6PDH) gene in M. neoaurum. With establishment of an intracellular cofactor regeneration strategy, the ratio of [NADPH]/[NADP+] was maintained at a relatively high level, the yield of BD increased from 17% (in MNR M3M-ayr1S.c) to 78% (in MNR M3M-ayr1&g6p with glucose supplementation), and the productivity was increased by 6.5 times. Furthermore, under the optimal glucose supplementation condition, the yield of BD reached 82%, which is the highest yield reported by transformation from PS with one-step. This study demonstrated an excellent strategy for production of many other valuable carbonyl reduction steroidal products from natural cheap raw materials. Importance Steroid C17-carbonyl reduction is one of the important transformations for the production of valuable steroidal medicines or intermediates for further synthesis of steroidal medicines, but it remains a challenge through either chemical or biological synthesis. Phytosterol can be obtained from low-cost residue of waste natural materials, and it is preferred as the economical and applicable substrate for steroid medicines production by Mycobacterium. This study explored a green and efficient one-step biocatalytic carbonyl reduction strategy for direct conversion of phytosterol to C17-hydroxylated steroids by bridging 17ß-Hydroxysteroid dehydrogenase with a cofactor regeneration strategy in Mycobacterium neoaurum. This work has practical value for the production of many valuable hydroxylated steroids from natural cheap raw materials.

14.
Phys Chem Chem Phys ; 23(36): 20489-20495, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34499059

RESUMO

As there is a rising interest in upgrading cellulose to high-performance bio-products, the studies on innovative reaction media and processes have been leaping forward. Green solvents in terms of cellulose dissolution and brief processes for upgrading are critical to green chemistry. However, most solvent systems generally exhibit defects in harsh pH operating windows with limited temperature ranges, environmental pollution, long reaction times, complicated processes, etc. In this work, we have provided a novel molten salt hydrate (CaCl2·6H2O-LiCl) as a green solvent and investigated the role of hydrated molten salts in the dissolution process via the solid state nuclear magnetic resonance (NMR) technique. The cellulose could be dissolved in CaCl2·6H2O-LiCl molten salt hydrated at 120 °C with 3.0% solubility and regenerated in-situ by cooling down to ambient temperature. The regenerated cellulose exhibited a high solubility and excellent stability. From 7Li single pulse NMR experiments, it was observed that two types of Li+ existed in the cellulose dissolution, and the Li+ significantly impacted the dissolving process and the dissolution ability of cellulose. This work would provide an environmental-friendly strategy to prepare cellulose solutions for biocompatible cellulose materials.

15.
Math Biosci Eng ; 18(5): 5573-5591, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34517501

RESUMO

As an epitome of deep learning, convolutional neural network (CNN) has shown its advantages in solving many real-world problems. Successful CNN applications on medical prognosis and diagnosis have been achieved in recent years. Their common goal is to recognize the insights from the subtle details from medical images by building a suitable CNN model with maximum accuracy and minimum error. The CNN performance is extremely sensitive to the parameter tuning for any given network structure. To approach this concern, a novel self-tuning CNN model is proposed with a significant characteristic of having a metaheuristic-based optimizer. The most optimal set of parameters is often found via our proposed method, namely group theory and random selection-based particle swarm optimization (GTRS-PSO). The insights of symmetric essentials of model structure and parameter correlation are extracted, followed by the hierarchical partitioning of parameter space, and four operators on those partitions are designed for moving neighborhoods and formulating the swarm topology accordingly. The parameters are updated by a random selection strategy at each interval of partitions during the search process. Preliminary experiments over two radiology image datasets: breast cancer and lung cancer, are conducted for a comprehensive comparison of GTRS-PSO versus other optimization algorithms. The results show that CNN with GTRS-PSO optimizer can achieve the best performance for cancer image classifications, especially when there are symmetric components inside the data properties and model structures.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Algoritmos , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Redes Neurais de Computação
16.
Nat Cell Biol ; 23(8): 915-924, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34341533

RESUMO

Metastasis is the leading cause of cancer-related deaths and enables cancer cells to compromise organ function by expanding in secondary sites. Since primary tumours and metastases often share the same constellation of driver mutations, the mechanisms that drive their distinct phenotypes are unclear. Here we show that inactivation of the frequently mutated tumour suppressor gene LKB1 (encoding liver kinase B1) has evolving effects throughout the progression of lung cancer, which leads to the differential epigenetic re-programming of early-stage primary tumours compared with late-stage metastases. By integrating genome-scale CRISPR-Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin accessibility in lung adenocarcinoma primary tumours. Using an in vivo model of metastatic progression, we further show that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and a metastatic-like sub-population of cancer cells within primary tumours. The expression of SOX17 is necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.


Assuntos
Adenocarcinoma/genética , Cromatina/metabolismo , Neoplasias Pulmonares/genética , Metástase Neoplásica/genética , Proteínas Serina-Treonina Quinases/fisiologia , Adenocarcinoma/fisiopatologia , Animais , Linhagem Celular Tumoral , Feminino , Proteínas HMGB/metabolismo , Humanos , Neoplasias Pulmonares/fisiopatologia , Masculino , Camundongos , Mutação , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição SOXF/metabolismo
17.
Insects ; 12(8)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34442232

RESUMO

Cordyceps, a parasitic complex of the fungus Ophiocordyceps sinensis (Berk.) (Hypocreales: Ophiocordycipitaceae) and the ghost moth Thitarodes (Lepidoptera: Hepialidae), is a historical ethnopharmacological commodity in China. Recently, artificial cultivation of Chinese cordyceps has been established to supplement the dwindling natural resources. However, much is unknown between the natural and cultivated products in terms of nutritional aspect, which may provide essential information for quality evaluation. The current study aims to determine the metabolic profiles of 17 treatments from 3 sample groups including O. sinensis fungus, Thitarodes insect and cordyceps complex, using Gas Chromatography - Quadrupole Time-of-Flight Mass Spectrometry. A total of 98 metabolites were detected, with 90 of them varying in concentrations among groups. The tested groups could be separated, except that fungal fruiting body was clustered into the same group as Chinese cordyceps. The main distinguishing factors for the groups studied were the 24 metabolites involved in numerous different metabolic pathways. In conclusion, metabolomics of O. sinensis and its related products were determined mainly by the fruiting bodies other than culture methods. Our results suggest that artificially cultured fruiting bodies and cordyceps may share indistinguishable metabolic functions as the natural ones.

18.
Artigo em Inglês | MEDLINE | ID: mdl-34338976

RESUMO

Systemic contact dermatitis (SCD) is a generalized reactivation of type IV hypersensitivity skin diseases in individuals with previous sensitization after a contact allergen is administered systemically. Patients with SCD may consider their dermatitis unpredictable and recalcitrant since the causative allergens are difficult to find. If a patient has a pattern of dermatitis suggestive of SCD but fails to improve with conventional treatment, SCD should be taken into consideration. If doctors are not familiar with the presentations of SCD and the possible routes of allergen sensitization and exposure, the diagnosis of SCD may be delayed. In this work, we summarized all of the routes through which allergens can enter the body and cause SCD, including oral intake, local contact (through skin, inhalation, nasal spray and anal application), implants, and other iatrogenic or invasive routes (intravenous, intramuscular, intraarticular, and intravesicular). This will provide a comprehensive reference for the clinicians to identify the culprit of SCD.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34436661

RESUMO

PURPOSE: The aim of the study was to evaluate the usefulness of a novel modified Meso-Rex bypass surgical technique with umbilical vein recanalization and intra-operative stenting to treat portal vein cavernous transformation. METHODS: In total, 13 portal vein cavernous transformation patients underwent Meso-Rex bypass surgery, consisting of bypass grafts between the superior mesenteric vein (SMV) and the recess of Rex as well as through the ligamentum teres hepatis without stent implantation (Group A, n = 9) and umbilical vein recanalization with intra-operative stent implantation (Group B, n = 4). RESULTS: In Group A, the bypass diameter was 0-6 mm (median 3 mm) and blood flow velocity 25-115 cm/s (median 72 cm/s) 1 month after Meso-Rex bypass surgery, with open bypass times of 0-67 months (median 6 months); 6 patients in this group developed postoperative Meso-Rex bypass occlusions. A patient in Group A treated with ligamentum teres hepatis recanalization needed a thrombectomy and stent implantation during a second surgery 2 days after the Meso-Rex bypass, because of bypass thrombosis and umbilical vein stenosis. In Group B, the average modified Meso-Rex bypass diameter was 5.5-6.5 mm (median 6 mm), and the bypass vessels remained open in all patients, with blood flow rates of 45-100 cm/s (median 76.5 cm/s) 1 month after the modified Meso-Rex bypass, up to the endpoint (15-33 months, median 24 months). The rate of bypass occlusions in Group A and Group B were 22.2% and 0%, 30.0% and 0%, and 55.6% and 0% at 1 month, 3 months, and 1 year, respectively, after bypass surgery. CONCLUSIONS: Our novel modified Meso-Rex bypass approach for portal vein cavernous transformation treatment was effective with excellent long-term bypass patency.

20.
PLoS Negl Trop Dis ; 15(8): e0009696, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34398890

RESUMO

Schistosomiasis is a neglected tropical disease of public health concern. The most devastating pathology in schistosomiasis japonica and mansoni is mainly attributed to the egg-induced granulomatous response and secondary fibrosis in host liver, which may lead to portal hypertension or even death of the host. Schistosome eggs induce M2 macrophages-rich granulomas and these M2 macrophages play critical roles in the maintenance of granuloma and subsequent fibrosis. Reactive oxygen species (ROS), which are highly produced by stimulated macrophages during infection and necessary for the differentiation of M2 macrophages, are massively distributed around deposited eggs in the liver. However, whether ROS are induced by schistosome eggs to subsequently promote M2 macrophage differentiation, and the possible underlying mechanisms as well, remain to be clarified during S. japonicum infection. Herein, we observed that extensive expression of ROS in the liver of S. japonicum-infected mice. Injection of ROS inhibitor in infected mice resulted in reduced hepatic granulomatous responses and fibrosis. Further investigations revealed that inhibition of ROS production in S. japonicum-infected mice reduces the differentiation of M2, accompanied by increased M1 macrophage differentiation. Finally, we proved that S. japonicum egg antigens (SEA) induce a high level of ROS production via both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and mitochondria in macrophages. Our study may help to better understand the mechanism of schistosomiasis japonica-induced hepatic pathology and contribute to the development of potential therapeutic strategies by interfering with ROS production.

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