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1.
J Neuroinflammation ; 18(1): 211, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530836

RESUMO

BACKGROUND: Central post-stroke pain (CPSP) is a chronic and intolerable neuropathic pain syndrome following a cerebral vascular insult, which negatively impacts the quality of life of stroke survivors but currently lacks efficacious treatments. Though its underlying mechanism remains unclear, clinical features of hyperalgesia and allodynia indicate central sensitization due to excessive neuroinflammation. Recently, the crosslink between neuroinflammation and endoplasmic reticulum (ER) stress has been identified in diverse types of diseases. Nevertheless, whether this interaction contributes to pain development remains unanswered. Epoxyeicosatrienoic acids (EETs)/soluble epoxy hydrolase inhibitors (sEHi) are emerging targets that play a significant role in pain and neuroinflammatory regulation. Moreover, recent studies have revealed that EETs are effective in attenuating ER stress. In this study, we hypothesized that ER stress around the stroke site may activate glial cells and lead to further inflammatory cascades, which constitute a positive feedback loop resulting in central sensitization and CPSP. Additionally, we tested whether EETs/sEHi could attenuate CPSP by suppressing ER stress and neuroinflammation, as well as their vicious cycle, in a rat model of CPSP. METHODS: Young male SD rats were used to induce CPSP using a model of thalamic hemorrhage and were then treated with TPPU (sEHi) alone or in combination with 14,15-EET or 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, the EET antagonist), tunicamycin (Tm, ER stress inducer), or 4-PBA (ER stress inhibitor). Nociceptive behaviors, ER stress markers, JNK and p38 (two well-recognized inflammatory kinases of mitogen-activated protein kinase (MAPK) signaling) expression, and glial cell activation were assessed. In addition, some healthy rats were intrathalamically microinjected with Tm or lipopolysaccharide (LPS) to test the interaction between ER stress and neuroinflammation in central pain. RESULTS: Analysis of the perithalamic lesion tissue from the brain of CPSP rats demonstrated decreased soluble epoxy hydrolase (sEH) expression, which was accompanied by increased expression of ER stress markers, including BIP, p-IRE, p-PERK, and ATF6. In addition, inflammatory kinases (p-p38 and p-JNK) were upregulated and glial cells were activated. Intrathalamic injection of sEHi (TPPU) increased the paw withdrawal mechanical threshold (PWMT), reduced hallmarks of ER stress and MAPK signaling, and restrained the activation of microglia and astrocytes around the lesion site. However, the analgesic effect of TPPU was completely abolished by 14,15-EEZE. Moreover, microinjection of Tm into the thalamic ventral posterior lateral (VPL) nucleus of healthy rats induced mechanical allodynia and activated MAPK-mediated neuroinflammatory signaling; lipopolysaccharide (LPS) administration led to activation of ER stress along the injected site in healthy rats. CONCLUSIONS: The present study provides evidence that the interaction between ER stress and neuroinflammation is involved in the mechanism of CPSP. Combined with the previously reported EET/sEHi effects on antinociception and neuroprotection, therapy with agents that target EET signaling may serve as a multi-functional approach in central neuropathic pain by attenuating ER stress, excessive neuroinflammation, and subsequent central sensitization. The use of these agents within a proper time window could not only curtail further nerve injury but also produce an analgesic effect.

2.
Pain Ther ; 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34482533

RESUMO

INTRODUCTION: Pain in ankylosing spondylitis is currently considered an inflammatory pain (IP). However, it was found that some patients still had the sensation of pain even without inflammation. Our study was to investigate the prevalence and characteristics of neuropathic pain (NeP) in Chinese Han ankylosing spondylitis (AS) patients. METHODS: The study consisted of three parts. Firstly, we assessed the prevalence and clinical data of NeP in 182 AS patients. Secondly, we evaluated pain improvement after etanercept therapy in 63 patients. Finally, serum neurotransmitters were measured for 20 AS patients and ten healthy controls (HC). RESULTS: Out of 182 AS patients, our study showed that 14 patients (7.70%) had likely NeP and 55 (30.21%) had uncertain NeP. There were significant differences among the three groups with respect to nocturnal pain (NP), peripheral pain (PP), total back pain (TBP), BASDAI, ASDAS-CRP, HAD-A, HAD-D, and BASDAI-fatigue except fort CRP concentrations. Principal component analysis (PCA) of AS pain revealed that the weight of NeP was greater than PP in the first principal component (0.703 vs. 0.639). Structural equation modeling (SEM) revealed that NeP altered disease activity (ß = 0.62, P < 0.001), which influenced psychological status (ß = 0.42, P < 0.001). Of 63 patients who used etanercept for 3 months, significant improvement was found in NP, TBP, and PP (all P < 0.0001) but not in PDQ (10.60 ± 6.85 vs. 9.98 ± 6.40, P = 0.0671). Serum norepinephrine concentrations in patients with PDQ > 19 were higher than those in patients with PDQ ≤ 19 and HC. CONCLUSIONS: We conclude that NeP contributes to pain in AS patients.

3.
Biomacromolecules ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499468

RESUMO

Fabricating advanced polymer composites with remarkable mechanical and thermal conductivity performances is desirable for developing advanced devices and equipment. In this study, a novel strategy to prepare anisotropic wood-based scaffolds with a naturally aligned microchannel structure from balsa wood is demonstrated. The wood microchannels were coated with polydopamine-surface-modified small graphene oxide (PGO) nanosheets via assembly. The highly aligned porous microstructures, with thin wood cell walls and large voids along the cellulose microchannels, allow polymers to enter, resulting in the fabrication of the wood-polymer nanocomposite. The tensile stiffness and strength of the resulting nanocomposite reach 8.10 GPa and 90.3 MPa with a toughness of 5.0 MJ m-3. The thermal conductivity of the nanocomposite is improved significantly by coating a PGO layer onto the wood scaffolds. The nanocomposite exhibits not only ultrahigh thermal conductivity (in-plane about 5.5 W m-1 K-1 and through-plane about 2.1 W m-1 K-1) but also satisfactory electrical insulation (volume resistivity of about 1015 Ω·cm). Therefore, the results provide a strategy to fabricate thermal management materials with excellent mechanical properties.

4.
Oxid Med Cell Longev ; 2021: 9965737, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34471470

RESUMO

Low back pain (LBP) is the primary cause of disability globally. There is a close relationship between Modic changes or endplate defects and LBP. Endplates undergo ossification and become highly porous during intervertebral disc (IVD) degeneration. In our study, we used a mouse model of vertebral endplate degeneration by lumbar spine instability (LSI) surgery. Safranin O and fast green staining and µCT scan showed that LSI surgery led to endplate ossification and porosity, but the endplates in the sham group were cartilaginous and homogenous. Immunofluorescent staining demonstrated the innervation of calcitonin gene-related peptide- (CGRP-) positive nerve fibers in the porous endplate of LSI mice. Behavior test experiments showed an increased spinal hypersensitivity in LSI mice. Moreover, we found an increased cyclooxygenase 2 (COX2) expression and an elevated prostaglandin E2 (PGE2) concentration in the porous endplate of LSI mice. Immunofluorescent staining showed the colocalization of E-prostanoid 4 (EP4)/transient receptor potential vanilloid 1 (TRPV1) and CGRP in the nerve endings in the endplate and in the dorsal root ganglion (DRG) neurons, and western blotting analysis demonstrated that EP4 and TRPV1 expression significantly increased in the LSI group. Our patch clamp study further showed that LSI surgery significantly enhanced the current density of the TRPV1 channel in small-size DRG neurons. A selective EP4 receptor antagonist, L161982, reduced the spinal hypersensitivity of LSI mice by blocking the PGE2/EP4 pathway. In addition, TRPV1 current and neuronal excitability in DRG neurons were also significantly decreased by L161982 treatment. In summary, the PGE2/EP4 pathway in the porous endplate could activate the TRPV1 channel in DRG neurons to cause spinal hypersensitivity in LSI mice. L161982, a selective EP4 receptor antagonist, could turn down the TRPV1 current and decrease the neuronal excitability of DRG neurons to reduce spinal pain.

6.
J Vet Med Sci ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34470981

RESUMO

A novel avian infectious bronchitis virus (IBV) variant, designated as GX-NN160421, was isolated from vaccinated chicken in Guangxi, China, in 2016. Based on analysis of the S1 gene sequence, GX-NN160421 belonged to the New-type 1 (GVI-1) strain. More importantly, three consecutive nucleotides (AAC) deletions were found in the highly conserved structure gene N. The serotype of GX-NN160421 was different from those of the commonly used vaccine strains. The mortality of the GX-NN160421 strain was 3.33%, which contrasted with 50% mortality in the clinical case, but high levels of virus shedding lasted at least 21 days. In conclusion, the first novel genotype IBV variant with three-nucleotide-deletion in the N gene was identified, and this unique variant is low virulent but with a long time of virus shedding, indicating the continuing evolution of IBV and emphasizing the importance of limiting exposure to novel IBV strains as well as extensive monitoring of new IBVs.

7.
Chemistry ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34472663

RESUMO

Electrocatalytic water splitting has been considered as a promising strategy for the sustainable evolution of hydrogen energy and storage of intermittent electric energy. Efficient catalysts for electrocatalytic water splitting are urgently demanded to decrease the overpotentials and promote the sluggish reaction kinetics. Carbon-based composites, including heteroatom-doped carbon materials, metals/alloys@carbon composites, metal compounds@carbon composites, and atomically dispersed metal sites@carbon composites have been widely used as the catalysts due to their fascinating properties. However, these electrocatalysts are almost powdery form, and should be cast on the current collector by using the polymeric binder, which would result in the unsatisfied electrocatalytic performance. In comparison, a self-supported electrode architecture is highly attractive. Recently, self-supported metal-organic frameworks (MOFs) constructed by coordination of metal centers and organic ligands have been considered as suitable templates/precursors to construct free-standing carbon-based composites grown on conductive substrate. MOFs-derived carbon-based composites have various merits, such as the well-aligned array architecture and evenly distributed active sites, and easy functionalization with other species, which make them suitable alternatives to non-noble metal-included electrocatalysts. In this review, we intend to show the research progresses by employment of MOFs as precursors to prepare self-supported carbon-based composites. Focusing on these MOFs-derived carbon-based nanomaterials, the latest advances in their controllable synthesis, composition regulation, electrocatalytic performances in hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and overall water splitting (OWS) are presented. Finally, the challenges and perspectives are showed for the further developments of MOFs-derived self-supported carbon-based nanomaterials in electrocatalytic reactions.

8.
Clin Immunol ; : 108852, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34520860

RESUMO

BACKGROUND: Majority of coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF). METHODS: We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Retrospective data were extracted from electronic medical records. RESULTS: The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D5) and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although twelve-day medication returned high CRP concentration to normal and blocked fibrinogen increase, the D-dimer levels remained high on 17 ±â€¯2 and 23 ±â€¯2 days of COVID-19 course. CONCLUSION: COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately, and administer suitable treatment.

9.
Theranostics ; 11(18): 8692-8705, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522207

RESUMO

Background: Metastasis is one of the main reasons for the high mortality associated with pancreatic ductal adenocarcinoma (PDAC), and autophagy regulates the metastatic migration of tumor cells, their invasion of tissues, and their formation of focal adhesions. Inhibiting autophagy may suppress tumor growth and metastasis, but the abundant extracellular matrix hinders the deep penetration of therapeutic agents. Methods: To enhance the penetration of drugs that can inhibit metastasis of pancreatic cancer, a pH-responsive drug delivery system was formulated. Gemcitabine (GEM), a first-line chemotherapeutic drug against PDAC, was loaded in 6PA-modified DGL (PDGL) nanoparticles to afford PDGL-GEM. Then PDGL-GEM was co-precipitated with the autophagy inhibitor chloroquine phosphate (CQ) and calcium phosphate to formulate PDGL-GEM@CAP/CQ. The size and morphology of the resulting "nanobomb" PDGL-GEM@CAP/CQ were characterized, and their uptake into cells, cytotoxicity and ability to inhibit autophagy were analyzed at pH 6.5 and 7.4. The anti-tumor and anti-metastasis effects of the nanobomb were explored on mice carrying Pan 02 pancreatic tumor xenografts or orthotopic tumors. Results: The pH-induced dissolution of calcium phosphate facilitated the release of CQ from the nanobomb and deep penetration of PDGL-GEM. The internalization of PDGL-GEM and subsequent intracellular release of GEM inhibited tumor growth, while CQ downregulated autophagy in tumor cells and fibroblasts. In fact, inhibition of xenograft and orthotopic tumor growth was greater with the complete PDGL-GEM@CAP/CQ than with subassemblies lacking GEM or CQ. More importantly, mechanistic studies in vitro and in vivo suggested that the nanobomb inhibits metastasis by downregulating MMP-2 and paxillin, as well as reducing fibrosis. Conclusion: The pH-sensitive PDGL-GEM@CAP/CQ shows potential for inhibiting proliferation and metastasis of pancreatic cancer through an autophagy-dependent pathway.

10.
Gene ; : 145968, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34530090

RESUMO

Resveratrol (Res) is a polyphenol with a variety of biological activities. However, whether Res can prevent myocardial ischemia-reperfusion (I/R) injury is not yet known. This study aimed to investigate the protective effect of Res on myocardial I/R injury and to explore its potential mechanism. H9c2 cells were used for the in vitro experiments and oxygen-glucose deprivation/reoxygenation (OGD/R) model was established. Rats were ligated and perfused by the left anterior descending branch with or without Res (50 mg/kg·bw) for 14 days.The higher level of oxidative stress and Fe2+ content was observed in OGD/R-induced H9c2 cells than that of normal cells. OGD/R-induced H9c2 cells showed increased ferroptosis, mainly by reducing the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1), but enhancing the expression of transferrin receptor 1 (TfR1). Both in vivo and in vitro experiments indicated that Res reduced the level of oxidative stress and Fe2+ content. In addition, Res inhibited ferroptosis, decreased TfR1 expression, and increased the expressions of FTH1 and GPX4 in OGD/R-induced H9c2 cells and I/R rats. Moreover, we found that Res inhibited ferroptosis by the regulation of ubiquity specific peptidase 19 (USP19)-Beclin1 autophagy. Res protects against myocardial I/R injury via reducing oxidative stress and attenuating ferroptosis. Res could be a potential agent to the prevention of myocardial I/R injury.

11.
J Genet Genomics ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34531148

RESUMO

Enhancers are critical cis-regulatory elements that regulate spatiotemporal gene expression and control cell fates. However, the identification of enhancers in native cellular contexts still remains a challenge. Here, we develop an inducible CRISPR activation (CRISPRa) system by transgenic expression of doxycycline (Dox)-inducible dCas9-VPR in mouse embryonic stem cells (iVPR ESC). With this line, a simple introduction of specific guide RNAs targeting promoters or enhancers allows us to realize the effect of CRISPRa in an inducible, reversible, and Dox concentration-dependent manner. Taking advantage of this system, we induce tiled CRISPRa across genomic regions (105 kilobases) surrounding T (Brachyury), one of the key mesodermal development regulator genes. Moreover, we identify several CRISPRa-responsive elements with chromatin features of putative enhancers, including a region the homologous sequence in which humans harbors a body height risk variant. Genetic deletion of this region in ESC does affect subsequent T gene activation and osteogenic differentiation. Therefore, our inducible CRISPRa ESC line provides a convenient platform for high-throughput screens of putative enhancers.

12.
ChemSusChem ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34467655

RESUMO

The sustainable production of adaptive, recyclable and imine-based dynamic covalent thermosetting resins (DCTRs) presents an opportunity for polymer scientists to address the prevalent environmental and energy concerns associated with current petroleum-based plastics. However, the imine-based DCTRs easily decompose in the presence of water, which can weaken the mechanical properties in imine-based polymers. In this study, we designed oxime-imine DCTRs that are stable in the presence of water and exhibit good mechanical properties. In the presence of one kind of amino group catalyst, the oxime-imine DCTRs could be completely recycled. Additionally, these well-designed oxime-imine DCTRs have good mechanical properties, high glass transition temperatures (166 °C), and good thermal stabilities. Taken together, this work offers a sustainable solution for the design and manufacture of high-value degradable materials intended for applications in which recyclability and reusability are indispensable.

13.
Nanoscale ; 13(31): 13328-13343, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34477739

RESUMO

Facing the barriers in each step of the in vivo delivery cascade, the low drug delivery efficiency remains problematic in tumor therapy. Although recently the nanofibril drug delivery systems have shown improved circulation and accumulation compared with nanoparticles, the poor deep penetration and cellular internalization hinder their application, especially for pancreatic cancer with dense stroma. To comprehensively address the hurdles in the delivery cascade, a matrix metalloproteinase 2 (MMP-2) responsive transformable beaded nanofibril, which integrates the merits of nanofibril and small-sized nanoparticles, is established. The beaded nanofibril (GD@PPF) is prepared by conjugating gemcitabine-loaded small-sized nanoparticles (GD) with fibrous PEG-PCL (PPF) via GPLGVRG, a substrate peptide of MMP-2. GD@PPF escapes the clearance of the reticuloendothelial system (RES), prolongs the circulation time, and increases the selective accumulation in the tumor as fibrous micelles. Once accumulated in the tumor, small positively-charged GD is released from the beaded nanofibrils in response to MMP-2 overexpression in the stroma of pancreatic cancer, enabling permeation in the dense tumor matrix and cellular internalization, which makes up for the shortcomings of fibrous micelles. Furthermore, the remaining fibrous PPF surround the tumor tightly to impede the efflux of drugs, leading to improved retention. GD@PPF is biocompatible and exhibits excellent antitumor effect in Pan 02 subcutaneous tumor models. Therefore, the MMP-2 responsive transformable beaded nanofibril, which enhances the delivery efficiency in multiple stage of the delivery cascade, presents a promising strategy for pancreatic cancer therapy.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Metaloproteinase 2 da Matriz , Micelas , Neoplasias Pancreáticas/tratamento farmacológico
14.
Se Pu ; 39(9): 930-940, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34486832

RESUMO

Polar pesticides can be primarily classified as fungicides, herbicides, and insecticides; their rich variety and low cost have led to their extensive utilization in agriculture. However, the overuse of polar pesticides can lead to environmental contamination, such as water or soil pollution, which can also increase the risk of pesticide exposure among human life directly, or indirectly through contact with animal and plant-derived food. There are considerable differences in the physical and chemical properties of polar pesticides, as well as their trace amounts in complex food and environmental samples, posing immense challenges to their accurate detection. As a kind of artificially prepared selective adsorbent, molecularly imprinted polymers (MIPs) possess specific recognition sites complementary to template molecules in terms of the spatial structure, size, and chemical functional groups. With many advantages such as easy preparation, low cost, as well as good chemical and mechanical stability, MIPs have been widely applied in sample pretreatment and the analysis of polar pesticide residues. MIPs are typically used as adsorption materials in solid phase extraction (SPE) methods, including magnetic solid phase extraction (MSPE), dispersed solid phase extraction (DSPE), and stir bar sorptive extraction (SBSE). To rapidly detect polar pesticide residues with high sensitivity, MIPs are also used in the preparation of fluorescent sensors and electrochemical sensors. Furthermore, MIPs can be employed as the substrate in surface-enhanced Raman spectroscopy and as the substrate for the ion source in mass spectrometry for polar pesticide residue analysis. Thus far, various molecularly imprinted materials have been reported for the efficient separation and analysis of polar pesticide residues in various complex matrices. However, there is no review that summarizes the recent advances in MIPs for the determination of polar pesticides. This review introduces imprinting strategies and polymerization methods for MIPs, and briefly summarizes some new molecular imprinting strategies and preparation technologies. The application of MIPs in recent years (particularly the last five years) to the detection of polar pesticide residues including neonicotinoids, organophosphorus, triazines, azoles, and urea is then systematically summarized. Finally, the future development direction and trends for MIPs are proposed considering existing challenges, with the aim of providing reference to guide future research on MIPs in the field of polar pesticide residue detection.


Assuntos
Impressão Molecular , Resíduos de Praguicidas , Praguicidas , Adsorção , Humanos , Polímeros Molecularmente Impressos , Resíduos de Praguicidas/análise , Praguicidas/análise , Extração em Fase Sólida
15.
Parasitol Res ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499198

RESUMO

Fatty acid uptake is extremely important for the survival and growth of the intracellular parasite Toxoplasma gondii. In this study, CRISPR-Cas9 gene editing technology was used to investigate the role of four lipid synthesis enzymes, namely, glycerol-3-phosphate dehydrogenase (G3PDH), malonyl CoA-acyl carrier protein transacylase (FabD), acyl-ACP thiolesterase (TE), and diacylglycerol acyltransferase (DGAT), in the virulence and infectivity of Type I RH and Type II Prugniaud (Pru) strains of T. gondii. Immunofluorescence analysis of the tachyzoite stage showed that FabD protein was located in the apicoplast; however, the expression level of the other three proteins was undetectable. Compared with wild-type (WT) strains, the growth of RHΔG3PDH, RHΔTE, and RHΔDGAT in vitro and their virulence in vivo were not significantly different. However, RHΔFabD exhibited a significantly reduced growth rate, compared with the WT strain. The deletion of FabD attenuated the virulence of Type II Pru strain and reduced the formation of cysts in vivo. These data improved our understanding of the role of lipid synthesis enzymes in the pathogenesis of T. gondii.

16.
J Mol Diagn ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34543749

RESUMO

Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in 4 unrelated low-GGT cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel non-recurrent structural variants in 3 patients (P1 - P3) were identified in trans: g.55396652_55403080del (6427bp deletion), g.55335906_55346620dup (10,715bp duplication), and g.55362063_55364293dup (2231bp duplication). One synonymous variant in P4 was recognized in trans (c.1029G>A, p.Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with FIC1 disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.

17.
Mol Med Rep ; 24(5)2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34476500

RESUMO

Cisplatin (DDP) resistance in patients suffering from ovarian cancer is a considerable hurdle to successful treatment. The present study aimed to identify a possible long non­coding RNA (lncRNA)­microRNA (miRNA)­mRNA axis participating in ovarian cancer DDP­resistance based on the critical roles of non­coding RNAs, including lncRNAs and miRNAs, in carcinogenesis. According to online data and experimental results, lncRNA HAND2­AS1 expression was significantly downregulated within ovarian carcinoma, especially within recurrent and DDP­resistant ovarian carcinoma. The expression of HAND2­AS1 was also shown to be markedly inhibited in SKOV3/DDP (DDP) cells with resistance to DDP. In SKOV3/DDP cells, HAND2­AS1 overexpression inhibited cell viability and promoted cell apoptosis upon DDP treatment through the Bcl­2/caspase­3 apoptotic signaling. It was hypothesized that PTEN mRNA expression was also markedly inhibited in SKOV3/DDP ovarian cancer cells, while HAND2­AS1 overexpression rescued PTEN proteins and blocked PI3K/AKT signaling activation. Moreover, miR­106a was found to bind directly to PTEN 3' UTR and HAND2­AS1. Upon DDP treatment, miR­106a overexpression in SKOV3/DDP cells promoted cell viability. It inhibited cell apoptosis through the Bcl­2/caspase­3 apoptotic signaling pathway and downregulated the protein levels of PTEN and upregulated PI3K/AKT signaling activity. Furthermore, miR­106a overexpression partially reversed the effect of HAND2­AS1 overexpression upon PTEN proteins and SKOV3/DDP cell proliferation upon DDP treatment. In conclusion, a lncRNA HAND2­AS1/miR­106a/PTEN axis that re­sensitizes DDP­resistant SKOV3/DDP cells to DDP treatment has been established.

18.
J Transl Med ; 19(1): 355, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404433

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of renal failure, whereas the effective and early diagnostic biomarkers are still lacking. METHODS: Fourteen cytokines and chemokines mRNA were detected in urinary extracellular vesicles (EVs) from the screening cohort including 4 healthy controls (HC), 4 diabetes mellitus (DM) and 4 biopsy-proven DN patients, and was validated in another 16 HC and 15 DM and 28 DN patients. Correlation analysis was performed between the candidate biomarkers and clinic parameters as well as kidney histological changes. The findings were also confirmed in DN rat model with single injection of STZ. RESULTS: The number of small EVs secreted in urine was increased in DN patients compared to DM patients and healthy controls, with expression of AQP1 (a marker of proximal tubules) and AQP2 (a marker of distal/collecting tubules). Small EVs derived CCL21 mRNA increased significantly in DN patients and correlated with level of proteinuria and eGFR. Interestingly, elevated CCL21 mRNA from urine small EVs was observed in DN patients with normal renal function and could discriminate early DN patients from DM more efficiently compared to eGFR and proteinuria. CCL21 also showed an accurate diagnostic ability in distinguishing incipient from overt DN. Histologically, CCL21 mRNA expression increased progressively with the deterioration of tubulointerstitial inflammation and showed the highest level in nodular sclerosis group (class III) in DN patients. Remarkable infiltration of CD3 positive T cells including both CD4 and CD8 positive T cell population were observed in DN patients with high-CCL21 expression. Besides, accumulation of CD3 positive T cells correlated with level of urinary small EVs derived CCL21 and co-localized with CCL21 in the tubulointerstitium in DN patients. Finally, the correlation of CCL21 expression in renal cortex and urinary small EVs was confirmed in STZ-induced DN rat model. CONCLUSIONS: Urinary small EVs derived CCL21 mRNA may serve as early biomarker for identifying DN linked with pathogenesis. CCL21 mRNA mediated T cell infiltration may constitute the key mechanism of chronic inflammation in DN.


Assuntos
Quimiocina CCL21 , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Vesículas Extracelulares , Animais , Aquaporina 2 , Biomarcadores , Quimiocina CCL21/genética , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/genética , Humanos , RNA Mensageiro/genética , Ratos
19.
J Org Chem ; 86(17): 11472-11481, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34343003

RESUMO

An efficient inverse electron-demand aza-Diels-Alder reaction of cyclic enamides and 1,2-diaza-1,3-dienes, which could be readily formed in situ from α-halogeno hydrazones and a base, has been successfully developed. With the developed approach, a wide range of fused polycyclic tetrahydropyridazines were smoothly obtained in up to 99% yield under benign reaction conditions. This reaction concept was also extended to acyclic enamide substrates for accessing 1,4,5,6-tetrahydropyridazines. A gram-scale experiment and further derivatizations of the polycyclic tetrahydropyridazine products were also conducted to verify the practicability of the methodology.

20.
Microbiol Spectr ; 9(1): e0059921, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34378967

RESUMO

Beneficial symbiotic bacteria have positive effects on some insects' (such as mosquitoes, cockroaches, and flies) biological activities. However, the effects of a lack of one specific symbiotic bacterium on the life activities of some insects and their natural gut microbiota composition remain unclear. Bacteriophages are viruses that specifically target and kill bacteria and have the potential to shape gut bacterial communities. In previous work, Pseudomonas aeruginosa that naturally colonized the intestines of housefly larvae was shown to be essential to protect housefly larvae from entomopathogenic fungal infections, leading us to test whether a deficiency in Pseudomonas aeruginosa strains in housefly larvae that was specifically caused using bacteriophages could remold the composition of the intestinal bacteria and affect the development of housefly larvae. Our research revealed that the phage, with a titer of 108 PFU/ml, can remove 90% of Pseudomonas aeruginosa in the gut. A single feeding of low-dose phage had no effect on the health of housefly larvae. However, the health of housefly larvae was affected by treatment with phage every 24 h. Additionally, treating housefly larvae with bacteriophages every 24 h led to bacterial composition changes in the gut. Collectively, the results revealed that deficiency in one symbiotic gut bacteria mediated by precise targeting using bacteriophages indirectly influences the intestinal microbial composition of housefly larvae and has negative effects on the development of the host insect. Our results indicated the important role of symbiotic gut bacteria in shaping the normal gut microbiota composition in insects. IMPORTANCE The well-balanced gut microbiota ensures appropriate development of the host insect, such as mosquitoes, cockroaches, and flies. Various intestinal symbiotic bacteria have different influences on the host gut community structure and thus exert different effects on host health. Therefore, it is of great importance to understand the contributions of one specific bacterial symbiont to the gut microbiota community structure and insect health. Bacteriophages that target certain bacteria are effective tools that can be used to analyze gut bacterial symbionts. However, experimental evidence for phage efficacy in regulating insect intestinal bacteria has been little reported. In this study, we used phages as precision tools to regulate a bacterial community and analyzed the influence on host health after certain bacteria were inhibited by bacteriophage. The ability of phages to target intestinal-specific bacteria in housefly larvae and reduce the levels of target bacteria makes them an effective tool for studying the function of gut bacteria.

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