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1.
Org Lett ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821663

RESUMO

A direct and site-specific alkylation of (sp3)C-H bond with aliphatic boronic acid was achieved. By simply heating glycinates and amines together with alkylboronic acids under an oxygen atmosphere, a variety of unnatural α-amino acids and peptides could be obtained in good yields.

2.
Blood ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827116

RESUMO

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-ALL. We report the phase 1 results. Following fludarabine/cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2, 1, or 0.5×106 cells/kg. The rate of dose-limiting toxicities (DLTs) within 28 days following KTE-X19 infusion was the primary endpoint. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age: 46 years [range, 18-77]). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 31% and 38% of patients, respectively. To optimize the benefit-risk ratio, revised adverse event (AE) management for CRS and NE (earlier steroid use for NE and tocilizumab only for CRS) was evaluated at 1×106 cells/kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NE, with no grade 4/5 NE. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1×106 cells/kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At 22.1 months (range, 7.1-36.1) median follow-up, the median duration of remission was 17.6 months (95% CI, 5.8-17.6) in patients treated with 1×106 cells/kg and 14.5 months (95% CI, 5.8-18.1) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1×106 cells/kg with revised AE management.

3.
Nanotoxicology ; : 1-17, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33840345

RESUMO

With substantial progress of nanotechnology, carbon nanotubes (CNTs) are widely used in a variety of industrial and commercial applications. There is rising concern about potential adverse health effects, such as pulmonary fibrosis, related to inhalation of CNTs. The detailed cellular and molecular mechanisms of pulmonary fibrosis induced by CNTs are still not clear. Epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) are considered as critical events in pathogenesis of pulmonary fibrosis. Alveolar macrophages (AMs) polarization plays a key role of regulating EMT and FMT in pulmonary fibrosis. In this study, we applied CNTs to stimulate primary mouse AMs under M1 or M2 polarization conditions, then analyzed the proportion of F4/80+CD11c+ or F4/80+CD206+ AMs, mRNA expression and activities of iNOS or Arg-1, as well as mRNA expression and content of TNF-α and IL-6 or TGF-ß and IL-10 to evaluate dynamic phenotypic and functional changes of AMs. Single-walled CNT (SWCNT), short-type multi-walled CNT (MWCNT), and long-type MWCNT exposure at dose of 50 µg/ml promote AMs polarization toward M1 phenotype at early stage, while promote AMs polarization toward M2 phenotype at late stage. The roles of AMs polarization during development of EMT and FMT were further investigated by conditioned medium (CM) experiments. CNTs-activated M2 AMs promote progression of EMT and FMT via secreting TGF-ß. Furthermore, up-regulating IRF4 may be involved in CNTs-induced M2 AMs polarization. In conclusion, this study demonstrates a new insight that CNTs exposure promotes AMs polarization toward M2 phenotype which facilitate EMT and FMT through secreting TGF-ß.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33652118

RESUMO

BACKGROUND & AIMS: The circadian clock is crucial for physiological homeostasis including gut homeostasis. Disorder of the circadian clock may contribute to many diseases including inflammatory bowel disease (IBD). However, the role and the mechanisms of circadian clock involvement in IBD still are unclear. METHODS: Disorder of the circadian clock including chronic social jet lag and circadian clock gene deficiency mice (Bmal1-/-, and Per1-/-Per2-/-) were established. Dextran sulfate sodium (DSS) and/or azoxymethane were used to induce mouse models of colitis and its associated colorectal cancer. Flow cytometry, immunohistochemistry, immunofluorescence, Western blot, and reverse-transcription quantitative polymerase chain reaction were used to analyze the characteristics of immune cells and their related molecules. RESULTS: Mice with disorders of the circadian clock including chronic social jet lag and circadian clock gene deficiency were susceptible to colitis. Functionally, regulatory B (Breg) cells highly expressing PDL1 in intestinal intraepithelial lymphocytes (IELs) helped to alleviate the severity of colitis after DSS treatment and was dysregulated in DSS-treated Bmal1-/- mice. Notably, interleukin 33 in the intestinal microenvironment was key for Bmal1-regulated PDL1+ Breg cells and interleukin 33 was a target of Bmal1 transcriptionally. Dysregulated PDL1+ B cells induced cell death of activated CD4+ T cells in DSS-treated Bmal1-/- mice. Consequently, circadian clock disorder was characterized as decreased numbers of Breg+ PDL1+ cells in IELs and dysfunction of CD4+ T cells promoted colitis-associated colorectal cancer (CRC) in mice. In clinical samples from CRC patients, low expression of Bmal1 gene in paracancerous tissues and cancer center area was associated closely with a poorer prognosis of CRC patients. CONCLUSIONS: Our study uncovers the importance of the circadian clock regulating PDL1+ Breg+ cells of IELs in IBD and IBD-associated CRC.

5.
Signal Transduct Target Ther ; 6(1): 115, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707428

RESUMO

The mechanisms and key factors involved in tumor environments for lung metastasis of CRC are still unclear. Here, using clinical samples from lung metastases of CRC patients, we found that intestinal immune network for IgA production was significantly dysregulated in lung metastases of CRC. Single-cell RNA sequencing discovered a subtype of B cells positive for Erbin, one member of the leucine-rich repeat and PDZ domain (LAP) family, was involved in the lung metastases. Erbin deletion in B cells suppressed lung metastasis of CRC in vivo. And, deletion of Erbin in B cells enhanced the killing effects of CD8+ T cells on tumor cells. Mechanistically, Erbin knockout attenuated TGFß-mediated suppression of migration of CXCR5+ IgA+ cells and STAT6-mediated PD1 expression. Our study uncovered a key role of Erbin in regulating PD1+ IgA+ B cells in lung metastasis of CRC. Targeting Erbin as well as combined use of neutralizing B cells and antibodies neutralizing PD1 suppresses lung metastasis of CRC in mice, suggesting the potential option for treatment of lung metastasis of CRC.

6.
Sci Rep ; 11(1): 5774, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707569

RESUMO

FDA-approved anti-PD-L1 antibody drug Atezolizumab is a human IgG1 without glycosylation by an N297A mutation. Aglycosylation of IgG1 has been used to completely remove the unwanted Fc-mediated functions such as antibody-dependent cytotoxicity (ADCC). However, aglycosylated Atezolizumab is very unstable and easy to form aggregation, which causes quick development of anti-drug antibody (ADA) in 41% of Atezolizumab-treated cancer patients, eventually leading to loss of efficacy. Here, we report the development of the anti-PD-L1 antibody drug Maxatezo, a glycosylated version of Atezolizumab, with no ADCC activity, better thermo-stability, and significantly improved anti-tumor activity in vivo. Using Atezolizumab as the starting template, we back-mutated A297N to re-install the glycosylation, and inserted a short, flexible amino acid sequence (GGGS) between G237 and G238 in the hinge region of the IgG1 heavy chain. Our data shows that insertion of GGGS, does not alter the anti-PD-L1's affinity and inhibitory activity, while completely abolishing ADCC activity. Maxatezo has a similar glycosylation profile and expression level (up to 5.4 g/L) as any normal human IgG1. Most importantly, Maxatezo's thermal stability is much better than Atezolizumab, as evidenced by dramatic increases of Tm1 from 63.55 °C to 71.01 °C and Tagg from 60.7 °C to 71.2 °C. Furthermore, the levels of ADA in mice treated with Maxatezo were significantly lower compared with animals treated with Atezolizumab. Most importantly, at the same dose (10 mg/kg), the tumor growth inhibition rate of Maxatezo was 98%, compared to 68% for Atezolizumab.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33529010

RESUMO

Developing alternatives to noble-metal-based catalysts toward the oxygen reduction reaction (ORR) process plays a key role in the application of low-temperature fuel cells. Carbon-based, precious-metal-free electrocatalysts are of great interest due to their low cost, abundant sources, active catalytic performance, and long-term stability. They are also supposed to feature intrinsically high activity and highly dense catalytic sites along with their sufficient exposure, high conductivity, and high chemical stability, as well as effective mass transfer pathways. In this Review, we focus on carbon-based, precious-metal-free nanocatalysts with synergistic modulation of active-site species and their exposure, mass transfer, and charge transport during the electrochemical process. With this knowledge, perspectives on synergistic modulation strategies are proposed to push forward the development of Pt-free ORR catalysts and the wide application of fuel cells.

8.
Sci Adv ; 7(7)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33568481

RESUMO

Notwithstanding the remarkable progress in the clinical treatment of ischemic disease, proangiogenic drugs mostly suffer from their abnormal angiogenesis and potential cancer risk, and currently, no off-the-shelf biomaterials can efficiently induce angiogenesis. Here, we reported that a semisynthetic sulfated chitosan (SCS) readily engaged anti-inflammatory macrophages and increased its secretion of endogenous vascular endothelial growth factor (VEGF) to induce angiogenesis in ischemia via a VEGF-VEGFR2 signaling pathway. The depletion of host macrophages abrogated VEGF secretion and vascularization in implants, and the inhibition of VEGF or VEGFR2 signaling also disrupted the macrophage-associated angiogenesis. In addition, in a macrophage-inhibited mouse model, SCS efficiently helped to recover the endogenous levels of VEGF and the number of CD31hiEmcnhi vessels in ischemia. Thus, both sulfated group and pentasaccharide sequence in SCS played an important role in directing the therapeutic angiogenesis, indicating that this highly bioactive biomaterial can be harnessed to treat ischemic disease.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33465759

RESUMO

The intestinal microbiome plays a pivotal role in the nutritional digestion and metabolism of the grass carp (Ctenopharyngodon idella). Here, we characterized the digesta and mucosal microbiome of the anterior, middle, and posterior intestine of the grass carp, using 16S rRNA next-generation sequencing. Based on 16S rRNA amplicon data, Proteobacteria, Firmicutes and Bacteroides were the dominant phyla in the intestine of grass carp. Our results also showed that microbial communities of the middle intestine exhibited higher alpha diversity indices compared with the anterior and posterior intestine. The clustering of microbial communities that had either colonized in the digesta or were attached to the mucosa, were significantly tighter in the posterior intestine, based on average unweighted Unifrac distances (P < 0.05). The digesta or mucosa of the anterior and middle intestines were similar in microbial composition, but were significantly different to the posterior intestine (P < 0.05). In digesta and mucosa samples from the posterior intestine, we observed a significantly increased abundance of cellulose-degrading microbiomes, such as Bacteroides, Clostridiales and Spirochaetia (P < 0.05). Our results suggested that the microbiomes of the posterior intestine, either attached to the mucosa or colonized in the digesta, were distinct from the microbiomes of the anterior and middle intestine in grass carp.

10.
Chemosphere ; 263: 127868, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32828052

RESUMO

Microcystins-LR (MCLR) is a potent reproductive system toxin. We have previously shown that MCLR induced endoplasmic reticulum (ER) stress and apoptosis in testis. ER is the main calcium storage site in cells, and its calcium homeostasis plays an important role in the regulation of apoptosis. Hence, in the present study, we have investigated the role of calcium (Ca2+) in inducing apoptosis and how it affect the mitochondria and endoplasmic reticulum in TM4 cells. Our study found that MCLR induced an increase in Ca2+ concentration in TM4 cells. Compared to the controls, MCLR induced phosphorylation of calmodulin-dependent protein kinase II (CaMKII) which was involved in MAPKs activation, resulting in the induction of mitochondrial apoptosis pathways. Ca2+ chelator Bapta-AM partially reversed MCLR-induced apoptosis, confirming the possible involvement of calcium homeostasis disruption after MCLR exposure. Meanwhile, MCLR activated unfolded protein response and activated the ER apoptotic pathway by activating caspase-12. In addition, exposure to MCLR causes mitochondrial defects and increased apoptosis by up-regulating caspase 3 and cytosol cytochrome c expression. Collectively, these results demonstrated that MCLR disturbed calcium homeostasis, which caused ER-mitochondria dysfunction, ultimately promoted cell apoptosis in Sertoli cells.


Assuntos
Cálcio , Estresse do Retículo Endoplasmático , Apoptose , Homeostase , Masculino , Microcistinas , Células de Sertoli
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 248: 119282, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33316652

RESUMO

Carbon quantum dots (CQDs), owing to their characteristic luminescent properties, have become a new favorite in the field of luminescence. They have been widely used in light emitting diode, ion detection, cell-imaging, ect. Herein a facile synthesis method of nitrogen-doped carbon quantum dots (N-CQDs) has been developedviaa one-step hydrothermal of glucose and m-phenylenediamine. The chemical composition, surface functional groups, and crystal structure of so prepared N-CQDs were systematically characterized. The characterizations indicate that nitrogen has been chemically doped in the CQDs and the N-CQDs crystallize in a graphene structure. Photoluminescence (PL) measurements show that the N-CQDs emit strong blue emission under the irradiation of ultraviolet. The emission is excitation-dependent, is resistant to photo bleaching and high ionic strength, and slightly decreases with the increase of temperature. The quantum yield of them is about 17.5%. The PL intensity of N-CQDs quenches linearly with the increase of the concentrations of Fe3+(0.5-1.0 mM) and CrO42-(0.3-0.6 mM), which are a kind of excellent fluorescent probe for the detection of Fe3+ and CrO42-. The quenching mechanism of Fe3+ and CrO42-is verified to be a static quenching mechanism based on inner filter effect. The N-CQDs are also found to be a good cell-imaging reagent of Hela cells.

12.
J Chem Phys ; 153(20): 204108, 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33261485

RESUMO

Finite temperature auxiliary field-based quantum Monte Carlo methods, including determinant quantum Monte Carlo and Auxiliary Field Quantum Monte Carlo (AFQMC), have historically assumed pivotal roles in the investigation of the finite temperature phase diagrams of a wide variety of multidimensional lattice models and materials. Despite their utility, however, these techniques are typically formulated in the grand canonical ensemble, which makes them difficult to apply to condensates such as superfluids and difficult to benchmark against alternative methods that are formulated in the canonical ensemble. Working in the grand canonical ensemble is furthermore accompanied by the increased overhead associated with having to determine the chemical potentials that produce desired fillings. Given this backdrop, in this work, we present a new recursive approach for performing AFQMC simulations in the canonical ensemble that does not require knowledge of chemical potentials. To derive this approach, we exploit the convenient fact that AFQMC solves the many-body problem by decoupling many-body propagators into integrals over one-body problems to which non-interacting theories can be applied. We benchmark the accuracy of our technique on illustrative Bose and Fermi-Hubbard models and demonstrate that it can converge more quickly to the ground state than grand canonical AFQMC simulations. We believe that our novel use of HS-transformed operators to implement algorithms originally derived for non-interacting systems will motivate the development of a variety of other methods and anticipate that our technique will enable direct performance comparisons against other many-body approaches formulated in the canonical ensemble.

13.
Plant Dis ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33231525

RESUMO

Celery (Apium graveolens) is one of the most widely grown vegetables in the world. A survey in Anding District of Gansu Province in 2019 showed that the incidence of celery leaf spot was 25%-45%. The disease mainly occurs in late June and July. The leaf spot is conducive to the onset at high temperature and humidity environment. The initial symptoms were many small light brown, irregular-shaped on the leaves. The lesions gradually enlarged in the later stage of the disease, and multiple lesions coalesced to form large irregular brown spots, eventually the whole leaves died. A 3~4mm leaf tissue was cut from the junction of the diseased leaf and the healthy area, the leaf tisse was surface-sterilized in 1.5% NaClO for 1 min and washed with sterile water. Then, it was incubated on potato dextrose agar (PDA) and obtained the pure culture (Q1). After 5 days of cultivation at 25°C, the fungal colonies were olivaceous to dark olive with white margins and abundant aerial mycelia. The conidia were obclavate or ellipsoid, pale brown, with 3~4 longitudinal septa and 2~7 transverse septa, and measured 20.0 to 50.0 × 3.5 to 14.0µm (n=50). Conidiophores were septate, arising singly, and measured 3.5 to 40.0 × 2.5 to 4.5 µm (n=50). Based on morphological characteristics, the fungus was preliminarily identified as A.tenuissima (Simmons 2007). To further confirm the identification, the internal transcribed spacer region (ITS), translation elongation factor 1-α gene (TEF), RNA polymerase II second largest subunit (RPB2), major allergen Alt a 1 gene (Alt a 1), endopolygalacturonase gene (endoPG), anonymous gene region (OPA10-2) and glyceraldehyde 3-phos-phatedehydrogenase (GAPDH) were amplified and sequenced using primers ITS1/ITS4 (Peever et al. 2004), EF1-728F/EF1-986R (Carbone et al. 1999), RPB2-5F2/RPB2-5R (Sung et al. 2007), Alt-for/Alt-rev (Hong et al. 2005), EPG-specific/EPG-3b (Peever et al. 2004), OPA10-2R/OPA10-2L (Peever et al. 2004) and Gpd1/Gpd2 (Berbee et al. 1999) (GenBank accession no.MN046364, MW016001, MW016002, MW016003, MW016004, MW016005, MW016006). DNA sequences of TEF, RPB2, endoPG, OPA10-2 and GAPDH were 100% identical to those of A. tenuissima (MN256108, MK605866, KP789503, JQ859829 and MK683802), but ITS and Alt a 1 were 100% similarity with A. tenuissima (MN615420, JQ282277) and A. alternate (MT626589, KP123847). The ITS and Alt a 1 sequence did not distinguish A. tenuissima from the A. alternate complex. Maximum likelihood phylogenetic analyses were performed for the combined data set with TEF, RPB2, and endoPG using MEGA6 under the Tamura-Nei model (Kumar et al. 2016). The isolate Q1 clustered with type strain A. tenuissima CBS 918.96. The 20 celery plants of 4-7 leaf age were used test the pathogenicity of Q1, the ten plants were sprayed with 20ml of spore suspension (1×105 spores/ml), the control was sprayed with 20mL sterile water, which were placed in a growth chamber (25℃, a 14h light and 10h dark period, RH > 80%). Eight days after inoculation, 40% of the leaves formed lesions, which were consistent with the field observation,the control group was asymptomatic. The pathogen was reisolated from infected leaves to fulfill Koch's postulates. To our knowledge, this is the first report of A. tenuissima causing leaf spot on celery in China.

14.
J Toxicol Sci ; 45(11): 681-693, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132242

RESUMO

Trichloroethylene (TCE) as a common organic solvent in industrial production can cause occupational medicamentosa-like dermatitis (OMDT) in some exposed workers. In addition to systemic skin damage, OMDT is also accompanied by severe kidney injury. Our previous studies show that complement (C) plays an important role in immune kidney injury caused by TCE. Specifically, C3 is mainly deposited on glomeruli. Recent studies have found that intracellular complement can be activated by cathepsin L (CTSL) and exert a series of biological effects. The purpose of this study was to explore where C3 on glomeruli comes from and what role it plays. A BALB/c mouse model of skin sensitization induced by TCE in the presence or absence of CTSL inhibitor (CTSLi,10 mg/kg). In TCE sensitization-positive mice, C3 was mainly expressed on podocytes and the expression of CTSL significantly increased in podocytes. Kidney function test and related indicators showed abnormal glomerular filtration and transmission electron microscopy revealed ultrastructure damage to podocytes. These lesions were alleviated in TCE/CTSLi positive mice. These results provide the first evidence that in TCE-induced immune kidney injury, intracellular complement in podocytes can be over-activated by CTSL and aggravates podocytes injury, thereby damaging glomerular filtration function. Intracellular complement activation and cathepsin L in podocytes may be a potential target for treating immune kidney injury induced by TCE.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/imunologia , Ativação do Complemento/efeitos dos fármacos , Podócitos/imunologia , Solventes/efeitos adversos , Tricloroetileno/efeitos adversos , Lesão Renal Aguda/fisiopatologia , Animais , Catepsina L/efeitos adversos , Complemento C3/metabolismo , Modelos Animais de Doenças , Feminino , Taxa de Filtração Glomerular , Glomérulos Renais/imunologia , Camundongos Endogâmicos BALB C , Podócitos/patologia , Podócitos/ultraestrutura
15.
Small ; 16(47): e2005302, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33136347

RESUMO

Free-standing electrodes with high energy density and long life are of critical importance to the development of lithium-ion batteries (LIBs) for flexible/wearable electronic devices. Herein, the free-standing and foldable V2 O3 /multichannel carbon nanofibers (V2 O3 /MCCNFs) composites are prepared via electrospinning and subsequent carbonization. Such V2 O3 /MCCNFs electrode delivers a superior capacity of 881.1 mAh g-1 at 0.1 A g-1 after 240 cycles. More importantly, the ultralong lifespan is achieved with a high capacity of 487.8 mAh g-1 even after 5000 cycles at a high current density of 5 A g-1 with only 0.00323% decay rate, which shows the best performance among the reported V2 O3 -based anodes and other metal oxides based free-standing anodes. Furthermore, this flexible electrode is further applied to the pouch cell, which exhibits prominent capacity of 348.3 mAh g-1 after 500 cycles at 1 A g-1 with 0.094% decay per cycle. The unprecedented performance can be ascribed to synergetic contributions of V2 O3 and multichannel carbon nanofibers, which not only promote the penetration of electrolyte and reduce the transport length of Li+ , but also increase active material/electrolyte contact area and buffer the volume change. This work paves the way to develop free-standing electrode for flexible/wearable electronic devices with ultralong lifespan.

16.
Small ; : e2005639, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33169499

RESUMO

The disordered dendritic growth of Li metal seriously hampers the practical application of lithium metal batteries. Great efforts are devoted to suppress the growth of dendrites, it is still necessary to explore measures of controlling dendritic growth and pave ways for normal cell operation in presence of dendrites. Herein, a modification technique of Li metal anode by a periodic Ni mesh with micrometer-sized grid is proposed for interfacial engineering. Periodic patterned Ni mesh is prepared using a novel laser direct-writing technique combined with selective electrodeposition process. The growth of Li dendrites is regulated under the effect of unique electric field distribution by the introduction of the Ni mesh. It is noteworthy that the controlled lateral growth of dendrites is successfully realized by the internal structure modification instead of any external electric or magnetic field as has been previously reported. The resultant anode exhibits a stable cycling performance with ultralow overpotential of 6-8 mV for over 1000 h at the current density of 0.5 mA cm-2 . It also presents superior electrochemical performance when assembled against LiFePO4 cathode into full cells, with an initial capacity of 133 mA h g-1 and a stable cycling performance over 160 cycles.

17.
Acta Biomater ; 117: 192-203, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33007486

RESUMO

Emerging evidence suggests that dysfunctional macrophages can cause chronic inflammation and impair tissue regeneration in diabetic wounds. Therefore, improving macrophage behaviors and functions may improve therapeutic outcomes of current treatments in diabetic wounds. Herein, we present a sulfated chitosan (SCS)-doped Collagen type I (Col I/SCS) hydrogel as a candidate for diabetic wound treatments, and assess its efficacy using streptozocin (STZ)-induced diabetic wound model. Results showed that Col I/SCS hydrogel significantly improved wound closure rate, collagen deposition, and revascularization in diabetic wounds. Flow cytometry analysis and immunofluorescent staining analysis showed that the Col I/SCS hydrogel accelerated the resolution of excessive inflammation by reducing the polarization of M1-like macrophages in chronic diabetic wounds. In addition, ELISA analysis revealed that the Col I/SCS hydrogel reduced the production of pro-inflammatory interleukin (IL)-6 and increased the production of anti-inflammatory cytokines including IL-4 and transforming growth factor-beta 1 (TGF-ß1) during wound healing. Moreover, the Col I/SCS hydrogel enhanced the transdifferentiation of macrophages into fibroblasts, which enhanced the formation of collagen and the extracellular matrix (ECM) in wound tissue. We highlight a potential application of manipulating macrophages behaviors in the pathological microenvironment via materials strategy. STATEMENT OF SIGNIFICANCE: Improving the chronic inflammatory microenvironment of diabetic wounds by regulating macrophage behaviors has been of wide concern in recent years. We designed a Col I/SCS hydrogel based on Collagen type I and sulfated chitosan (SCS) without exogenous cells or cytokines, which could significantly improve angiogenesis and resolve chronic inflammation in diabetic wounds, and hence accelerate diabetic wound healing. The Col I/SCS hydrogel could facilitate the polarization of M1-to-M2 macrophages and activate the transdifferentiation of macrophages to fibroblasts. Additionally, the Col I/SCS hydrogel also equilibrated the content of pro-inflammatory and anti-inflammatory cytokines. This strategy may afford a new avenue to improve macrophage functions and accelerate diabetic chronic wound healing.

18.
Sci Rep ; 10(1): 14407, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873840

RESUMO

This research investigated the association between prolonged disposable diaper (DD) wearing in infancy and primary enuresis (PNE). As a case-control study, we collected data from 376 children with enuresis and 379 healthy children who were sex- and age-matched at three tertiary care institutions in mainland China from August 2017 to July 2018. The results of adjusted logistic regression showed the odds ratios (95% confidence intervals) for PNE across the categories of age of daytime DD use cessation were as follows: ≥ 25 months: 1.00, 18-24 months: 0.25 (0.17-0.37), and ≤ 17 months: 0.11 (0.06-0.20), independent of age, mother education, residence, toilet training approach, breastfeeding duration, UTI, constipation, anaphylactic disease and family history. After a similar multivariable adjustment, increased age of daytime DD use (per-month) had a positive correlation with PNE, OR = 1.17, 95% CI 1.13-1.20 and non-linear relationship was detected, whose point was 21 months (the effect sizes and the 95%CI on the left and right sides of inflection point were 1.04 (0.99-1.10), P = 0.131 and 1.25 (1.18-1.31), P < 0.001). Subgroup analysis found that the effect of duration of disposable diaper exposure for each additional month, those children had accepted assisted infant toilet training/elimination communication (AITT/EC) practice had a lower risk of PNE (OR = 1.08, 95% CI 1.04-1.12), compared with those without AITT/EC practice (OR = 1.20, 95% CI 1.14-1.27), P for interaction < 0.001. In conclusion, the children diagnosed with primary enuresis after age 5 stopped using disposable diapers at daytime later than the control group. Association between duration of DD exposure and the risk of childhood enuresis is modified by AITT/EC practice. Timely cessation use of disposable diaper and practice AITT/EC may shorten the time to nocturnal continence, and the prospective cohort studies are needed to verify the discoveries.

19.
Biomaterials ; 258: 120284, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32798743

RESUMO

Critical-sized bone defects and nonunions following fracture are common among elderly patients and severely reduce the quality of life. Dysfunctional senescent endothelial and mesenchymal stromal cells (MSCs) inhibit bone defect repair. Here we provide a method to obtain surrogate vascularized juvenile bone by subcutaneous implantation of recombinant human bone morphogenic protein-2 (rhBMP-2)-loaded absorbable gelatin scaffolds. RhBMP-2-induced ossicles showed fewer senenscent MSCs whereas much more type H blood vessels (strongly positive for CD31 and endomucin (Emcn)) and osteoprogenitor cells than native bone (femur and tibiae) even in old mice. Treatment with this juvenile ossicles improved the regenerative capacity in critical-sized cranial defects versus standard treatment in both young and old mice. Furthermore, ossicles with custom size shape were obtained by 3D-printing for irregular bone defects repair. These customizable juvenile ossicles developed in aged individuals provide an alternative to resecting native bone in autologous bone transplantation, with superior regenerative efficacy in elderly patients due to their juvenile phenotype.

20.
Hepatol Commun ; 4(8): 1168-1182, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32766476

RESUMO

Alcohol-related liver disease is a major public health burden, and the gut microbiota is an important contributor to disease pathogenesis. The aim of the present study is to characterize functional alterations of the gut microbiota and test their performance for short-term mortality prediction in patients with alcoholic hepatitis. We integrated shotgun metagenomics with untargeted metabolomics to investigate functional alterations of the gut microbiota and host co-metabolism in a multicenter cohort of patients with alcoholic hepatitis. Profound changes were found in the gut microbial composition, functional metagenome, serum, and fecal metabolomes in patients with alcoholic hepatitis compared with nonalcoholic controls. We demonstrate that in comparison with single omics alone, the performance to predict 30-day mortality was improved when combining microbial pathways with respective serum metabolites in patients with alcoholic hepatitis. The area under the receiver operating curve was higher than 0.85 for the tryptophan, isoleucine, and methionine pathways as predictors for 30-day mortality, but achieved 0.989 for using the urea cycle pathway in combination with serum urea, with a bias-corrected prediction error of 0.083 when using leave-one-out cross validation. Conclusion: Our study reveals changes in key microbial metabolic pathways associated with disease severity that predict short-term mortality in our cohort of patients with alcoholic hepatitis.

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