Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 478
Filtrar
1.
Commun Biol ; 4(1): 30, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398021

RESUMO

Diabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5'-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33432521

RESUMO

Multidrug resistance (MDR) is considered as a critical limiting factor for the successful chemotherapy, which is mainly characterized by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2. In this study, folate-targeted polymeric micellar carrier was successfully constructed to co-delivery of doxorubicin (DOX) and SIS3 (FA/DOX/SIS3 micelles), a specific Smad3 inhibitor which sensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic agents. The ratio of DOX to SIS3 in polymeric micelles was determined based on the anti-tumor activity against resistant breast cells. In addition, FA/DOX/SIS3 micelles exhibited a much longer circulation time in blood and were preferentially accumulated in resistant tumor tissue. Pharmacodynamic studies showed that FA/DOX/SIS3 micelles possessed superior anti-tumor activity than other DOX-based treatments. Overall, FA/DOX/SIS3 micelles are a promising formulation for the synergistic treatment of drug-resistant tumor.

3.
J Neurol ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387013

RESUMO

BACKGROUND AND PURPOSE: Subtyping relapsing-remitting multiple sclerosis (RRMS) patients may help predict disease progression and triage patients for treatment. We aimed to subtype RRMS patients by structural MRI and investigate their clinical significances. METHODS: 155 relapse-remitting MS (RRMS) and 210 healthy controls (HC) were retrospectively enrolled with structural 3DT1, diffusion tensor imaging (DTI) and resting-state functional MRI. Z scores of cortical and deep gray matter volumes (CGMV and DGMV) and white matter fractional anisotropy (WM-FA) in RRMS patients were calculated based on means and standard deviations of HC. We defined RRMS as "normal" (- 2 < z scores of both GMV and WM-FA), DGM (z scores of DGMV < - 2), and DGM-plus types (z scores of DGMV and [CGMV or WM-FA] < - 2) according to combinations of z scores compared to HC. Expanded disability status scale (EDSS), cognitive and functional MRI measurements, and conversion rate to secondary progressive MS (SPMS) at 5-year follow-up were compared between subtypes. RESULTS: 77 (49.7%) patients were "normal" type, 37 (23.9%) patients were DGM type and 34 (21.9%) patients were DGM-plus type. 7 (4.5%) patients who were not categorized into the above types were excluded. DGM-plus type had the highest EDSS. Both DGM and DGM-plus types had more severe cognitive impairment than "normal" type. Only DGM-plus type showed decreased functional MRI measures compared to HC. A higher conversion ratio to SPMS in DGM-plus type (55%) was identified compared to "normal" type (14%, p < 0.001) and DGM type (20%, p = 0.005). CONCLUSION: Three MRI-subtypes of RRMS were identified with distinct clinical and imaging features and different prognosis.

4.
Carbohydr Polym ; 256: 117556, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33483059

RESUMO

Acute kidney injury (AKI) is a common and serious clinical syndrome of acute renal dysfunction in a short period. One of therapeutic interventions for AKI is to reduce ROS massively generated in the mitochondria and then ameliorate cell damage and apoptosis induced by oxidative stress. In this study, stepwise-targeting chitosan oligosaccharide, triphenyl phosphine-low molecular weight chitosan-curcumin (TPP-LMWC-CUR, TLC), was constructed for sepsis-induced AKI via removing excessive ROS in renal tubular epithelial cells. Benefiting from good water solubility and low molecular weight, TLC was rapidly and preferentially distributed in the renal tissues and then specifically internalized by tubular epithelium cells via interaction between Megalin receptor and LMWC. The intracellular TLC could further delivery CUR to mitochondria due to high buffering capacity of LMWC and delocalized positive charges of TPP. Both in vitro and in vivo pharmacodynamic results demonstrated the enhanced therapeutic effect of TLC in the treatment of AKI.

5.
Cell Stem Cell ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33450186

RESUMO

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.

6.
Hum Brain Mapp ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33463862

RESUMO

Transient ischemic attack (TIA), an important risk factor for stroke, is associated with widespread disruptions of functional brain architecture. However, TIA-related structural alterations are not well established. By analyzing structural MRI data from 50 TIA patients versus 40 healthy controls (HCs), here we systematically investigated TIA-related morphological alterations in multiple cortical surface-based indices (cortical thickness [CT], fractal dimension [FD], gyrification index [GI], and sulcal depth [SD]) at multiple levels (local topography, interregional connectivity and whole-brain network topology). For the observed alterations, their associations with clinical risk factors and abilities as diagnostic and prognostic biomarkers were further examined. We found that compared with the HCs, the TIA patients showed widespread morphological alterations and the alterations depended on choices of morphological index and analytical level. Specifically, the patients exhibited: (a) regional CT decreases in the transverse temporal gyrus and lateral sulcus; (b) impaired FD- and GI-based connectivity mainly involving visual, somatomotor and ventral attention networks and interhemispheric connections; and (c) altered GI-based whole-brain network efficiency and decreased FD-based nodal centrality in the middle frontal gyrus. Moreover, the impaired morphological connectivity showed high sensitivities and specificities for distinguishing the patients from HCs. Altogether, these findings demonstrate the emergence of morphological index-dependent and analytical level-specific alterations in TIA, which provide novel insights into neurobiological mechanisms underlying TIA and may serve as potential biomarkers to help diagnosis of the disease. Meanwhile, our findings highlight the necessity of using multiparametric and multilevel approaches for a complete mapping of cerebral morphology in health and disease.

7.
Clin Cancer Res ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414134

RESUMO

PURPOSE: We performed detailed genomic analysis on 87 cases of de novo diffuse large B-cell lymphoma of germinal center type (GCB DLBCL) to identify characteristics that are associated with survival in those treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). EXPERIMENTAL DESIGN: The cases were extensively characterized by combining the results of immunohistochemistry, cell-of-origin gene expression profiling (Nanostring), double-hit gene expression profiling (DLBCL90), fluorescence in situ hybridization (FISH) cytogenetic analysis for double/triple-hit lymphoma, copy number analysis (CNA), and targeted deep sequencing using a custom mutation panel of 334 genes. RESULTS: We identified four distinct biologic subgroups with different survivals, and with similarities to the genomic classifications from two large retrospective studies of DLBCL. Patients with the double-hit signature but no abnormalities of TP53, and those lacking EZH2 mutation and/or BCL2 translocation, had an excellent prognosis. However, patients with an EZB-like profile had an intermediate prognosis, whereas those with TP53 inactivation combined with the double-hit signature had an extremely poor prognosis. This latter finding was validated using two independent cohorts. CONCLUSIONS: We propose a practical schema to utilize genomic variables to risk-stratify patients with GCB DLBCL. This schema provides a promising new approach to identify high-risk patients for new and innovative therapies.

8.
Development ; 148(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33318148

RESUMO

Androgens/androgen receptor (AR)-mediated signaling pathways are essential for prostate development, morphogenesis and regeneration. Specifically, stromal AR signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we have directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single-cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were additionally characterized in relation to prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation of mesenchymal rather than epithelial cells dysregulated the expression of the master regulators and significantly impaired prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling in the cellular niche controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.

9.
Nat Prod Res ; : 1-9, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33342293

RESUMO

Phytochemical investigation on the ethanol extract of green walnut husks (Juglans mandshurica Maxim.) led to the isolation of two previously unknown compounds, including a macrolide compound (13S)-8-oxo-(9E, 11E)-8-oxo-octadeca-9,11-dien-13-olide (1) and a diarylheptanoid compound 1-(3'-methoxy-4'-hydroxyphenyl)-7-(3″,4″-dimethoxyphenyl)heptan-3-one (2), together with 19 known compounds. The structures of these 21 compounds were elucidated by extensive analyses of NMR and HR-MS data, and the basis of spectroscopic analysis.

10.
Chemistry ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300648

RESUMO

Mechanoresponsive luminescence (MRL) active materials promise smart devices for sensing, optoelectronics, and security. Herein is the first report on the MRL-activity of two Re(I) complexes, opening up new opportunities for applications in this field. Both complexes exhibit marked solid-state luminescence enhancement (SLE) effect. Pristine microcrystalline powders emit in the yellow-green region, grinding led to an amorphous phase with concomitant emission red-shift and shrinking of photoluminescence (PL) quantum yields and lifetimes. Quantum chemical calculations revealed the existence of two low-lying triplet excited states of very close energy levels, i.e. 3IL and 3MLCT, having respectively almost pure intraligand and metal-to-ligand charge transfer character. Transition between these states could be promoted by rotation around the pyridyltriazole-phenylbenzoxazole (pyta-PBO) bond. In microcrystals, where rotations are hindered, the 3IL state induces prominent PL emission at short wavelengths. Upon grinding, rotation is facilitated and the transition to the 3MLCT state results in a larger proportion of long-wavelength PL. FTIR spectroscopic analyses and variable temperature PL spectroscopy showed that the opening of vibrational modes favours non-radiative deactivation of the triplet states in the amorphous phase. In solutions, PL only arises from the 3MLCT state. The same mechanism accounts for the spectroscopic differences observed when passing from crystals to amorphous powders, and then to solutions, clarifying the link between SLE and MRL for these complexes.

11.
Biomed Pharmacother ; 133: 110802, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33202286

RESUMO

Hyperlipidaemia is one of the major risk factors for atherosclerosis, coronary heart disease, stroke and diabetes. In the present study, we synthesized a new anthraquinone compound, 1,8-dihydroxy-3-succinic acid monoethyl ester-6-methylanthraquinone, and named it Kanglexin (KLX). The aim of this study was to evaluate whether KLX has a lipid-lowering effect and to explore the potential molecular mechanism. In this study, Sprague-Dawley rats were fed a high fat diet (HFD) for 5 weeks to establish a hyperlipidaemia model; then, the rats were orally administered KLX (20, 40, and 80 mg kg-1·d-1) or atorvastatin calcium (AT, 10 mg kg-1·d-1) once a day for 2 weeks. KLX had prominent effects on reducing blood lipids, hepatic lipid accumulation, body weight and the ratio of liver weight/body weight. Furthermore, KLXdramatically reduced the total cholesterol (TC) and triglyceride (TG) levels and lipid accumulation in a HepG2 cell model of dyslipidaemia induced by 1 mmol/L oleic acid (OA). KLX may decrease lipid levels by phosphorylating adenosine monophosphate-activated protein kinase (AMPK) and the downstream sterol regulatory element binding protein 2 (SREBP-2)/proprotein convertase subtilisin/kexin type 9 (PCSK9)/low-density lipoprotein receptor (LDLR) signalling pathway in the HFD rats and OA-treated HepG2 cells. The effects of KLX on the AMPK/SREBP-2/PCSK9/LDLR signalling pathway were abolished when AMPK was inhibited by compound C (a specific AMPK inhibitor) in HepG2 cells. In summary, KLX has an efficient lipid-lowering effect mediated by activation of the AMPK/SREBP-2/PCSK9/LDLR signalling pathway. Our findings may provide new insight into and evidence for the discovery of a new lipid-lowering drug for the prevention and treatment of hyperlipidaemia, fatty liver, and cardiovascular disease in the clinic.

12.
Aging (Albany NY) ; 122020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33234726

RESUMO

It has been reported that allergen dosage can impact the differentiation of dendritic cells (DCs)-mediated T cells. However, the mechanisms of such dose-dependent differentiation are poorly understood. In this study, bone marrow-derived immature DCs stimulated with Ovalbumin (OVA) of different concentrations (0, 10, 100, 1000, 10000µg/ml, respectively). DCs were then co-cultured with naïve T cells. RNA-sequencing detection and DNA methylation of DCs were performed. We show that when DCs were stimulated with low-dose (10µg/ml), 77 genes were up-regulated and 87 genes down-regulated. Most activated genes were related to ribosome synthesis and ion channel inhibition. At the medium-dose (100µg/ml), 339 genes were up-regulated and 168 genes down-regulated. Most activated genes involved cytokine synthesis and regulation of immune responses. At high-dose (10000µg/ml), 2497 genes were up-regulated and 1156 genes down-regulated. TNF signaling pathway, NF-kappa B signaling pathway, antigen processing and presentation signaling pathway were mostly up-regulated. The related co-stimulators, co-inhibitory molecules, inhibitory cytokines, negative regulating enzymes were highly expressed. The monocarbate, coenzyme, fatty acid, glucolipid, starch, sucrose and other metabolism-related signaling pathways were down-regulated. The profiles of DNA methylation and RNA synthesis of DCs varied with different doses of OVA, which serves to induce T cells to differentiate in various directions.

13.
Adv Sci (Weinh) ; 7(19): 2001561, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33042763

RESUMO

High performance, flexibility, safety, and robust integration for micro-supercapacitors (MSCs) are of immense interest for the urgent demand for miniaturized, smart energy-storage devices. However, repetitive photolithography processes in the fabrication of on-chip electronic components including various photoresists, masks, and toxic etchants are often not well-suited for industrial production. Here, a cost-effective stamping strategy is developed for scalable and rapid preparation of graphene-based planar MSCs. Combining stamps with desired shapes and highly conductive graphene inks, flexible MSCs with controlled structures are prepared on arbitrary substrates without any metal current collectors, additives, and polymer binders. The interdigitated MSC exhibits high areal capacitance up to 21.7 mF cm-2 at a current of 0.5 mA and a high power density of 6 mW cm-2 at an energy density of 5 µWh cm-2. Moreover, the MSCs show outstanding cycling performance and remarkable flexibility over 10 000 charge-discharge cycles and 300 bending cycles. In addition, the capacitance and output voltage of the MSCs are easily adjustable through interconnection with well-defined arrangements. The efficient, rapid manufacturing of the graphene-based interdigital MSCs with outstanding flexibility, shape diversity, and high areal capacitance shows great potential in wearable and portable electronics.

14.
J Anal Methods Chem ; 2020: 7560710, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014510

RESUMO

The quality control of Saussurea involucrata has been greatly improved by macroscopic and microscopic identification and chemical profiling described in Chinese Pharmacopoeia since 2005. However, these methods have their own limitations, e.g., their dependence on personal experience and expertise, and it is a huge challenge to identify closely related species that share similar or identical morphological characteristics and chemical profiles. A novel and generally accepted identification strategy is urgently needed as a complement to regulations for protecting the public health interests. In this work, a comprehensive chromatographic fingerprint method was developed and tested on 43 samples from four haplotypes of S. involucrata according to DNA barcoding. Three common patterns consisting of 20, 14, and 7 common peaks were generated by frequency filters of median, upper quartile, and 100%, respectively. Based on two formerly screened patterns, S. involucrata can be effectively identified from its five easily confused snow lotus species, including the most closely related plant (S. orgaadayi) in the orthogonal partial least-squares discriminant analysis (OPLS-DA) models. The model is supported by good R and Q coefficients. In addition, different haplotypes of S. involucrata can be discriminated in the OPLS-DA model using the 20 common peaks. Among them, peaks 9, 11, 16 (zaluzanin C), and 18 (dehydrocostus lactone) have been identified as fingerprint markers of S. involucrata via S-plots and VIP values (>1). Additionally, peaks 19 and 20 were identified as linolenic acid and linoleic acid with anti-inflammatory activity, and they were isolated from the herb for the first time. Collectively, the chromatographic fingerprint of S. involucrata can be an effective and integrated method for the identification of authentic herbs from adulterant species or related plants, and discrimination of its different haplotypes provides an objective and reliable tool for quality control.

15.
J Tradit Chin Med ; 40(5): 875-882, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33000590

RESUMO

OBJECTIVE: To identify, rapidly and accurately, the chemical composition of the traditional Uighur formulation Baixuan Xiatare (BXXTR-FU). METHODS: We investigated if application of three-stage infrared (IR) spectroscopy enabled identification of the main chemical constituents (and their origins) in BXXTR-FU. RESULTS: The characteristic peaks of herbal material(s) and BXXTR-FU were assigned. In Fourier transform-IR (FT-IR) spectroscopy of BXXTR-FU, peaks at 1616 and 1605 cm-1 of BXXTR-FU were considered to denote anthraquinones and their derivatives; 1066 cm-1 was regarded as the characteristic absorption peak of resin glycosides. In second-derivative IR (SD-IR) spectroscopy, the main carbonyl types of BXXTR-FU in the range 1743-1636 cm-1 were assigned: 1651 cm-1 belonged to the carbonyl stretching vibrations of flavonoids and chromones; 1717 cm-1 belonged to tannins; 1699 cm-1 belonged to carboxylic acids; 1636 cm-1 belonged to anthraquinones and their derivatives. SD-IR spectroscopy further confirmed that the characteristic absorption peaks at 1636, 1618 and 1603 cm-1 could be used as markers that BXXTR-FU contained anthraquinones and their derivatives. Synchronous 2D-IR correlation spectra of chemical groups further confirmed the results of FT-IR and SD-IR spectroscopy. CONCLUSION: Our study strongly supported the necessity and importance of three-stage IR spectroscopy owing to its rapid and accurate identification of herbal formulations.

16.
Pharmacol Biochem Behav ; 199: 173062, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33098854

RESUMO

BACKGROUND: Stress may be one of the main causes of fear and anxiety. Previous studies have shown that the nucleus accumbens is involved in emotional responses. However, in the nucleus accumbens, the mRNA and miRNA profiles of stress susceptibility and resilience of psychological stress still need to be studied. MATERIALS AND METHODS: In this study, by observing the conspecific being attacked, the witness group experienced psychological stress. After five days of psychological stress, the fear memory of mice was measured by social interaction test, and the degree of anxiety was measured by elevated plus maze. mRNA and miRNA profiles in the nucleus accumbens tissue of control, susceptible and resilient mice were established by high-throughput sequencing. RESULTS: In susceptible mice versus resilient mice, the Differentially expressed genes (DEGs) may be related to psychological stress-induced susceptibility. DEGs enriched in Cell adhesion molecules, Neuroactive ligand-receptor interaction, Gap junction, PI3K-Akt, VEGF, Jak-STAT, Ras, and Chemokine pathways were up-regulated. DEGs enriched in cGMP-PKG, B cell receptor, and NOD-like receptor pathways were down- regulated. The sequencing results of mRNAs and miRNAs were verified by qRT-PCR and dual luciferase reporter assay. CONCLUSION: The imbalance of different synapses and pathways in the nucleus accumbens may be related to susceptibility and resilience caused by psychological stress.

17.
J Med Chem ; 63(21): 12978-12991, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33100009

RESUMO

Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure-activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15 was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.

18.
Cancer Immunol Res ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093217

RESUMO

Lymphomas with central nervous system (CNS) involvement confer a worse prognosis than those without CNS involvement, and patients currently have limited treatment options. T cells genetically engineered with CD19-targeted chimeric antigen receptors (CAR) are effective against B-cell malignancies and show tremendous potential in the treatment of systemic lymphoma. We aimed to leverage this strategy toward a more effective therapy for patients with lymphoma with CNS disease. NOD-scid IL2Rgammanull (NSG) mice with CNS and/or systemic lymphoma were treated with CD19-CAR T cells via intracerebroventricular (ICV) or intravenous (IV) injection. CAR T cells isolated after treatment were rigorously examined for phenotype, gene expression, and function. We observed that CAR T cells infused ICV, but not IV, completely and durably eradicated both CNS and systemic lymphoma. CAR T cells delivered ICV migrated efficiently to the periphery, homed to systemic tumors, and expanded in vivo, leading to complete elimination of disease and resistance to tumor rechallenge. Mechanistic studies indicated that ICV-delivered CAR T cells are conditioned by exposure to cerebrospinal fluid in the ICV environment for superior antilymphoma activity and memory function compared with IV-delivered CAR T cells. Further analysis suggested that manipulating cellular metabolism or preactivating therapeutic CAR T cells with antigen ex vivo may improve the efficacy of CAR T cells in vivo Our demonstration that ICV-delivered CD19-CAR T cells had activity against CNS and systemic lymphoma could offer a valuable new strategy for treatment of B-cell malignancies with CNS involvement.

19.
Biomed Pharmacother ; 132: 110933, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33128943

RESUMO

Diabetic foot is one of the main causes of non-traumatic amputation. However, there is still lack of effective drugs to treat diabetic foot in clinical practice. Kanglexin (KLX) is a new anthraquinone compound with cardiovascular protective effects. Here we report that KLX accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling. Firstly, KM mice were injected (ip) with streptozocin to establish type 1 diabetic model. The full thickness wound with the diameter of 5 mm was prepared on the back of each mice. The wounds were treated with KLX once a day for 14 consecutive days. Results showed that KLX significantly accelerated the closure of diabetic wounds. Pathological studies of skin tissues around the wounds showed that KLX promoted the formation of granulation tissue and new blood vessels, increased collagen deposition and reduced inflammatory cell infiltration. Besides, KLX significantly alleviated advanced glycation end products (AGEs) - induced abnormal proliferation, migration and tubule formation of human umbilical vein endothelial cells (HUVECs), and up-regulated phospho-ERK1/2 both in the diabetic wound tissue and AGEs - treated HUVECs. Moreover, molecular docking results indicated that KLX had the potential to bind with FGF receptor 1 (FGFR1), and subsequent experiments confirmed that FGFR1 inhibitor PD173074 reversed the effect of KLX on promoting the phosphorylation of ERK1/2 and angiogenesis, suggesting that KLX promoted angiogenesis through FGFR1/ERK signaling. In conclusion, our study provides a new effective compound for treating diabetic wounds. More importantly, KLX has the potential to be developed as a topical drug to promote diabetic wound healing.

20.
Int J Biol Macromol ; 164: 4415-4422, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926904

RESUMO

The genome of the thermophilic bacteriophage GVE2 encodes a putative tailspike protein (GVE2 TSP). Here we report the crystal structure of the truncated GVE2 TSP at 2.0-Å resolution lacking 204 amino acid residues at its N-terminus (ΔnGVE2 TSP), possessing a "vase" outline similar to other TSP's structures. However, ΔnGVE2 TSP displays structural characteristics distinct from other TSPs. Despite lacking 204 amino acid residues, the head domain forms an asymmetric trimer compared to symmetric in other TSPs, suggesting that its long N-terminus may be unique to the long-tailed bacteriophages. Furthermore, the α-helix of the neck is 5-7 amino acids longer than that of other TSPs. The most striking feature is that its binding domain consists of a ß-helix with 10 turns, whereas other TSPs have 13 turns, even including the phage Sf6 TSP, which is the closest homologue of GVE2 TSP. The C-terminal structure is also quite different with those of other TSPs. Furthermore, we observed that ΔnGVE2 TSP can slow down growth of its host, demonstrating that this TSP is essential for the phage GVE2 to infect its host. Overall, the structural characteristics suggest that GVE2 TSP may be more primitive than other phage TSPs.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA