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1.
Mol Cancer Ther ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999045

RESUMO

Immunotherapy using OX40 agonist antibodies shows great preclinical efficacy in mouse tumor models. But in a clinical setting, OX40 agonist antibody alone or in combination with checkpoint blockade exhibit only modest efficacy due to lack of sufficient activation. We hypothesize that the limited antitumor activity in patients may due to insufficient clustering of OX40 antibody in the tumor. To test this hypothesis, we generated a tetravalent PD-L1/OX40 BsAb by fusing two PD-L1 VHH fragments to the C-terminus of a non-blocking agonistic anti-OX40 antibody. The resulting BsAb has intact function of each parental Ab, including efficiently blocking PD1/PD-L1 interaction and inducing OX40 activation. In addition, this BsAb showed significantly enhanced potency in activation of OX40-expressing T cells when PD-L1-expressing tumor cells or DCs were present, through PD-L1-mediated crosslinking of OX40. Moreover, the BsAb exhibited superior antitumor activities over the parental monospecific antibodies alone or in combination in multiple in vivo tumor models. These results demonstrated a great potential for further clinical development of the potent immunostimulatory PD-L1/OX40 bispecific antibody.

2.
Int Immunopharmacol ; 89(Pt B): 107008, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069927

RESUMO

Psoriasis is a highly prevalent inflammatory skin disease. Plaque psoriasis is the most common type of psoriasis, and the interleukin (IL)-23/IL-17 axis plays a key role in disease progression. In this article, we describe IBI112, a highly potent anti-IL-23 monoclonal antibody under clinical development, which efficiently neutralizes IL23p19, a subunit of IL-23, to abrogate IL-23 binding to its receptor and block downstream signal transducer and activator of transcription 3 (STAT3) phosphorylation. Specifically, IBI112 blocked IL-23 induced downstream IL-17 production from splenocytes. In addition, IBI112 administration reduced skin thickness in a psoriasis-like epidermal hyperplasia mouse model challenged by continuous hIL-23 injection. IBI112 showed synergism with an anti-IL-1R antibody in controlling disease progression in an imiquimod (IMQ) -induced psoriasis model. Moreover, with mutations in Fc fragment of IBI112, extended half-life was observed when compared to the wild-type IgG1 version in both human-FcRn-knock-in mice and cynomolgus monkeys. IBI112 was well tolerated after high dose administration in cynomolgus monkeys. In summary, we have developed an extended half-life, anti-IL-23p19 monoclonal antibody, IBI112, which efficiently neutralized IL-23, blocked IL-23-induced IL-17 production, and alleviated disease symptoms in two mouse models of psoriasis.

3.
Diabetes ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948607

RESUMO

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO of autophagy related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO-induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.

4.
Biofouling ; 36(7): 792-799, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32873073

RESUMO

The complexity of the root canal system results in areas where mechanical instrumentation is impossible during endodontic treatment. To disinfect these areas, the effect of irrigation on biofilm debridement is of great significance but has not yet been well explored. Using an in vitro Enterococcus faecalis biofilm model and a biofilm reactor, the present study provides a better understanding of the relative contributions of mechanical and chemical effects of irrigation on biofilm removal, as well as the factors influencing their coupling efficiency. The results clearly demonstrate that, the mechanical effect of irrigation alone does not significantly influence the stability of biofilms. However, the mechanical effect promotes biofilm eradication by coupling with the chemical effect. In addition, both the irrigant concentration and the irrigant-biofilm contact time are among the key factors affecting the mechano-chemical coupling. This knowledge may serve to better direct endodontists in designing irrigation regimes during root canal therapy.

5.
Environ Int ; 145: 106098, 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32916414

RESUMO

BACKGROUND: Several studies with small sample size have reported inconsistent associations between single metal and preeclampsia (PE). Very few studies have investigated metal mixtures and PE. METHODS: Blood concentrations of chromium (Cr), cadmium, mercury (Hg), arsenic (As), lead (Pb), nickel, cobalt, and antimony were measured using inductively coupled plasma-mass spectrometry among 427 PE women and 427 matched controls from Taiyuan, China. Multivariate logistic regression models, weighted quantile sum (WQS) regression, and principal component analysis were employed to examine exposure to single metals and metal mixtures in relation to PE. RESULTS: An increased prevalence of PE was associated with Cr (OR = 1.76, 95% CI: 1.18, 2.62 and 1.90, 1.22, 2.93 for the middle and high vs. low), Hg (OR = 1.60, 95% CI: 1.08, 2.38 for the high vs. low) and As (OR = 1.64, 95% CI: 1.07, 2.52 for the middle vs. low). The WQS index, predominated by Cr, Hg, Pb, and As, was positively associated with PE. A principal component characterized by Cr and As also exhibited excessive association with PE. The highest PE prevalence was found among women who were overweight/obese before pregnancy and had high Cr levels compared to women who had pre-pregnancy normal body mass index (BMI) and low Cr levels. CONCLUSIONS: Our study provided evidence that exposure to multiple metals was associated with increased prevalence of PE, and the observed association with multiple metals was dominated by Cr, As. Our study also suggested that pre-pregnancy BMI might modify the association between Cr and PE.

6.
Burns ; 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32782165

RESUMO

OBJECTIVE: Among downstream interleukin-18 (IL-18) targets, Fas ligand (FasL) in particular, has been strongly implicated in many conditions. Our study aims to explore the role of IL-18 in hypertrophic scar through enhancing FasL expression. METHODS: IL-18 expression in hypertrophic scar tissues and normal tissues were explored by immunohistochemistry, qRT-PCR and Western blotting, and the expression of IL-18 in normal skin fibroblasts and hypertrophic scar fibroblasts by immunofluorescence. Hypertrophic scar fibroblasts treated with recombinant human IL-18 (rhIL-18) were assessed with MTT, Annexin V-FITC/PI, qRT-PCR, ELISA and western blotting. In the hypertrophic scar of rabbit ears, rhIL-18 was injected to determine histological changes with HE and Masson staining. Additionally, the scars were rated based on contour and overall severity using a visual analog scale scores (VAS). RESULTS: IL-18 was decreased in hypertrophic scar tissues and fibroblasts compared to normal skin tissues and fibroblasts, respectively. Decreased proliferation and increased apoptosis of hypertrophic scar fibroblasts were found after rhIL-18 treatment with enhanced expression of FasL, sFasL FADD, Caspase-8, Caspase-9 and Caspase-3 in a dose-dependent manner. The VAS and thickness of scars in rabbit ears was decreased as time went on after rhIL-18 treatment, with decreases in scar elevation index (SEI) and the increases in FasL expression. CONCLUSION: IL-18 curbs proliferation and promotes apoptosis of hypertrophic scar fibroblasts by enhancing FasL expression. IL-18is a potential target for treatment of hypertrophic scar.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32761423

RESUMO

CD47, an immune checkpoint receptor frequently unregulated in various blood and solid tumors, interacts with ligand SIPRα on innate immune cells, and conveys a "do not eat me" signal to inhibit macrophage-mediated tumor phagocytosis. This makes CD47 a valuable target for cancer immunotherapy. However, the therapeutic utility of CD47-SIRPα blockade monoclonal antibodies is largely compromised due to significant red blood cell (RBCs) toxicities and fast target-mediated clearance as a result of extensive expression of CD47 on normal cells. To overcome these limitations and further improve therapeutic efficacy, we designed IBI322, a CD47/PD-L1 bispecific antibody which attenuated CD47 activity in monovalent binding and blocked PD-L1 activity in bivalent binding. IBI322 selectively bound to CD47+PD-L1+ tumor cells, effectively inhibited CD47-SIRPα signal and triggered strong tumor cell phagocytosis in vitro, but only with minimal impact on CD47 single positive cells such as human RBCs. In addition, as a dual blocker of innate and adaptive immune checkpoints, IBI322 effectively accumulated in PD-L1-positive tumors and demonstrated synergistic activity in inducing complete tumor regression in vivo. Furthermore, IBI322 showed only marginal RBCs depletion and was well tolerated in non-human primates (NHP) after repeated weekly injections, suggesting a sufficient therapeutic window in future clinical development of IBI322 for cancer treatment.

8.
Sci Rep ; 10(1): 13689, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792492

RESUMO

To describe the epidemiological and clinical characteristics of patients with Corona Virus Disease 2019 (COVID-19) in Beijing. To analyze the application of corticosteroids in patients with severe pneumonia. We collected information on demographic characteristics, exposure history, clinical characteristics, corticosteroids use, and outcomes of the 65 confirmed cases of COVID-19 at Fifth Medical Center of PLA General Hospital from Jan 20 to Feb 23, 2020. The final follow-up date observed was April 15th, 2020. The number of patients with mild, general, severe, and critical type were 10 (15.38%), 32 (49.23%), 8 (12.31%), and 15 (23.08%), respectively. The median incubation period was 6 days. Notable outliers were 1 patient at 16 days and 1 patient at 21 days. In lymphocyte subgroup analysis, decreases in total, T, CD4, and CD8 lymphocytes were more common as the disease worsened (All P < 0.05). Methylprednisolone (mPSL) was applied to 31 (47.69%) patients with pneumonia, including 10 (31.25%) general, 8 (100%) severe, and 13 (86.67%) critical patients, respectively. Corticosteroids inhibited Interleukin-6(IL-6) production (P = 0.0215) but did not affect T lymphocyte (P = 0.0796). There was no significant difference between patients using lower dose (≤ 2 mg/kg day) and higher dose (> 2 mg/kg day) mPSL in inhibiting IL-6 production (P = 0.5856). Thirty of 31 patients (96.77%) had stopped mPSL due to improvement of pneumonia. Virus RNA clearance time lengthened with disease progression (P = 0.0001). In general type, there was no significant difference in virus clearance time between patients with (15, 12-19 days) and without (14.5, 11-18 days) (P = 0.7372) mPSL use. Lymphocyte, especially T lymphocyte, in severe and critical patients showed a dramatic decrease. Application of lower dose corticosteroids (≤ 2 mg/kg day) could inhibit IL-6 production (a representative of cytokines) as effectively as a higher dose. Proper use corticosteroids in general type patients did not delay virus clearance.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Glucocorticoides/uso terapêutico , Metilprednisolona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Idoso , Pequim/epidemiologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Criança , Pré-Escolar , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Contagem de Linfócitos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/farmacologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , RNA Viral/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
9.
J Am Chem Soc ; 142(36): 15569-15574, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32790301

RESUMO

Despite the extensive studies of the nanozymes showing their superior properties compared to natural enzymes and traditional artificial enzymes, the development of highly specific nanozymes is still a challenge. The catechol oxidase specifically catalyzing the oxidations of o-diphenol to the corresponding o-quinone is important to the biosynthesis of melanin and other polyphenolic natural products. In this study, we first propose that MOF-818, containing trinuclear copper centers mimicking the active sites of natural catechol oxidase, shows efficient catechol oxidase activity with good specificity and no peroxidase-like characteristics. MOF-818 has good specificity and high catalytic activity as a novel catechol oxidase nanozyme.

10.
Colloids Surf B Biointerfaces ; 196: 111298, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32798987

RESUMO

Honokiol (HK), an active compound derived from Magnolia officinalis Rehd. et Wils, possesses many beneficial biological activities for human beings. However, its poor solubility and low bioavailability severely limits its application. In this way, to improve the pharmaceutical properties, the HK was complexed in hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and its oral bioavailability and antitumor effects were evaluated. The HK/HP-ß-CD inclusion complex (1:1) was prepared by saturated aqueous solution method. The inclusion complex (HK-HP-ß-CD) obtained had a higher solubility, about 1497 times that of the free HK. The dissolution rate and the oral bioavailability of HK was also significantly higher from inclusion complex than from free HK. Furthermore, the HK-HP-ß-CD exhibited higher antitumor activity against Human Hepatoma Cell Line (HepG2) than free HK. More cells were arrested in the sub-G1 phase of the cell cycle and were induced to undergo late apoptosis when treated with the HK-HP-ß-CD than when treated with free HK.

11.
Ann Vasc Surg ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768530

RESUMO

A 27-year-old male patient suffering from dizziness and right amaurosis was diagnosed with Takayasu arteritis (TA). Computed tomography angiography showed that all the supra-aortic arteries were occluded except an aberrant right subclavian artery. The patient underwent drug-coated balloon dilatation at the lesion of the right common carotid artery and performed well after the procedure. Six months later, the patient's symptoms have not recurred and computed tomography angiography showed the right carotid artery remains patency. The supra-aortic artery lesions in TA may be a potential novel indication for a drug-coated balloon.

12.
Int J Legal Med ; 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483669

RESUMO

Genotypes of 42 Y chromosome STR (Y-STR) loci were analyzed for a sample of 1420 unrelated males and 1160 father-son pairs from a Chinese Han population. Deletions of Y-STR loci were detected at DYS389I, DYS389II, DYS437, DYS446, DYS447, DYS448, and DYS557 loci. The most common deletion occurred at DYS448 and DYS557 with a frequency of 0.0056 and 0.0035, respectively. On the other hand, duplications of alleles were observed at DYF387S1a/b, DYS385a/b, DYS460, DYS527a/b, DYS459a/b, and DYS557 loci. The DYF387S1a/b, DYS527a/b, and DYS385a/b showed the highest duplicated frequencies of 0.0148, 0.0134, and 0.0099, respectively. The Y-STRs located on palindromes significantly exhibited more deletions or duplications than those non-palindromic loci. Also, duplications were more frequent than deletions. Hence, deletions or duplications of Y-STRs related to their positions on the Y chromosome. All the 52 deleted or duplicated events occurred in the two-generation families inherited stably. Furthermore, the deletions may show the Chinese Han population specificity, but the duplications may not have a similar phenomenon. Our results will be helpful to correct interpretation of the genetic profile of Y-STR loci in forensic casework.

13.
J Agric Food Chem ; 68(29): 7581-7590, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32579349

RESUMO

The grain size and shape of rice are limited by the growth of the spikelet hulls and are important selective target during domestication and breeding. In this study, we identified a glycine- and proline-rich protein (OsGPRP3), which belongs to a conserved family rarely studied. We found that OsGPRP3 was highly expressed in the seed at 10 days after pollination (DAP) using qRT-PCR, pOsGPRP3::GUS and in situ hybridization. Knockout and knockdown of OsGPRP3 led to significant decrease of 1000-grain weight, grain width, and grain thickness. We further found that the content of storage protein and total lipid were decreased in osgprp3 lines. In particular, the contents of C14:0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), and C18:2 (linoleic acid) were reduced in osgprp3 lines. Cytological experiments revealed that the cell width of spikelet hull in osgprp3 lines was significantly reduced than that in WT. Taken together, our results reveal that OsGPRP3 regulates the grain size and shape of rice by influencing the cell width of spikelet hulls and the accumulation of storage protein and lipids.

15.
Nanotechnology ; 31(37): 375402, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32480386

RESUMO

Transition metal element doping into semiconducting materials has been a promising method for the preparation of active photocatalysts for the efficient use of solar energy. In this study, we report the facile synthesis of Fe doped SrWO4 nanoparticles by a solvothermal method for photocatalytic nitrogen reduction. The intrinsic bandgap of SrWO4 is greatly narrowed by the Fe-dopant which not only extends the light absorption from UV to visible light range, but also reduces the charge recombination. The narrowed band structure still fulfils the thermodynamic requirements of nitrogen reduction reaction. At optimal doping concentration, Fe doped SrWO4 shows much higher photocatalytic nitrogen fixation performance. The present study provides a route toward the development of active photocatalysts for nitrogen fixation.

16.
Injury ; 51(8): 1726-1732, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534817

RESUMO

Chronic ankle instability predominantly occurs due to multiple exercise-related diseases. Conservative treatment methods regarding this condition have not effectively improved in recent years, which is why more focus has been put on exploring different novel reconstruction procedures of the lateral ankle ligament for the treatment of chronic ankle instability. OBJECTIVES: This study aims to obtain the overall effectiveness of various lateral ankle ligament reconstruction methods for chronic ankle ligament instability. METHODS: We gathered data from PubMed and EMBASE databases using the keywords: ankle, malleolar, and reconstruction. Newcastle - Ottawa quality assessment was carried out for the obtained studies; effect volume combination and image drawing were performed by Stata14, and Excel was used for data statistics. RESULTS: A total of 12 articles were included in the quantitative analysis by performing full-text reading and data inclusion. Among them, 476 patients (485 ankle joints) were treated. The results showed that the overall valid efficiency of "excellent" was 59% and "good" lateral ligament reconstruction was 26%, I2=87.3%, P = 0.000; the subgroup analysis anatomic reconstruction group I2=0.0%, P = 0.993; the autograft group I2=0.0%, P = 1.000; allograft group I2=0.0%, P = 0.993. CONCLUSION: Reconstruction of the lateral ankle ligament is a relatively stable treatment for chronic ankle instability.

17.
BMC Immunol ; 21(1): 37, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552667

RESUMO

BACKGROUND: RelB, a member of the NF-κB family, plays a critical role in the development of T cells. However, the role of RelB in Foxp3+ regulatory T cells (Tregs) remains controversial. RESULTS: Using a bone marrow chimeric mouse model, we demonstrated that the expansion of Foxp3+ Tregs in vivo could be mediated by extrinsic mechanisms. RelB plays an important role in inhibiting the homeostatic proliferation of Tregs, but not their survival. Even with the heightened expansion, RelB-/- Treg cells displayed normal suppressive function in vitro. Among the expanded populations of Treg cells, most were nTreg cells; however, the population of iTregs did not increase. Mechanistically, RelB seems to regulate Treg proliferation independently of the signal transducer and activator of transcription 5 (STAT5) pathway. CONCLUSIONS: These data suggest that RelB regulates Treg proliferation independently of the STAT5 pathway, but does not alter the function of Tregs. Further studies are warranted to uncover such mechanisms.

18.
Arterioscler Thromb Vasc Biol ; 40(8): 1870-1890, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32493169

RESUMO

OBJECTIVE: Neointima formation is a primary cause of intermediate to late vein graft (VG) failure. However, the precise source of neointima cells in VGs remains unclear. Approach and Results: Herein we clarify the relative contributions of mature vascular smooth muscle cells (SMCs) and endothelial cells (ECs) to neointima formation in a mouse model of VG remodeling via the genetic-inducible fate mapping approaches. Regardless of the magnitude of neointima formation, the recipient arterial and the donor venous SMCs contributed ≈55% of the neointima cells at the anastomotic regions, whereas only donor venous SMCs donated ≈68% of the neointima cells at the middle bodies. A small portion of the SMC-derived cells became non-SMC cells, most likely vascular stem cells, and constituted 2% to 11% of the cells in each major layer of VGs. In addition, the recipient arterial ECs were the major cellular source of re-endothelialization but did not contribute to neointima formation. The donor venous ECs donated ≈17% neointima cells in the VGs with mild neointima formation and conditional media from ECs after endothelial-to-mesenchymal transition suppressed vascular SMC dedifferentiation. CONCLUSIONS: The recipient arterial and donor venous mature SMCs dominate but contribute distinctly to intimal hyperplasia at the anastomosis and the middle body regions of VGs. The recipient arterial ECs are the major cellular source of re-endothelialization but do not donate neointima formation in VGs. Only the donor venous ECs undergo endothelial-to-mesenchymal transition. Endothelial-to-mesenchymal transition is marginal for generating neointima cells but is likely required for controlling the quality of VG remodeling.


Assuntos
Células Endoteliais/patologia , Veias Jugulares/transplante , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/patologia , Animais , Hiperplasia , Mesoderma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Remodelação Vascular
19.
J Mol Cell Cardiol ; 145: 59-73, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32553594

RESUMO

Deubiquitinating enzymes (DUBs) appear to be a new class of regulators of cardiac homeostasis and disease. However, DUB-mediated signaling in the heart is not well understood. Herein we report a novel mechanism by which cylindromatosis (CYLD), a DUB mediates cardiac pathological remodeling and dysfunction. Cardiomyocyte-restricted (CR) overexpression of CYLD (CR-CYLD) did not cause gross health issues and hardly affected cardiac function up to age of one year in both female and male mice at physiological conditions. However, CR-CYLD overexpression exacerbated pressure overload (PO)-induced cardiac dysfunction associated with suppressed cardiac hypertrophy and increased myocardial apoptosis in mice independent of the gender. At the molecular level, CR-CYLD overexpression enhanced PO-induced increases in poly-ubiquitinated proteins marked by lysine (K)48-linked ubiquitin chains and autophagic vacuoles containing undegraded contents while suppressing autophagic flux. Augmentation of cardiac autophagy via CR-ATG7 overexpression protected against PO-induced cardiac pathological remodeling and dysfunction in both female and male mice. Intriguingly, CR-CYLD overexpression switched the CR-ATG7 overexpression-dependent cardiac protection into myocardial damage and dysfunction associated with increased accumulation of autophagic vacuoles containing undegraded contents in the heart. Genetic manipulation of Cyld in combination with pharmacological modulation of autophagic functional status revealed that CYLD suppressed autolysosomal degradation and promoted cell death in cardiomyocytes. In addition, Cyld gene gain- and/or loss-of-function approaches in vitro and in vivo demonstrated that CYLD mediated cardiomyocyte death associated with impaired reactivation of mechanistic target of rapamycin complex 1 (mTORC1) and upregulated Ras genes from rat brain 7 (Rab7), two key components for autolysosomal degradation. These results demonstrate that CYLD serves as a novel mediator of cardiac pathological remodeling and dysfunction by suppressing autolysosome efflux in cardiomyocytes. Mechanistically, it is most likely that CYLD suppresses autolysosome efflux via impairing mTORC1 reactivation and interrupting Rab7 release from autolysosomes in cardiomyocytes.

20.
Acta Crystallogr C Struct Chem ; 76(Pt 5): 389-397, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32367818

RESUMO

The crystal structures of the antimicrobial drug tinidazole [TNZ; systematic name: 1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole, C8H13N3O4S] and the 1:1 cocrystal of TNZ with the naturally occurring compound vanillic acid (VA; systematic name: 4-hydroxy-3-methoxybenzoic acid, C8H8O4), namely, the TNZ-VA cocrystal, were determined by single-crystal X-ray analysis at 100 K. The supramolecular structure of the TNZ-VA cocrystal is composed of a carboxylic acid dimer and an O-H...N(heterocycle) synthon in the form of layers made up of O-H...N and O-H...O hydrogen bonds. The layers are joined via C-H...O hydrogen bonds, π-π stacking and C-H...π interactions. The energy framework analysis, together with interaction energy calculations using the DLPNO-CCSD(T) method, indicates that the TNZ-VA cocrystal inherits strong interactions from the TNZ and VA crystals, which accounts for the enhanced thermal stability and reduced dissolution rate. To the best of our knowledge, this is the first example of a cocrystal containing TNZ.

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