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1.
Br J Pharmacol ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32167156

RESUMO

BACKGROUND AND PURPOSE: DMSO has been found to promote tissue repair. However, the role of DMSO in diabetic skin wound healing and the underlying molecular mechanisms are still unclear. EXPERIMENTAL APPROACH: The effects of DMSO on wound healing were evaluated by HE staining, immunohistochemistry, and collagen staining using a wound model of full-thickness skin resection on the backs of nondiabetic or diabetic mice. Real-time cell analysis and 5-ethynyl-2´-deoxyuridine incorporation assays were used to study the effect of DMSO on primary fibroblast proliferation. A transwell assay was used to investigate keratinocyte migration. The associated signalling pathway was identified by western blotting and inhibitor blocking. The effect of DMSO on the translation rate of downstream target genes was studied by RT-qPCR of polyribosome mRNA. KEY RESULTS: We found that low-concentration DMSO significantly accelerated skin wound closure by promoting fibroblast proliferation in both nondiabetic and diabetic mice. In addition, increased migration of keratinocytes may also contribute to accelerated wound healing, which was stimulated by increased TGF-ß1 secretion from fibroblasts. Furthermore, we demonstrated that this effect of DMSO depends on AKT/mTOR-mediated translational control and the promotion of the translation of a set of cell proliferation-related genes. As expected, DMSO-induced wound healing and cell proliferation were impaired by rapamycin, an inhibitor of AKT/mTOR signalling. CONCLUSION AND IMPLICATIONS: DMSO can promote skin wound healing in diabetic mice by activating the AKT/mTOR pathway. Low-concentration DMSO presents an alternative medication for chronic cutaneous wounds, especially for diabetic patients.

2.
Clin Exp Med ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32078076

RESUMO

Identification of risk factors for treatment resistance and relapse would be crucial to personalization therapy in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). Current evidence with regard to the risk factors for treatment resistance and relapse remains limited and inconclusive. We aimed to assess the predictors for treatment resistance and relapse in a single-center cohort of Chinese patients with MPO-AAV in this study. In total, 184 patients with MPO-AAV were included. Treatment resistance occurred in 64 (34.9%) of 184 patients and was positively associated with lung involvement (odds ratio [OR] 3.581, 95% CI 1.137-11.278, p = 0.029) and the initial serum creatinine level (OR 1.004, 95% CI 1.001-1.007, p = 0.010) and was negatively associated with platelet (OR 0.992, 95% CI 0.987-0.998, p = 0.007) and serum C3 levels (OR 0.998, 95% CI 0.996-0.999, p = 0.004). Relapse occurred in 29 (24.17%) of 120 patients in whom remission was achieved and was independently associated with lung involvement (hazard ratio [HR] 4.595, 95% CI 1.272-16.599, p = 0.020) and cardiovascular involvement (HR 3.689, 95% CI 1.237-11, p = 0.019,). The serum globulin was demonstrated to be negatively associated with relapse independently (HR 0.876; 95% CI 0.806-0.953; p = 0.002). This retrospective study of MPO-AAV patients in a single Chinese center suggests that treatment resistance was positively associated with lung involvement and the initial serum creatinine level and was negatively associated with platelet and serum C3 levels. Lung involvement and cardiovascular involvement were associated with an increased risk of relapse, while the higher serum globulin was demonstrated to be in association with a decreased risk of relapse.

3.
Lab Invest ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896816

RESUMO

Heterotopic ossification (HO) is a debilitating condition that results from traumatic injuries or genetic diseases, for which the underlying mechanisms remain unclear. Recently, we have demonstrated the expression of neurotrophin-3 (NT-3) and its role in promoting HO formation via mediating endothelial-mesenchymal transition (EndMT) of vascular endothelial cells. The current study investigated the role of NT-3 on the surrounding mesenchymal cells and its potential origin throughout HO formation at injured Achilles tendons in rats. We used an Achilles tenotomy to induce HO formation in vivo and cultured primary tendon-derived stem cells (TDSCs) to investigate the underlying mechanisms mediating the osteogenesis in vitro. Furthermore, RAW264.7 cells were employed to identify the origin of NT-3. The mRNA levels of NGF, BDNF, NT-3, and NT-4 and their tyrosine protein kinase (Trk) receptors as well as p75 receptor were elevated at injury sites. NT-3 and TrkC showed the highest induction. Neutralization of the NT-3-induced effects by the pan-Trk inhibitor GNF5837 reduced the expression of bone/cartilage-related genes while injection of NT-3 promoted HO formation with elevated mRNA of bone/cartilage-related markers at injured sites. In vitro, NT-3 accelerated osteogenic differentiation and mineralization of TDSCs through activation of the ERK1/2 and PI3K/Akt signaling pathways. Moreover, the colocalization of NT-3 and macrophages, including M1 and M2 macrophages, was observed in injured sites throughout HO formation, and in vitro studies demonstrated that activated macrophages mediated the secretion of NT-3. In addition, an increasing concentration of serum or supernatant NT-3 was observed both in vivo and in vitro. Depletion of macrophages with clodronate-loaded liposomes reduced HO formation as well as secretion and mRNA expression of NT-3. Our study suggests that macrophage-derived NT-3 may promote HO formation and osteogenesis of TDSCs via the ERK1/2 and PI3K/Akt signaling pathways, which may provide new insights for the therapeutic directions of HO in the future.

4.
Cell Commun Signal ; 18(1): 14, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31987048

RESUMO

CSDE1 (cold shock domain containing E1) plays a key role in translational reprogramming, which determines the fate of a number of RNAs during biological processes. Interestingly, the role of CSDE1 is bidirectional. It not only promotes and represses the translation of RNAs but also increases and decreases the abundance of RNAs. However, the mechanisms underlying this phenomenon are still unknown. In this review, we propose a "protein-RNA connector" model to explain this bidirectional role and depict its three versions: sequential connection, mutual connection and facilitating connection. As described in this molecular model, CSDE1 binds to RNAs and cooperates with other protein regulators. CSDE1 connects with different RNAs and their regulators for different purposes. The triple complex of CSDE1, a regulator and an RNA reprograms translation in different directions for each transcript. Meanwhile, a number of recent studies have found important roles for CSDE1 in human diseases. This model will help us to understand the role of CSDE1 in translational reprogramming and human diseases. Video Abstract.

5.
Inflammation ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31897918

RESUMO

Casticin, a flavonoid isolated from Vitex trifolia, has been shown to have anti-inflammatory and antitumor effects in previous studies. Osteoarthritis (OA) is a disease based on degenerative pathological changes. The disease process is often accompanied by inflammatory pathological changes. However, there is no safe and effective drug for prevention and treatment. In the present study, we aimed to clarify the role of casticin in the murine model of destabilization of the medial meniscus (DMM). Male BALB/c mice were randomly divided into three groups: Sham, DMM-induced OA treated with vehicle, and DMM-induced OA treated with casticin. Our results indicated that the casticin treatments markedly reduced the destruction of cartilage and OARSI grades compared with those of the vehicle-treated mice. The levels of matrix metalloproteinase-13 (MMP13) in cartilage were also significantly reduced in the casticin-treated mice. Casticin also significantly regulated oxidative stress and reduced inflammation in the cartilage of mice with OA. These results suggest that casticin prevents the development of posttraumatic OA in mice. Consequently, decreased reactive oxygen species levels and suppressed proinflammatory cytokine production were confirmed in casticin-treated IL-1ß-stimulated ADTC5 cells. After casticin treatment, the NF-κB signaling pathway was significantly inhibited in the cells. It can be concluded that casticin can alleviate arthritis-related cartilage degeneration by inhibiting ROS-mediated NF-κB signaling pathway in vitro and in vivo.

6.
Oncoimmunology ; 8(12): e1673126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31741776

RESUMO

Toll-like receptor 3 (TLR3) is a viral sensor that induces apoptosis in response to double-stranded RNA (dsRNA). Common genetic changes in the TLR3 gene may influence breast cancer susceptibility and development. However, all of the polymorphisms in the previous study were only markers of the TLR3 gene, not causative polymorphisms. In this study, we performed a case-control study focusing on the relationship between rs5743305 (-926T>A), a single nucleotide polymorphism (SNP) in the promoter region of TLR3, and breast cancer. We found that the genetic variant rs5743305 increased the risk of breast cancer under the dominant and codominant models (dominant model: AT+AA vs TT.: OR = 1.3023, 95%CI: 1.0778-1.5736, P = .0062; codominant model: AA vs. TT: OR = 1.3919, 95%CI: 1.0177-1.9036, P = .0384; AT vs. TT: OR = 1.2799, 95%CI: 1.0475-1.5639, P = .0158) but not under the recessive model (TT vs. AT+AA, OR = 1.2387, 95%CI: 0.9197-1.6682, P = .1588). The same trends were found in the age-adjusted logistic regression study and stage 2 study. Furthermore, the electrophoretic mobility shift assay (EMSA) and luciferase reporter assay showed that rs5743305 decreased the transcriptional activity of TLR3. There was consistently reduced TLR3 mRNA and protein expression in human breast cancer samples from patients with TLR3 - 926A. Therefore, TLR3 rs5743305 increases the risk of breast cancer by decreasing the transcriptional activity of TLR3. This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing.

7.
Cancer Commun (Lond) ; 39(1): 77, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753025

RESUMO

Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkinsonism (AR-JP) via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene, which itself belongs to an E3 ubiquitin ligase. Since the discovery of the Parkin gene in the late 1990s, researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP, the Parkin gene is associated with many diseases, including type 2 diabetes, leprosy, Alzheimer's, autism, and cancer. Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis. In general, the Parkin gene, a well-established tumor suppressor, is deficient and mutated in a variety of malignancies. Parkin overexpression inhibits tumor cell growth and promotes apoptosis. However, the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood. This article describes the structure, functions, and post-translational modifications of Parkin, and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.

8.
Oxid Med Cell Longev ; 2019: 9030563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781356

RESUMO

ROS functions as a second messenger and modulates multiple signaling pathways under the physiological conditions. However, excessive intracellular ROS causes damage to the molecular components of the cell, which promotes the pathogenesis of various human diseases. Cardiovascular diseases are serious threats to human health with extremely high rates of morbidity and mortality. Dysregulation of cell death promotes the pathogenesis of cardiovascular diseases and is the clinical target during the disease treatment. Numerous studies show that ROS production is closely linked to the cell death process and promotes the occurrence and development of the cardiovascular diseases. In this review, we summarize the regulation of intracellular ROS, the roles of ROS played in the development of cardiovascular diseases, and the programmed cell death induced by intracellular ROS. We also focus on anti-ROS system and the potential application of anti-ROS strategy in the treatment of cardiovascular diseases.

9.
Exp Ther Med ; 18(5): 3984-3990, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611938

RESUMO

Rapidly progressive glomerulonephritis (RPGN), characterized by rapid kidney dysfunction caused by aggressive glomerulonephritis, is usually associated with crescentic glomerulonephritis (CrGN). In the present study, the data from patients with CrGN were retrospectively analyzed at a tertiary medical center in China with the aim of investigating the clinicopathological features and the association of the type of CrGN with the prognosis. The renal biopsies of 49 patients diagnosed with CrGN were obtained between December 2011 and July 2016. Of the 49 patients, 11 patients (22.45%) had type I CrGN, 19 (38.78%) had type II CrGN and 19 (38.78%) had type III CrGN. The majority of CrGN patients exhibited multiple-system involvement and 28 patients (57.14%) had kidney enlargement. Proportions of patients with acute kidney injury (AKI), acute kidney diseases without AKI, and chronic kidney disease were 28.57, 46.94 and 24.49%, respectively. Among the 3 types of CrGN, patients with type I CrGN tended to have a higher proportion of AKI with more cellular crescent formation, and higher serum creatinine and retinol binding protein. Circulating anti-GBM antibodies were present in all type I CrGN patients and anti-neutrophilic cytoplasmic autoantibodies were detected in 84.21% of patients with type III CrGN. Type III CrGN patients had a superior kidney survival, whereas type I CrGN patients had the worst kidney prognosis (P<0.001). There was no significant difference in overall patient survival among the 3 types of CrGN. CrGN remains the primary cause of critical illness in RPGN patients. There was much heterogeneity between the different subtypes of CrGN. Patients with type I tended to have an acute onset and had the poorest kidney survival.

10.
Nanoscale ; 11(42): 19959-19968, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31603162

RESUMO

Hydrogen, regarded as one of the most promising green and sustainable energy resources, could be generated by splitting water with electrochemical methods. The challenge for efficient hydrogen generation is the sluggish kinetics at the anodes for the oxygen evolution reaction (OER). Here, a novel catalyst with remarkably enhanced OER activity was prepared by coupling FeOOH and NiCoP/C. The enhanced OER activity of the hybrid catalyst should be ascribed to the synergistic effect of the individual components. First, NiCoP/C derived from ZIF-67 with a hollow rhombic dodecahedral architecture not only allows exposure of numerous active sites but also provides high conductivity. Second, the re-localization of electrons at the coupling interface optimizes the adsorption/desorption nature of intermediate oxygenated species and imparts a high OER activity. The hybrid NiCoP/C@FeOOH catalyst exhibits very high OER activity with a low overpotential of 271 mV for producing a current density of 10 mA cm-2 in 1 M KOH aqueous solution, markedly surpassing the individual counterparts of pure NiCoP/C nanocages and bare FeOOH. This work represents a universal strategy for boosting the OER kinetics of catalysts and pushing boundaries for high-efficiency water oxidation.

11.
Front Genet ; 10: 809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552102

RESUMO

Lung cancer is the most commonly diagnosed type of cancer and the leading cause of cancer-associated death worldwide. MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules of ∼20-25 nucleotides in length. Single nucleotide polymorphisms are a class of genetic variation in the human genome, which when present in miRNA genes are associated with the risk of developing cancer. This study aimed to identify whether the miRNA (miR)-608 polymorphism rs4919510 influenced the incidence of lung cancer, and to explore the underlying mechanisms of miR-608 in the pathogenesis of the disease. A total of 37 patients with non-small cell lung cancer (NSCLC) were selected to determine the expression levels of miR-608; 96 NSCLC patients and 136 cancer-free healthy controls were recruited to determine the incidence of miR-608 rs4919510 in lung cancer patients. Additionally, the impact of miR-608 on the expression of predicted target genes, cell migration, viability, proliferation, and apoptosis was also assessed. We found that the presence of miR-608 rs4919510 did not affect the susceptibility of patients to NSCLC or the maturation of miR-608. miR-608 expression levels were found to be downregulated in NSCLC tissues. Furthermore, overexpression of miR-608 promoted doxorubicin-induced apoptosis in NSCLC cell lines A549 and HCC4006 by inhibiting the expression of transcription factor activating enhancer-binding protein 4 (TFAP4), and high expression levels of TFAP4 were observed in NSCLC tissues. Therefore, our results may provide valuable insights for the chemotherapeutical treatment of NSCLC.

12.
ACS Appl Mater Interfaces ; 11(40): 36649-36657, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31535845

RESUMO

Designing high efficient and noble metal-free bifunctional electrocatalysts for both hydrogen and oxygen generation is still critical and challenged. In this study, hierarchical dodecahedral-structured CoP/CN@MoS2 is prepared through a two-step calcination treatment and a solvothermal approach. The metal-organic framework of ZIF-67 is chosen to serve as the template and for providing Co sources, in which ZIF-67 is first transformed to Co nanoparticles embedded in nitrogen-doped carbon polyhedrons and then transformed to CoP/CN. MoS2 nanosheets are further grown on the surface of dodecahedral-structured CoP/CN with a solvothermal method. Benefiting from the synergistic coupling effect of CoP and MoS2 and the nitrogen-doped carbon matrix, advanced hydrogen evolution reaction (HER) both in acid and alkaline solution as well as splendid oxygen evolution reaction (OER) performance in alkaline aqueous were achieved. Moreover, the coupling effect of CoP/CN and MoS2 is disclosed theoretically by density functional theory calculations to validate the increased HER activity. The as-prepared hybrid CoP/CN@MoS2 not only exhibits decent HER activity in acidic (η10 = 144 mV) and alkaline solutions (η10 = 149 mV), but also exhibits splendid OER activity (η10 = 289 mV) in 1.0 M KOH. This work represents a solid step toward boosting the electrocatalytic kinetics of nonprecious catalysts.

13.
Int Immunopharmacol ; 76: 105883, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536905

RESUMO

BACKGROUND: Pulse methylprednisolone (MP) was routinely used before commencing standard immunosuppressive therapy for induction of remission in patients with dialysis-dependent anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in spite of the paucity of evidence of benefit. The aim of this study was thus to determine whether the addition of pulse MP to standard induction immunosuppressive therapy in severe myeloperoxidase (MPO) -AAV patients who were on dialysis at onset is associated with an improvement in kidney recovery and patient survival. Furthermore, we analyzed the factors associated with restoration of kidney function and mortality in a single Chinese cohort. METHODS: 69 MPO-AAV patients who were on dialysis at the time of diagnosis were included in this study. The MP group (n = 30) received pulse MP (5-10 mg/kg/day) for 3 days before the standard immunosuppressive therapy. The Non-MP group (n = 39) had no MP pulses. The outcomes and adverse events between the two groups were compared. In addition, the predictive value of the clinical and histological parameters for kidney and patient survival was assessed using univariate and multivariate logistic regression analysis. RESULT: There was no difference in patient survival, kidney recovery and the rates of adverse events between the two groups. A higher Birmingham Vasculitis Activity Score (BVAS) was shown to be a negative prognostic factor for kidney function restoration (p = 0.046, OR 0.811, 95% CI 0.660-0.997). BVAS was also demonstrated to be an independent predictor for both all-cause death (p = 0.007, OR 1.324, 95% CI 1.079-1.624) and therapy-related death (p = 0.003, OR 1.574, 95% CI 1.171-2.115). Patients' eGFR at the presentation of the disease was shown to be an independent predictor for therapy-related death (p = 0.027, OR 2.535, 95% CI 1.112-5.779). CONCLUSIONS: This retrospective study of MPO-AAV patients who required dialysis at presentation in a single Chinese center suggests that the addition of pulse MP to standard immunosuppressive induction therapy for remission appears to confer no benefit in terms of improving patient outcomes. Further research is required to determine the role of pulse MP in severe MPO-AAV.

14.
Oral Dis ; 25(7): 1769-1779, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31365165

RESUMO

OBJECTIVES: This study aimed to investigate the role of JAK2-STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) in periapical disease caused by Enterococcus faecalis, as well as the correlation between lipoteichoic acid (LTA) in E. faecalis and the activity of the JAK2-STAT3 signaling pathway and osteoclast formation. MATERIALS AND METHODS: A rat model of periapical periodontitis induced by E. faecalis was established. Periapical bone resorption was confirmed by HE staining. The expression of JAK2, p-JAK2, STAT3, and p-STAT3 was assessed with immunohistochemical staining. Osteoclasts were observed through enzyme histochemical staining. LTA acted on mouse osteoclast precursor cells (RAW264.7 cells); a JAK2 inhibitor (AG490) was used to inhibit the JAK2-STAT3 pathway in RAW264.7 cells. The expression of proteins in the JAK2-STAT3 pathway and TRAP (tartrate resistant acid phosphatase) in RAW264.7 cells was also detected. RESULTS: Rat periapical periodontitis was successfully established and bone resorption peaked at day 21. The expression of critical components in the JAK2-STAT3 pathway increased with the progression of inflammation. LTA promoted the differentiation of RAW264.7 cells into osteoclasts. NFATc1 was highly expressed and was inhibited by AG490. CONCLUSIONS: JAK2-STAT3 signaling pathway plays an important role in the process of periapical bone resorption and osteoclastogenesis.


Assuntos
Reabsorção Óssea , Enterococcus faecalis/fisiologia , Janus Quinase 2/metabolismo , Osteoclastos/fisiologia , Osteogênese , Periodontite Periapical/fisiopatologia , Fator de Transcrição STAT3/metabolismo , Animais , Regulação da Expressão Gênica , Janus Quinase 2/genética , Camundongos , Osteoclastos/microbiologia , Periodontite Periapical/etiologia , Ratos , Fator de Transcrição STAT3/genética , Transdução de Sinais
15.
J BUON ; 24(3): 1060-1066, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424661

RESUMO

PURPOSE: Breast cancer is caused by rare populations of self-renewing cancer stem cells that might also play a role in tumor relapse. Genes that regulate cancer stem cells are, therefore, of great interest in controlling cancer. EZH2 gene expression is reported to be elevated during breast cancer progression and it plays a role in expanding breast stem cell populations. In the current study, we analyzed the correlation between the silencing effect of EZH2 and breast cancer stem cell expansion. METHODS: We used CD44+/CD24-/low cells to develop initial-, moderate-, and advanced-stage breast cancers in female NOD/SCID mice. Immunohistochemistry and western blotting were used to study the expression of aldehyde dehydrogenase 1 (ALDH1) and EZH2 in different stages of breast cancer. RESULTS: Histology showed that as tumors progressed, the pathological condition changed exhibiting enlarged nuclei, higher cell proliferation, and more invasive cells. In EZH2-silenced mice histopathology also showed enlarged cell nucleus, lesion formation and cell aggregation. Immunohistochemistry and western blotting analyses of EZH2 and ALDH1 demonstrated elevated expression as tumors progressed to the next level. Interestingly, the expression of ALDH1 in EZH2-silenced breast cancer tissue showed prolonged overexpression. CONCLUSIONS: We conclude that the normal expression of EZH2 in cancer tissue controls cancer stem cell expansion, because it is highly elevated in EZH2-silencing cancer tissue.

16.
Antioxid Redox Signal ; 31(16): 1177-1193, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31456416

RESUMO

Aims: Cardiomyocyte death critically contributes to the pathogenesis of cardiac disorders, such as myocardial infarction, heart failure, and cardiac ischemia/reperfusion (I/R) injury. As one of the main forms of cardiac cell death, necrosis plays a critical role in heart diseases. Multiple signaling pathways of necrosis have been demonstrated, in which death receptors, receptor-interacting serine/threonine-protein 1 and 3 kinases, and cyclophilin-D (CypD) have been deeply implicated. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondrial permeability transition pore (mPTP)-CypD-dependent death pathway, is poorly understood. Parkin functions as an E3 ubiquitin protein ligase that mainly mediates mitophagy cascades. As yet, it is not clear whether Parkin participates in regulating necrosis and myocardial I/R injury. Results: Here, our results showed that Parkin mediated mitophagy and inhibited necrosis under oxidative stress. In further exploring the underlying mechanisms, we found that Parkin suppressed mPTP opening by catalyzing the ubiquitination of CypD in necrotic cascades, which were not involved in Parkin-regulated mitophagy. Parkin inhibited necrosis, reduced myocardial I/R injury, and improved cardiac function. Innovation: Our present work reveals a highlighted connection between the mitochondrial matrix-localized Parkin and the mPTP-CypD-dependent necrotic signaling pathway in cardiac injury. Conclusion: Our results revealed a novel myocardial necrotic regulating model composed of Parkin, CypD, and mPTP, which may provide potential therapeutic targets and strategies to modulate the levels of these molecules.

17.
ACS Nano ; 13(10): 11853-11862, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31461618

RESUMO

Single-atom catalysts (SACs) have emerged as one of the most promising alternatives to noble metal-based catalysts for highly efficient oxygen reduction reaction (ORR). While SACs can offer notable benefits in terms of lowering overall catalyst cost, there is still room for improvement regarding catalyst activity. To this end, we designed and successfully fabricated an ORR electrocatalyst in which atomic clusters are embedded in an atomically dispersed Fe-N-C matrix (FeAC@FeSA-N-C), as shown by comprehensive measurements using aberration-corrected scanning transmission electron microscopy (AC-STEM) and X-ray absorption spectroscopy (XAS). The half-wave potential of FeAC@FeSA-N-C is 0.912 V (versus reversible hydrogen electrode (RHE)), exceeding that of commercial Pt/C (0.897 V), FeSA-N-C (0.844 V), as well as the half-wave potentials of most reported non-platinum-group metal catalysts. The ORR activity of the designed catalyst stems from single-atom active centers but is markedly enhanced by the presence of Fe nanoclusters, as confirmed by both experimental measurements and theoretical calculations.

18.
Cancer Lett ; 464: 25-36, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461670

RESUMO

Patients with Her2-positive breast cancer exhibit de novo resistance or develop acquired resistance in less than one year after Her2 targeting treatment, but the mechanism is not fully elucidated. Compensatory pathways such as the IGF-1R/IRS-1 pathway, are activated, leading to aberrant enhanced PI3K/Akt/mTOR pathway activity to attenuate the efficacy of trastuzumab. Cullin7 could participate in the degradation of IRS-1 in a mTOR/S6K dependent manner. Whether Cullin7 participates in trastuzumab resistance needs to be further investigated. Here, we reveals that Cullin7 is overexpressed in trastuzumab-resistant Her2 positive breast cancer cells. Knockdown of Cullin7 reduces degradation of Ser phosphorylation of IRS-1, attenuates activation of the PI3K/AKT pathway, and partly restores trastuzumab sensitivity in trastuzumab-resistant Her2 positive breast cancer cells. IGFBP-3 expression is decreased in trastuzumab-resistant Her2 positive breast cancer cells, which leads to release of the Wnt signaling pathway inhibition and an increase in Cullin7 expression, as mediated by TCF7L2. Overexpression of Cullin7 in Her2-amplified breast cancer tissues has clinical implications because it positively correlates with shorter disease-free survival (DFS) and inadequate response to trastuzumab. Thus, our results suggest a critical role for Cullin7 in response to trastuzumab, which has significant implications for selection of the optimal therapeutic strategy for Her2 positive breast cancers.

19.
J Immunother ; 42(8): 284-296, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31261167

RESUMO

Folate receptor alpha (αFR) is overexpressed in 90% of ovarian cancers, one of the most lethal gynecologic cancers. Recent studies have suggested that natural killer (NK) cells may be better chimeric antigen receptor (CAR) drivers because of their favorable innate characteristics, such as directly recognizing and killing tumor cells. However, the therapeutic effects of CAR-engineered NK cells targeting αFR in ovarian cancer have not been reported. In this research, 3 generations of anti-αFR CAR were constructed, namely αFR-ζ (first generation), αFR-28ζ (second generation), and αFR-28BBζ (third generation), and were highly expressed on the surface of NK-92 cells by lentivirus gene transfection. Three anti-αFR CAR-engineered NK-92 cells can specifically kill αFR-positive tumor cells in vitro, especially ovarian cancer cells with high αFR expression. Compared with NK-92 cells expressing αFR-ζ or αFR-28ζ, NK-92 cells expressing αFR-28BBζ showed not only higher antigen-specific cytotoxicity and proliferation but also lower antigen-induced apoptosis. Moreover, stronger degranulation and cytokine secretion were detected in NK-92 cells expressing αFR-28BBζ cocultured with αFR-positive tumor cells. Real-time cell analysis and live cell imaging recorded the process of NK-92 cells expressing αFR-28BBζ killing ovarian cancer cells in vitro. Furthermore, NK-92 cells expressing αFR-28BBζ can effectively eliminate cancer cells in a mouse xenograft model of ovarian cancer and significantly prolong the survival of tumor-bearing mice. These results demonstrate that the anti-αFR CARs redirect NK-92 cells with specific antitumor activity, and the third-generation anti-αFR CAR-engineered NK-92 cells display more potent cytotoxicity against αFR-positive ovarian cancer, laying the foundation for future clinical research.

20.
J Cell Mol Med ; 23(8): 4900-4912, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31232522

RESUMO

Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron-dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.

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