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1.
Nanomaterials (Basel) ; 12(1)2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-35010112

RESUMO

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome's interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors-vadadustat and roxadustat-to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

3.
Small Methods ; 5(12): e2101302, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34928034

RESUMO

Thermal management plays an important role in miniaturized and integrated nanoelectronic devices, where finding ways to enable efficient heat-dissipation can be critical. 2D materials, especially graphene and hexagonal boron nitride (h-BN), are generally regarded as ideal materials for thermal management due to their high inherent thermal conductivity. In this paper, a new method is reported, which can be used to characterize thermal transport in 2D materials. The separation of pumping from detection can obtain the temperature at different distances from the heat source, which makes it possible to study the heat distribution of 2D materials. Using this method, the thermal conductivity of graphene and molybdenum disulfide is measured, and the thermal diffusion for different shapes of graphene is explored. It is found that thermal transport in graphene changes when the surrounding environment changes. In addition, thermal transport is restricted at the boundary. These processes are accurately simulated using the finite element method, and the simulated results agree well with the experiment. Furthermore, by depositing a layer of h-BN on graphene, the heat-dissipation characteristics of graphene become tunable. This study introduces and describes a new method to investigate and optimize thermal management in 2D materials.

4.
Front Oncol ; 11: 753330, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646782

RESUMO

The extracellular matrix (ECM) plays a central role in the formation of the tumor microenvironment. The deposition of the ECM is associated with poor prognosis in a variety of tumors. Aberrant ECM deposition could undermine the effect of chemotherapy and immunotherapy. However, there is no systematic analysis on the relationship between the ECM and prognosis or chemotherapy effect. In the present study, we applied the gene set variation analysis (GSVA) algorithm to score 2199 canonical pathways in 2125 cases of probe or sequencing data and identified the core matrisome as the driving factor in gastric cancer progression. We classified gastric cancer samples into three clusters according to the composition of the ECM and evaluated clinical and multi-omics characterization of ECM phenotypes. The ECM score was evaluated by GSVA score of core matrisome and a higher ECM score predicted poor prognosis of gastric cancer [Hazard Ratio (HR), 2.084; p-value < 2 × 10-16]. In The Cancer Genome Atlas (TCGA) cohort and KUGH, YUSH, and KUCM cohorts, we verified that patients with a low ECM score could benefit from chemotherapy. By contrast, patients with a high ECM score did not achieve satisfactory response from chemotherapy. Determining the characteristics of the ECM microenvironment might help to predict the prognosis and chemotherapy response of patients with gastric cancer, and help to resolve the enigma of chemoresistance acquisition, as well as providing inspiration to develop combination therapy.

5.
Front Mol Neurosci ; 14: 697416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34707480

RESUMO

Ischemic stroke is one of the leading causes of death and disability worldwide. Microglia/macrophages (MMs)-mediated neuroinflammation contributes significantly to the pathological process of ischemic brain injury. Microglia, serving as resident innate immune cells in the central nervous system, undergo pro-inflammatory phenotype or anti-inflammatory phenotype in response to the microenvironmental changes after cerebral ischemia. Emerging evidence suggests that epigenetics modifications, reversible modifications of the phenotype without changing the DNA sequence, could play a pivotal role in regulation of MM polarization. However, the knowledge of the mechanism of epigenetic regulations of MM polarization after cerebral ischemia is still limited. In this review, we present the recent advances in the mechanisms of epigenetics involved in regulating MM polarization, including histone modification, non-coding RNA, and DNA methylation. In addition, we discuss the potential of epigenetic-mediated MM polarization as diagnostic and therapeutic targets for ischemic stroke. It is valuable to identify the underlying mechanisms between epigenetics and MM polarization, which may provide a promising treatment strategy for neuronal damage after cerebral ischemia.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34714119

RESUMO

AIMS: Rhodiola sacra is a widely-used pharmaceutical component with multiple functions, including anti-oxidation and anti-inflammation. However, the exact mechanisms involved in neuroprotection against transient global cerebral ischemia (tGCI) remains to be elucidated. Herein we aim to close the gap in understanding on whether rhodiola sacra reduces neuronal death in hippocampal CA1 and demonstrate how rhodiola sacra offers neuroprotection after tGCI. RESULTS: The results show that rhodiola sacra (2.4 g/kg/d by feeding) pretreatment or/and postreatment significantly alleviated neuronal injury, inhibited glial activation and improved cognitive function in male rats subjected to tGCI. The neuroprotection of prophylaxis with rhodiola sacra is equivalent to that of therapeutics. The binding mode of adenosine monophosphate-activated protein kinase (AMPK) α2-subunit with rhodiola sacra was predicted by molecular docking. Furthermore, rhodiola sacra upregulates phosphorylated AMPK and promotes nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2). Additionally, rhodiola sacra increases heme oxygenase-1 (HO-1) expression and activity and reduces malondialdehyde (MDA) content in CA1 after tGCI. However, the neuroprotection of rhodiola sacra is abolished by Nrf2 knockdown with small interfering RNA (siRNA) after tGCI. Similarly, the inhibition of AMPK with Compound C or siRNA against AMPK α2 aggravates neuronal death after tGCI through decreasing nuclear Nrf2 and the expression and activity of HO-1, and increasing the release of MDA. Innovation and Conclusion: For the first time this study demonstrates that as a prophylactic or therapeutic agent rhodiola sacra prevents oxidant stress, protects neurons and improves cognitive function through activating the AMPK/Nrf2 pathway in tGCI rats.

7.
Cell Death Dis ; 12(10): 890, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588421

RESUMO

Gastric cancer is one of the most common malignancies worldwide and vasculogenic mimicry (VM) is considered to be the leading cause for the failure of anti-angiogenesis therapy in advanced gastric cancer patients. In the present study, we investigate the role of tenascin-c (TNC) in the formation of VM in gastric cancer and found that TNC was upregulated in gastric cancer tissue than in the corresponding adjacent tissues and correlated with VM and poor prognosis of gastric cancer. Furthermore, knockdown of TNC significantly inhibited VM formation and proliferation of gastric cancer cells in vitro and in vivo, with a reduction in cell migration and invasion. Mechanistically, TNC knockdown suppressed the phosphorylation of ERK and subsequently inhibited the process of EMT, both of which play an important role in VM formation. Our results indicated that TNC plays an important role in VM formation in gastric cancer. Combining inhibition of TNC and ERK may be a potential therapeutic approach to inhibit gastric cancer growth and metastasis and decrease antiangiogenic therapeutic resistance.

8.
Oncogene ; 40(38): 5764-5779, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34341514

RESUMO

Anoikis is a type of programmed cell death induced by loss of anchorage to the extracellular matrix (ECM). Anoikis resistance (AR) is crucial for the survival of metastatic cancer cells in blood, lymphatic circulation and distant organs. Compared to ordinary cancer cells, anoikis resistant cancer cells undergo various cellular and molecular alterations, probably characterizing the cells with unique features not limited to anoikis resistance. However, the molecular mechanisms connecting anoikis resistance to other metastatic properties are still poorly understood. Here, the biological interaction between anoikis resistance and angiogenesis as well as their involvement into peritoneal metastasis of gastric cancer (GC) were investigated in vitro and in vivo. The prognostic value of key components involved in this interaction was evaluated in the GC cohort. Compared to ordinary GC cells, GCAR cells exhibited stronger metastatic and pro-angiogenic traits corresponding to elevated PDGFB secretion. Mechanistically, transcription factor C/EBPß facilitated PDGFB transcription by directly binding to and interacting with PDGFB promoter elements, subsequently increasing PDGFB secretion. Secreted PDGFB promoted the survival of detached GC cells through a C/EBPß-dependent self-feedback loop. Moreover, secreted PDGFB promoted angiogenesis in metastases via activation of the MAPK/ERK signaling pathway in vascular endothelial cells. Both C/EBPß activation level and PDGFB expression were significantly elevated in GC and correlated with metastatic progression and poor prognosis of patients with GC. Overall, interaction between GCAR cells and vascular endothelial cells promotes angiogenesis and peritoneal metastasis of GC based on C/EBPß-mediated PDGFB autocrine and paracrine signaling. C/EBPß-PDGFB-PDGFRß-MAPK axis promises to be potential prognostic biomarkers and therapeutic targets for peritoneal metastasis of GC.

9.
Cancer Cell Int ; 21(1): 418, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372874

RESUMO

BACKGROUND: WD40 repeat (WDR)43 is an RNA-binding protein that belongs to the WDR domain protein family. Its biological function is largely unclear, particularly in colorectal cancer (CRC). METHODS: In the present study, we searched the TCGA database and found the correlation between WDR43 and CRC. Subsequently, the high expression of WDR43 in human clinical samples of CRC was validated and we further examined the biological functions of it in CRC cells. Finally, we explored potential downstream proteins or pathways and established subcutaneous xenograft model to verify our findings. RESULTS: Immunohistochemistry of 16 patient specimens confirmed that the expression of WDR43 was elevated in CRC. WDR43 knockdown was shown to increase apoptosis and inhibit the proliferation, migration and invasion of CRC cells in vitro and reduce tumorigenesis in animal models. In addition, it was found that WDR43 knockdown inhibited vimentin (VIM) expression in CRC cells and overexpression of VIM can partially reverse the effects of WDR43 both in vitro and in vivo. CONCLUSION: In conclusion, the role of WDR43 in the occurrence and development of CRC was investigated in the present study. WDR43 may serve as a valuable biomarker and provide new options for the diagnosis and treatment of colorectal cancer.

10.
Clin Transl Med ; 11(8): e522, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34459127

RESUMO

BACKGROUND: Peritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism acts as a non-negligible regulator in epithelial-mesenchymal transition (EMT), which is crucial for the metastasis of GC. As apolipoprotein C2 (APOC2) is a key activator of lipoprotein lipase for triglyceride metabolism, the exact mechanism of APOC2 remains largely unknown in GC. METHODS: Tandem mass tags identified differentially expressed proteins between human PM and GC tissues, and showed that APOC2 overexpressed in PM tissues, which was further confirmed by immunoblotting, immunohistochemistry, and ELISA. Global gene expression changes were identified in APOC2 knockdown cells via RNA-sequencing. The role of APOC2 in lipid metabolism of GC cells was assessed via the Seahorse XF analyzer and lipid staining assays. The biological role of APOC2 in GC cells was determined by 3D Spheroid invasion, apoptosis, colony formation, wound healing, transwell assay, and mouse models. The interaction between APOC2 and CD36 was analyzed by co-immunoprecipitation and biolayer interferometry. The underlying mechanisms were investigated using western blot technique. RESULTS: APOC2 overexpressed in GC PM tissues. Upregulation of APOC2 correlated with a poor prognosis in GC patients. APOC2 promoted GC cell invasion, migration, and proliferation via CD36-mediated PI3K/AKT/mTOR signaling activation. Furthermore, APOC2-CD36 axis upregulated EMT markers of GC cells via increasing the phosphorylation of PI3K, AKT, and mTOR. Knockdown either APOC2 or CD36 inhibited the malignant phenotype of cancer cells, and delayed GC PM progression in murine GC models. CONCLUSION: APOC2 cooperates with CD36 to induce EMT to promote GC PM via PI3K/AKT/mTOR pathway. APOC2-CD36 axis may be a potential target for the treatment of aggressive GC.

11.
J Nutr ; 151(9): 2835-2842, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34191031

RESUMO

BACKGROUND: Brain iron accumulation is a feature of Alzheimer disease (AD) but whether a chronic dietary iron overload contributes to AD induction is unknown. We previously showed that young mice fed a high iron diet did not display cognitive impairment despite the AD pathological markers in hippocampus. OBJECTIVES: We aim to compare the impact of high dietary iron on brain pathologic changes and cognitive function in young and old mice. METHODS: Male C57BL/6J mice at 1 mo and 13 mo of age were fed with either a control diet (66 mg Fe/kg; Young-Ctrl and Old-Ctrl) or a high iron diet (14 g Fe/kg; Young-High Fe and Old-High Fe) for 7 mo, and outcomes were evaluated at 8 mo and 20 mo of age. Iron concentrations in brain regions were measured by atomic absorption spectrophotometry. Perls's Prussian blue staining and amyloid-ß (Aß) immunostaining were performed. Protein expression in the cerebral cortex and hippocampus was determined by immunoblotting. Superoxide dismutase activity and malondialdehyde concentration were examined. Cognitive functions were tested with the Morris water maze system. Two-factor ANOVA was used to analyze most data. RESULTS: Compared with Old-Ctrl mice, Old-High Fe mice showed significantly higher iron concentrations in cerebral cortex (60% higher), cerebellum (60% higher), and hippocampus (90% higher), paralleled by lower superoxide dismutase activity and greater malondialdehyde concentration in cerebral cortex and hippocampus and worse cognitive function. In contrast, these variables did not significantly differ between the 2 young groups. Nevertheless, ferritin, phospho-tau, and Aß1-42 expression in hippocampus and ferritin and Aß1-42 expression in cerebral cortex were induced by the high iron diet irrespective of the age of mice (40-200% greater). CONCLUSIONS: High dietary iron induced cognitive defects in old mice but not young mice, suggesting that elderly people should avoid consuming abnormally high concentrations of iron.

12.
Cell Death Dis ; 12(7): 630, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145219

RESUMO

Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.


Assuntos
Região CA1 Hipocampal/enzimologia , Hipóxia/enzimologia , Ataque Isquêmico Transitório/enzimologia , Mitocôndrias/enzimologia , Mitofagia , Neurônios/enzimologia , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Região CA1 Hipocampal/ultraestrutura , Modelos Animais de Doenças , Hipóxia/genética , Hipóxia/patologia , Ataque Isquêmico Transitório/genética , Ataque Isquêmico Transitório/patologia , Masculino , Mitocôndrias/genética , Mitocôndrias/ultraestrutura , Neurônios/ultraestrutura , Proteínas Quinases/genética , Transporte Proteico , Ratos Wistar , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
13.
Sci Adv ; 7(17)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33893103

RESUMO

The delivery of therapeutics through the circulatory system is one of the least arduous and less invasive interventions; however, this approach is hampered by low vascular density or permeability. In this study, by exploiting the ability of monocytes to actively penetrate into diseased sites, we designed aptamer-based lipid nanovectors that actively bind onto the surface of monocytes and are released upon reaching the diseased sites. Our method was thoroughly assessed through treating two of the top causes of death in the world, cardiac ischemia-reperfusion injury and pancreatic ductal adenocarcinoma with or without liver metastasis, and showed a significant increase in survival and healing with no toxicity to the liver and kidneys in either case, indicating the success and ubiquity of our platform. We believe that this system provides a new therapeutic method, which can potentially be adapted to treat a myriad of diseases that involve monocyte recruitment in their pathophysiology.

14.
J Neuroinflammation ; 18(1): 97, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879157

RESUMO

BACKGROUND: Our previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI. METHODS: Transient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death. RESULTS: Hypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI. CONCLUSIONS: These data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.


Assuntos
Regulação para Baixo , Hipóxia/metabolismo , Ataque Isquêmico Transitório/metabolismo , Necroptose , Neuroproteção , Proteínas Quinases/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Região CA1 Hipocampal/metabolismo , Técnicas de Silenciamento de Genes , Precondicionamento Isquêmico , Masculino , Fármacos Neuroprotetores , Fosforilação , Ratos , Ratos Wistar , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
15.
J Exp Clin Cancer Res ; 40(1): 126, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33838681

RESUMO

BACKGROUND: NOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism. METHODS: NLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry. RESULTS: NLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription. CONCLUSIONS: We showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais/metabolismo , Macrófagos Associados a Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Polaridade Celular/fisiologia , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Nus
16.
BMC Palliat Care ; 20(1): 50, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33765995

RESUMO

BACKGROUND: In many countries, nurses are ill-prepared to provide care to patients with terminal illnesses. Limited education and training affect their ability to deliver proper palliative care. Only a few studies have explored appropriate and effective training methods of palliative care in China. Therefore, we aimed to provide evidence for a palliative care training system by appraising the effects of a mixed-method intervention on participants' knowledge of palliative care and attitudes towards dying patients and death. METHODS: An e-learning intervention approach was adopted for 97 nurses from oncology departments across five hospitals, using a mobile terminal combined with a virtual forum and face-to-face interactions. We conducted a pre- and post-training evaluation through the Palliative Care Quiz of Nursing (PCQN), Frommelt Attitude Toward Care of the Dying Scale Form B (FATCOD-B), and Death Attitude Profile-Revised (DAP-R). RESULTS: After a three-week intervention, there was a significant increase in the PCQN and FATCOD-B scores as compared to the baseline. For PCQN, the total score increased from 10.3 ± 1.9 to 11.1 ± 2.2 (p = .011) and the score for management of pain and other symptoms increased from 7.7 ± 1.7 to 8.4 ± 1.7 (p = .003). FATCOD-B scores increased noticeably from 100.6 ± 7.9 to 102.9 ± 8.9 (p = .019). The DAP-R scores showed no obvious difference between pre- and post-intervention results. CONCLUSIONS: The mixed-method intervention was effective in improving participants' knowledge and attitudes about palliative care. The implementation of training for nurses at appropriate intervals during both education and professional life is required, especially regarding the improvement in participants' attitudes towards death. Therefore, palliative care training in China should receive more attention.


Assuntos
Cuidados Paliativos , Assistência Terminal , Atitude do Pessoal de Saúde , Atitude Frente a Morte , Competência Clínica , Humanos , Inquéritos e Questionários
17.
Acta Biomater ; 123: 325-334, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33454386

RESUMO

Polyethylene glycol (PEG) modification is one of the promising approaches to overcome both mucus and alveolar macrophage uptake barriers in the deep lung for sustained therapy of pulmonary diseases such as asthma. To investigate the feasibility of using PEG-modified microspheres to bypass both barriers, we prepared a collection of polyethylene glycol-distearoyl glycero-phosphoethanolamine (PEG-DSPE)-modified poly (lactide-co-glycolide) (PLGA) microspheres bearing specific PEG molecular weights (0.75, 2, 5, and 10 kDa) and PEG-DSPE/PLGA molar ratios (0.25:1 and 1:1). Drug release, mucus penetration, and macrophage uptake were evaluated in vitro, and the corresponding in vivo activities of microspheres in rats were investigated. It was found that the PEG2000-DSPE/PLGA 1:1 group showed enhanced mucus permeability and reduced macrophage uptake in vitro compared to the PEG2000-DSPE/PLGA 0.25:1 group. At high PEG molar ratios, only the PEG 2000-based group showed significantly prolonged lung retention in vivo compared to the control group. The systemic exposure of the PEG2000-DSPE/PLGA 1:1 group was significantly lower than that of the PEG2000-DSPE/PLGA 0.25:1 group (39% of AUC reduction). Additionally, when using the same molar ratio of 1:1, the PEG 2000 group significantly lowered the systemic drug exposure compared to that of the PEG 5000 and 10000 groups (48% and 33% of AUC reduction, respectively), thus making it a promising sustained lung delivery candidate for pulmonary disease treatment.


Assuntos
Nanopartículas , Animais , Liberação Controlada de Fármacos , Pulmão , Microesferas , Polietilenoglicóis , Ratos
18.
Gastrointest Endosc ; 94(1): 133-144.e3, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33221323

RESUMO

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is a promising technique for removing superficial GI tumors, but ESD is technically difficult. The aim of this study was to establish a clinical score model for grading technically difficult colorectal ESD. METHODS: Data on patients, lesions, and outcomes of colorectal ESD at 2 centers were analyzed. The objective parameter of successful ESD within 60 minutes was set as an endpoint to evaluate the difficulty. Independent predictors of difficulty in the derivation cohort were identified by multiple logistic regression analysis and used to develop a clinical score. We validated the score model in the validation cohort. RESULTS: The clinical score comprised tumor size of 30 to 50 mm (1 point) or ≥50 mm (2 points), at least two-thirds circumference of the lesion (2 points), location in the cecum (1 point), flexure (2 points) or dentate line (1 point), and laterally spreading tumor nongranular lesions (1 point). Areas under the receiver operator characteristic curves for the score model were comparable (derivation [.70] vs internal validation [.69] vs external validation [.69]). The probability of successful ESD within 60 minutes in easy (score = 0), intermediate (score = 1), difficult (score = 2-3), and very difficult (score ≥4) categories were 75.0%, 51.3%, 35.6%, and 3.4% in the derivation cohort; 73.3%, 47.9%, 31.8%, and 16.7% in the internal validation cohort; and 79.5%, 66.7%, 43.3%, and 20.0% in the external validation cohort, respectively. CONCLUSIONS: This clinical score model accurately predicts the probability of successful ESD within 60 minutes and can be applied to grade the technical difficulty before the procedure.


Assuntos
Neoplasias Colorretais , Ressecção Endoscópica de Mucosa , Ceco , Neoplasias Colorretais/cirurgia , Humanos , Estudos Retrospectivos , Resultado do Tratamento
19.
Curr Mol Med ; 21(10): 922-930, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33222668

RESUMO

Gastric cancer is one of the most common malignancies worldwide and the third leading cause of cancer-related death. In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor, alone or in combination with oxaliplatin against gastric cancer cells in vitro. Cell counting kit-8 assays and EdU staining were performed to examine the proliferation of cancer cells. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the elements of the mTOR pathway and P-gp in gastric cancer cell lines. OSI-027 inhibited the proliferation of MKN-45 and AGS cells by arresting the cell cycle in the G0/G1 phase. At the molecular level, OSI-027 simultaneously blocked mTORC1 and mTORC2 activation, and resulted in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4). Additionally, OSI-027 also downregulated P-gp, which enhanced oxaliplatin-induced apoptosis and suppressed multidrug resistance. Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potentially valuable treatment for gastric cancer.

20.
Bosn J Basic Med Sci ; 21(3): 331-338, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33091333

RESUMO

Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis.


Assuntos
Aminopiridinas/farmacologia , Neoplasias Encefálicas/secundário , Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lactamas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinases da Matriz/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Sobrevivência Celular , Regulação para Baixo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metaloproteinases da Matriz/metabolismo , Células Tumorais Cultivadas
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