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1.
Mol Ther ; 31(9): 2734-2754, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37415332

RESUMO

Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPRFlox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPRFlox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Animais , Camundongos , Cisplatino/efeitos adversos , Necroptose , Injúria Renal Aguda/metabolismo , Rim/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BL
2.
Neurosci Bull ; 39(12): 1789-1806, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37335428

RESUMO

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.


Assuntos
Plexo Braquial , Hipotermia , Neuralgia , Humanos , Camundongos , Animais , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipotermia/complicações , Hipotermia/metabolismo , Plexo Braquial/lesões , Edema/complicações , Edema/metabolismo
4.
Front Pharmacol ; 13: 961190, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36278219

RESUMO

Transient ischemic attack (TIA) poses a great threat of cerebrovascular diseases to a large number of patients, despite its reversible neurological dysfunction. Long non-coding RNAs (lncRNAs) have been proven to play critical roles in the pathophysiological development of cerebrovascular events. Exploring the function of lncRNAs in modulating TIA prognosis would help to develop individualized therapeutics. A total of 231 participants with the first onset of TIA were recruited in the study, including 65 subsequent stroke patients. The expression of lncRNA potassium voltage-gated channel subfamily Q member 1 opposite strand 1 (KCNQ1OT1) was upregulated in patients with recurrent ischemic events after TIA. Additionally, KCNQ1OT1 could be regarded as an independent predictor for subsequent ischemic stroke. The optimal diagnostic value was determined at 1.29 with a sensitivity of 63% and a specificity of 72%. Fewer patients would survive from further ischemic stroke with their KCNQ1OT1 level over 1.29. Furthermore, the expression of KCNQ1OT1 was elevated with a growing serum high-sensitivity C-reactive protein (hs-CRP) level. KCNQ1OT1 might be involved in the regulation of early inflammatory response during recurrence of TIA.

6.
Bioorg Chem ; 124: 105794, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35533545

RESUMO

The side effects of acute Kidney Injury (AKI) and nephrotoxicity limit the application of cisplatin in cancer treatment. Inflammation and oxidative stress paly important role in the pathogenesis of cisplatin-induced AKI. Gastrin-releasing peptide receptor (GRPR) plays an important role in inflammatory response. In this study, we designed 34 new Pd176252 analogs, most synthesized compounds could reduce cisplatin-induced HK2 cell death. Of these compounds, 9b had strong binding affinity with GRPR, and significantly increased HK2 cell viability. Compound 9b significantly downregulated the level of creatinine, blood urea nitrogen (BUN), and malondialdehyde (MDA), and recovered the glutathione (GSH) level in cisplatin-induced AKI model. It also decreased the level of kidney injury molecule-1(KIM-1) in vitro and vivo. In the further pathogenesis studies, 9b downregulated level of inflammatory factors (TNF-α, IL-1ß, IL-6 and MCP-1), suppressed the nuclear factor-kappa B (NF-kB) phosphorylation, and decreased GRPR level. The results suggested that ameliorating cisplatin-induced AKI actions of 9b was involved in downregulation of TNF-α, IL-1ß, IL-6, and MCP-1, inhibition of NF-kB activation, and reduction of GRPR and oxidative stress level.


Assuntos
Injúria Renal Aguda , Cisplatino , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Apoptose , Cisplatino/farmacologia , Glutationa/metabolismo , Humanos , Interleucina-6/metabolismo , Rim , NF-kappa B/metabolismo , Estresse Oxidativo , Receptores da Bombesina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Anticancer Agents Med Chem ; 22(17): 3009-3024, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35490428

RESUMO

BACKGROUND: GRPR is over-expressed in cancer cells and is a potential drug target for the treatment of cancer. PD176252, as the most representative non-peptide inhibitor of GRPR, can inhibit the growth of cancer cells, but its low selectivity to cancer cells and normal cells limits its further application. OBJECTIVE: The aim of this study was to design and synthesize novel GRPR inhibitor with stronger anti-cancer activity and higher affinity with GRPR than the lead compound PD176252. METHODS: A series of 1, 3, 4-oxadiazole derivatives as PD176252 analogues (4a-4j, 6a-6q) were synthesized and their cytotoxic activity was investigated on four cancer lines with high expression of GRPR (gastric (HGC-27), colon (HCT- 116), prostate (PC-3), and lung (A549)) and one human cell line (gastric mucosal epithelial (GES-1)) by MTT assay. Flow cytometry analysis and Western Blot were used to determine whether the compound induced programmed apoptosis of cancer cells. Competitive binding experiment was used to verify the affinity between GRPR and the optimal compound. RESULTS: Compound 6m exhibited significant growth inhibition on all tested cancer cell lines, especially gastric cancer cells (HGC-27 cellular IC50 0.37 ± 0.04µM). Also, the selectivity of 6m to HGC-27 was much higher than that of PD176252. Flow cytometric analysis and Western Blot proved that 6m significantly promoted the apoptosis of HGC- 27 cells. Moreover, competitive binding experiment confirmed the close binding of 6m with GRPR, which indicated 6m with a higher affinity than lead compound PD176252. CONCLUSION: Our results suggested that 6m, as a novel GRPR inhibitor, had a higher affinity with GRPR and potential anti-cancer effect than PD176252, which can be used as a template for further optimization.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/farmacologia , Masculino , Oxidiazóis/farmacologia
8.
J Cell Mol Med ; 26(2): 475-490, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34890108

RESUMO

At present, growing evidence indicates that long non-coding RNAs (lncRNAs) participate in the progression of glioma. The function of LOXL1-AS1 in vasculogenic mimicry (VM) in glioma remains unclear. First, the expressions of TIAR, the lncRNA LOXL1-AS1, miR-374b-5p and MMP14 were examined by qRT-PCR and Western blot in both, glioma tissues and glioma cell lines. Proliferation, migration, invasion and tube formation assays were conducted to evaluate the roles of TIAR, LOXL1-AS1, miR-374b-5p and MMP14 in malignant cellular behaviours in glioma cells. A nude mouse xenograft model and dual staining for CD34 and PAS were used to assess whether VM was affected by TIAR, LOXL1-AS1 or miR-374b-5p in vivo. In this study, low levels of TIAR and high levels of LOXL1-AS1 were found in glioma cells and tissues. TIAR downregulated the expression of LOXL1-AS1 by destabilizing it. LOXL1-AS1 acted like a miRNA sponge towards miR-374b-5p so that downregulation of the former greatly inhibited cell proliferation, migration, invasion and VM. Additionally, miR-374b-5p overexpression repressed malignant biological behaviours and VM in glioma by modifying MMP14. In summary, we demonstrated that TIAR combined with LOXL1-AS1 modulates VM in glioma via the miR-374b-5p/MMP14 axis, revealing novel targets for glioma therapy.


Assuntos
Glioma , MicroRNAs , RNA Longo não Codificante , Aminoácido Oxirredutases/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Humanos , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo
9.
Anticancer Agents Med Chem ; 22(10): 1945-1961, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34674626

RESUMO

BACKGROUND: Chalcone is a broad-spectrum natural product with anti-cancer and anti-inflammatory activities. However, low potency, low selectivity, and serious side effects limit its druggability. L-Tryptophan is an essential precursor molecule of an anti-cancer active substance. Also, the indole moiety inhibits the proliferation of tumor cells by binding to colchicine sites. A decrease in kidney cell activity caused by kidney inflammation is the primary side effect of cancer therapy. OBJECTIVE: The purpose of this work was to design, synthesize, and perform bioactivity evaluation of novel chalcone derivatives possessing tryptophan moiety with dual activities of anti-cancer and partially restoring the proliferation of normal kidney cells pre-treated with cisplatin. METHODS: A series of novel chalcone derivatives possessing tryptophan moiety (5a-5g, 6a-6o) were designed, synthesized, and evaluated for anti-cancer activity against four cancer cell lines (gastric (HGC-27), colon (HCT-116), prostate (PC-3), and lung (A549)), and a human normal cell line (gastric mucosal epithelial (GES-1)). The activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin was evaluated by MTT assay. Cell cycle, apoptosis, and apoptosis proteins (Bax and Bcl-2) were used to evaluate the anti-cancer mechanism of the most potent compound. Moreover, a docking study was performed to explain the high anti-cancer activity of 6n. The expressions of TNF-α, IL- 6, and MCP-1 were detected by ELISA. RESULTS: Most of the compounds exhibited high anti-cancer activity against the HGC-27 cell line and exhibited low toxicity against the normal cell line. Based on three rounds of a structure optimization, 6n was discovered as the most potent compound against HGC-27 cells with an IC50 value of 2.02 µM and an SI value of 28.47. Further studies demonstrated that 6n could induce cell cycle arrest at the G2/M phase and the apoptosis of the HGC-27 cell line by reducing the expression of Bcl-2 and improving the expression level of Bax. Molecular docking result displayed 6n bound to the colchicine site. At the same time, 6n also exhibited moderate activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin by reducing the expression of inflammatory substances. CONCLUSION: Our findings collectively suggested that 6n should be further studied as a potential anti-cancer agent that could partially restore the proliferation of normal kidney cells pre-treated with cisplatin in gastric cancer patients by an anti-inflammatory pathway.


Assuntos
Antineoplásicos , Chalcona , Chalconas , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Chalcona/farmacologia , Chalconas/química , Cisplatino/farmacologia , Colchicina/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Rim , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triptofano/farmacologia , Proteína X Associada a bcl-2
10.
Int Immunopharmacol ; 101(Pt A): 108293, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34763232

RESUMO

BACKGROUND: Glioblastoma (GBM), characterized by deregulated cell proliferation and immune cells infiltration, is a common and lethal tumor of the central nervous system. Recently, the infiltration of immune cells has attracted attention as a potential novel GBM immunotherapy option. Homeobox C cluster (HOXC) is an evolutionarily conserved family of transcriptional factors that are involved in embryogenesis and tumorigenesis. Nevertheless, the correlations of HOXCs with the prognosis and immune infiltration of GBM remain blurred. METHODS: The RNA-seq data with corresponding clinical characteristics were downloaded from TCGA and GTEx databases. The correlations between HOXCs and clinical characteristics were calculated using univariable and multivariate Cox regression. R language with ggplot2, survminer, survival, GSVA, and pROC packages were employed to analyze the data and present the plots. MethSurv, UALCAN and cBioPortal were employed to evaluate the DNA methylation and mutation status of HOXCs in GBM. We also verified the expression and prognosis of HOXCs by qPCR and immunohistochemistry in a cohort of 36 patients. RESULTS: We identified that HOXC6/8/10/13 were crucial biomarkers for diagnosis and prognostic judgement in GBM. Gene set variation analysis revealed that levels of expression of HOXCs were associated with the infiltration of various immune cells. The qPCR and immunohistochemistry data validated the prognostic values of HOXC6/8/10/13 in GBM. Finally, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that HOXCs might be involved in DNA-binding transcription activator activity and the apelin signaling pathway. CONCLUSION: This research highlights that HOXC6/8/10/13 are involved in the immune infiltrates, also provide potential clinical utility as therapeutic targets in GBM.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Proteínas de Homeodomínio/metabolismo , Linfócitos do Interstício Tumoral/patologia , Biomarcadores Tumorais/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida
11.
Kaohsiung J Med Sci ; 37(10): 851-862, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34153159

RESUMO

LIM homeobox transcription factor 1-beta (LMX1B) has recently been found to be highly expressed in advanced gliomas and is associated with poor survival. However, the regulatory molecular mechanism of LMX1B expression in gliomas remains unclear. In this study, bioinformatics analysis showed that miR-485-5p may be the potential upstream regulator of LMX1B, and long noncoding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) may function as a competitive endogenous RNA to sponge miR-485-5p. In addition, the expression of SNHG3 and LMX1B in advanced glioma tissues was significantly upregulated, while the expression of miR-485-5p was significantly downregulated. SNHG3 overexpression reduced the expression of miR-485-5p; increased the expression of LMX1B; and promoted the proliferation, migration, and invasion of glioma cells. In contrast, miR-485-5p overexpression reduced the expression of LMX1B and inhibited cell proliferation, migration, and invasion. The luciferase reporter assay and RNA immunoprecipitation assay further confirmed the interaction between SNHG3 and miR-485-5p and between miR-485-5p and LMX1B. In addition, subcutaneous and orthotropic xenograft models confirmed that lncRNA SNHG3 silencing or miR-485-5p overexpression significantly reduced the growth of glioma xenografts and prolonged survival time. These results indicate that lncRNA SNHG3 can regulate the expression of LMX1B by sponging miR-485-5p, thereby promoting the proliferation, migration, and invasion of glioma cells. This study provides the first evidence that the SNHG3/miR-485-5p/LMX1B axis is involved in glioma tumorigenesis and highlights the potential of SNHG3 and miR-485-5p as therapeutic targets for glioma.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Proteínas com Homeodomínio LIM/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Regulação para Cima , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Glioma/genética , Humanos
12.
Prep Biochem Biotechnol ; 51(9): 833-841, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427036

RESUMO

Cinnamaldehyde (CA) is one of the major active pharmaceutical ingredient of cinnamon bark. Hydrodistillation (HD) is usually used in CA extraction, however, the extraction yield is lower. The cell wall is a key factor limiting the extraction of essential oils. In-situ reactive heat breaking cell wall (RHB) could destroy the cell wall, which was conducive to the diffusion of CA. The aim of this work was to examine the effect of RHB pretreatment to HD extraction. Response surface methodology (RSM) was used to optimize RHB pretreatment parameters, and Box-Behnken Design (BBD) method was performed to evaluate the effects of different operating parameters. The maximum yield was increased to 3.31 ± 0.11% (w/w) from 2.08 ± 0.042% (w/w) after RSM optimization. Scanning electron microscopic (SEM) analysis showed that RHB destroyed and disrupted the cell wall of cinnamon bark. The GC analysis demonstrated that the purity of cinnamaldehyde was improved and no new components were presented in the extraction product from the cinnamon via RHB pretreatment. In conclusion, RHB is an effective pretreatment method for the CA extraction, and also may be used in the other herbal medicine extraction.


Assuntos
Parede Celular/química , Cinnamomum zeylanicum/química , Temperatura Alta , Óxidos de Enxofre/química , Acroleína/análogos & derivados , Acroleína/química , Acroleína/isolamento & purificação
13.
J Cell Mol Med ; 25(1): 463-472, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33336871

RESUMO

Glioma is the most prevalent and lethal primary brain tumour. Abundant long non-coding RNAs ( lncRNAs) are aberrant and play crucial roles in the oncogenesis of glioma. The exact functions of linc00475 in glioma remain blurred. Here, we analysed the expression levels of linc00475 by qRT-PCR and discovered that linc00475 was up-regulated in glioma and predicted a poor prognosis in patients with glioma. Besides, inhibiting linc00475 restrained the progression of glioma in vitro and in vivo. Further experiments confirmed that linc00475 regulated the progression of glioma by acting as a sponge for miR-141-3p. Moreover, we detected the binding sites of linc00475 and miR-141-3p, the YAP1- 3'UTR and miR-141-3p by luciferase reporters. The rescue assays confirmed that inhibiting linc00475 restrained the progression of glioma through the miR-141-3p/YAP1 pathway. Collectively, our research demonstrates the key roles of linc00475 in glioma, which could be a promising therapeutic target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Glioma/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Glioma/genética , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , RNA Longo não Codificante/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
14.
Neural Regen Res ; 16(6): 1024-1030, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33269746

RESUMO

Apoptosis is an important programmed cell death process involved in ischemia/reperfusion injury. MicroRNAs are considered to play an important role in the molecular mechanism underlying the regulation of cerebral ischemia and reperfusion injury. However, whether miR-670 can regulate cell growth and death in cerebral ischemia/reperfusion and the underlying mechanism are poorly understood. In this study, we established mouse models of transient middle artery occlusion and Neuro 2a cell models of oxygen-glucose deprivation and reoxygenation to investigate the potential molecular mechanism by which miR-670 exhibits its effects during cerebral ischemia/reperfusion injury both in vitro and in vivo. Our results showed that after ischemia/reperfusion injury, miR-670 expression was obviously increased. After miR-670 expression was inhibited with an miR-670 antagomir, cerebral ischemia/reperfusion injury-induced neuronal death was obviously reduced. When miR-670 overexpression was induced by an miR-670 agomir, neuronal apoptosis was increased. In addition, we also found that miR-670 could promote Yap degradation via phosphorylation and worsen neuronal apoptosis and neurological deficits. Inhibition of miR-670 reduced neurological impairments after cerebral ischemia/reperfusion injury. These results suggest that microRNA-670 aggravates cerebral ischemia/reperfusion injury through the Yap pathway, which may be a potential target for treatment of cerebral ischemia/reperfusion injury. The present study was approved by the Institutional Animal Care and Use Committee of China Medical University on February 27, 2017 (IRB No. 2017PS035K).

15.
Front Cell Dev Biol ; 8: 605972, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363165

RESUMO

Our review aims to highlight the neurological complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the available treatments according to the existing literature, discussing the underlying mechanisms. Since the end of 2019, SARS-CoV-2 has induced a worldwide pandemic that has threatened numerous lives. Fever, dry cough, and respiratory symptoms are typical manifestations of COVID-19. Recently, several neurological complications of the central and peripheral nervous systems following SARS-CoV-2 infection have gained clinicians' attention. Encephalopathy, stroke, encephalitis/meningitis, Guillain-Barré syndrome, and multiple sclerosis are considered probable neurological signs of COVID-19. The virus may invade the nervous system directly or induce a massive immune inflammatory response via a "cytokine storm." Specific antiviral drugs are still under study. To date, immunomodulatory therapies and supportive treatment are the predominant strategies. In order to improve the management of COVID-19 patients, it is crucial to monitor the onset of new neurological complications and to explore drugs/vaccines targeted against SARS-CoV-2 infection.

16.
Front Cell Neurosci ; 14: 193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760250

RESUMO

Cerebral ischemic stroke is regarded as one of the most serious diseases in the human central nervous system. The secondary ischemia and reperfusion (I/R) injury increased the difficulty of treatment. Moreover, the latent molecular regulating mechanism in I/R injury is still unclear. Based on our previous clinical study, we discovered that FK506 binding protein 5 (FKBP5) is significantly upregulated in patients, who suffered acute ischemic stroke (AIS), with high diagnostic value. Levels of FKBP5 were positively correlated with patients' neurological impairments. Furthermore, a transient middle cerebral artery occlusion (tMCAO) model of mice was used to confirm that FKBP5 expression in plasma could reflect its relative level in brain tissue. Thus, we hypothesized that FKBP5 participated in the regulation of cerebral I/R injury. In order to explore the possible roles FKBP5 acted, the oxygen and glucose deprivation and reoxygenation (OGD/R) model was established to mimic I/R injury in vitro. FKBP5 expressing levels were changed by plasmid stable transfection. The altered expression of FKBP5 influenced cell viability and autophagy after OGD/R injury notably. Besides, AKT/FOXO3 cascade was involved in the FKBP5-regulating process. In the present study, FKBP5 was verified upregulated in cerebral I/R injury, related to the severity of ischemia and reperfusion injury. Additionally, our analyses revealed that FKBP5 regulates autophagy induced by OGD/R via the downstream AKT/FOXO3 signaling pathway. Our findings provide a novel biomarker for the early diagnosis of ischemic stroke and a potential strategy for treatment.

17.
J Cancer ; 10(13): 2961-2968, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281473

RESUMO

LncRNAs have been proved to be involved in the promotion of glioma cell malignant development. However, the exact roles and molecular mechanisms of linc01023 in glioma remain blurred. In this study, we confirm linc01023 is up-regulated in glioma tissues and cell lines. In addition, elevated linc01023 expression indicates shorter survival times in patients with glioma. Moreover, loss-of-function studies reveal that restoration of linc01023 restrains glioma cell proliferation, migration and invasion by regulating IGF1R/AKT pathway in vitro and in vivo. Collectively, the study indicates that linc01023 plays an oncogenic role in glioma through activation of IGF1R/AKT signal pathway, and it could be a candidate therapeutic target.

18.
Food Sci Nutr ; 7(6): 2113-2122, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31289659

RESUMO

Adding a certain proportion of Pleurotus eryngii can improve the nutritional value of wheat-flour foods and enhance the utilization of this mushroom. In this research, partial wheat flour was substituted with P. eryngii powder (PEP) or soluble polysaccharide (SPPE) at different addition levels, and the effects of PEP and SPPE on the rheological and microstructural properties of dough were investigated. Farinographic assay results suggested that PEP significantly (p < 0.05) increased the water absorption of wheat flour but decreased the development time and stability of dough significantly (p < 0.05). Furthermore, it was capable of providing weaker extensographic characteristics and harder dough with the increasing of PEP addition levels. The dynamic oscillatory tests indicated that the PEP addition approximately increased the storage (G') and loss (G″) moduli in the entire frequency range, while the tan δ roughly decreased with the increasing of PEP addition levels, which could be attributed to the low solubility and strong water-trapping capacity of the dietary fiber in PEP. Due to the good water solubility and easy formation of hydrogen bonds, the addition of SPPE had inconsistent results with the PEP addition. The inner microstructure of dough showed that the continuity of gluten networks had been disrupted by PEP and SPPE addition and then resulted in a weaker extension and harder dough. This research could provide a foundation for the application of PEP in wheat-flour foods, and PEP addition levels of 2.5%-5.0% are recommended.

19.
Medchemcomm ; 10(5): 757-763, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31191866

RESUMO

Cisplatin is a clinical chemotherapy drug for cancers; however, its remarkably high kidney toxicity and other toxicities pose a danger to patients. As the small molecule inhibitor of GRPR, PD176252 can inhibit the growth and proliferation of various cancer cells, but the characteristics of high toxicity and poor water solubility has limited its use as a drug. When we studied PD176252 for the reduction of toxicity of cisplatin, we modified its structure to synthesize 16 analogues. Surprisingly, the analogues showed reduced cisplatin-induced renal toxicity, and unlike PD176252, the analogues 5d and 5m were almost non-toxic to the normal HK2 cells. Furthermore, the analogue 5d and PD176252 were subjected to cisplatin-induced inflammatory response in vitro. The results showed that 5d was able to better prevent this condition by effectively inhibiting its inflammatory response. Thus, this study will help in clinically reducing the side effects of cisplatin.

20.
Anticancer Agents Med Chem ; 19(8): 992-1001, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961511

RESUMO

BACKGROUND: Cancer patients treated with targeted anti-cancer drug suffer from itch or pruritus. Itch or pruritus is an unpleasant sensation that brings about a negative impact on quality of life, and serious itch may lead to dose reduction and even discontinuation. Gastrin releasing peptide receptor (GRPR) plays a critical role in itch, inflammation and cancer, and GRPR antagonist has obvious effect on cancer, inflammation and itch. The aim of this paper is to develop a new agent with anti-cancer and anti-itch activity. METHODS: A series of GRPR antagonist PD176252 analogues (3a-3l) were designed and synthesized. Both anticancer and anti-itch activities were evaluated. Anti-cancer activity was evaluated in three human cancer cell lines in vitro, the anti-itch activity in evaluated with Kunming mice by intrathecal injection of chloroquine phosphate as a modeling medium. And the cytotoxicity on normal cells was evaluated. RESULTS: Of the tested compounds, compound 3i showed potently anti-cancer activity to all cancer cell lines tested with IC50 values of 10.5µM (lung), 11.6µM (breast) and 12.8µM (liver) respectively and it also showed significant inhibition of the scratching behavior. Comparing with PD17625, compound 3i and 3g gave better inhibition activities against all cancer cell lines, compound 3b, 3c and 3i showed better anti-itch activity. The compound 3i is safe for normal breast and liver normal cells, but it has high cytotoxicity on normal lung cell. CONCLUSION: The synthesized compounds have dual anti-cancer and anti-itch activity, so the development of drug with dual anti-tumor and anti-itch property is possible.


Assuntos
Antineoplásicos/farmacologia , Antipruriginosos/farmacologia , Desenho de Fármacos , Indóis/farmacologia , Prurido/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antipruriginosos/síntese química , Antipruriginosos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/síntese química , Indóis/química , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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