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1.
Biomed Res Int ; 2019: 9096201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781650

RESUMO

Background: Oxycodone is a widely used opioid analgesic, which is involved in cancer pain and non-cancer pain. This study is intended to understand the publication characteristics of oxycodone research field and assess the quality of pertinent articles from 1998 to 2017. Methods: Oxycodone-related publications from 1998 to 2017 were retrieved from the Web of Science (WOS) and PubMed database. These papers were coded across several categories, such as total number, journals, countries, institutions, authors and citations reports. And the analysis of co-occurrence keywords was handled by VOSviewer software. Results: According to search strategies, a total of 2659 articles on oxycodone were published in world from 1998 to 2017 in WOS. Among the top 10 most productive organizations, six of them were American institutes, two of them were pharmaceutical enterprises and the other three were Finnish, Australian and Canadian institutes, which is similar with the distribution by country/region. Drewes AM from Denmark published most articles and PAIN MEDICINE is the most productive journal in oxycodone area. Meanwhile, clinical studies occupy a dominant position during the past 20 years. The 10 most cited papers were listed. Among these articles, 8 of them are reviews and 2 of those are meta-analysis. And the last decade (2008-2017) displayed that the newest keywords focus on "double-blind", "randomized controlled trial" and "neuropathic pain". Conclusions: The findings provided a comprehensive overview of oxycodone research. In view of the adverse effects of oxycodone, high-quality oxycodone studies both in basic studies and clinical trials need to be completed.

2.
Chem Commun (Camb) ; 55(91): 13737-13740, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31661086

RESUMO

A highly transparent and stretchable electrode based on a Au nanomesh, electrodeposited with a thin layer of MnO2 with a transparency of 84.7% is introduced. The as-prepared transparent, stretchable, and imperceptible supercapacitor (TSPS) exhibits a specific capacitance of 0.53 mF cm-2 and excellent bending stability, together with high stretchability (up to 160% strain).

3.
J Pharmacol Exp Ther ; 370(3): 682-694, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30796131

RESUMO

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related death in the United States, is highly aggressive and resistant to both chemo- and radiotherapy. It remains one of the most difficult-to-treat cancers, not only due to its unique pathobiological features such as stroma-rich desmoplastic tumors surrounded by hypovascular and hypoperfused vessels limiting the transport of therapeutic agents, but also due to problematic early detection, which renders most treatment options largely ineffective, resulting in extensive metastasis. To elevate therapeutic effectiveness of treatments and overt their toxicity, significant enthusiasm was generated to exploit new strategies for combating PDAC. Combination therapy targeting different barriers to mitigate delivery issues and reduce tumor recurrence and metastasis has demonstrated optimal outcomes in patients' survival and quality of life, providing possible approaches to overcome therapeutic challenges. This paper aims to provide an overview of currently explored multimodal therapies using either conventional therapy or nanomedicines along with rationale, up-to-date progress, as well as the key challenges that must be overcome. Understanding the future directions of the field may assist in the successful development of novel treatment strategies for enhancing therapeutic efficacy in PDAC.

4.
Toxicol Appl Pharmacol ; 368: 26-36, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776389

RESUMO

Cardiac dysfunction is a vital complication during endotoxemia (ETM). Accumulating evidence suggests that enhanced glycolytic metabolism promotes inflammatory and myocardial diseases. In this study, we performed deep mRNA sequencing analysis on the hearts of control and lipopolysaccharide (LPS)-challenged mice (40 mg/kg, i.p.) and identified that the glycolytic enzyme, 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase 3 (PFKFB3) might play an indispensable role in ETM-induced cardiac damage. Quantitative real-time PCR validated the transcriptional upregulation of PFKFB3 in the myocardium of LPS-challenged mice and immunoblotting and immunostaining assays confirmed that LPS stimulation markedly increased the expression of PFKFB3 at the protein level both in vivo and in vitro. The potent antagonist 3-(3pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) was used to block PFKFB3 activity in vivo (50 mg/kg, i.p.) and in vitro (10 µM). Echocardiographic analysis and TUNEL staining showed that 3PO significantly alleviated LPS-induced cardiac dysfunction and apoptotic injury in vivo. 3PO also suppressed the LPS-induced secretion of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6 and lactate in the serum, in addition to lactate in the myocardium. PFKFB3 inhibition also diminished the nuclear translocation and phosphorylation of transcription factor nuclear factor-κB (NF-κB) in both adult cardiomyocytes and HL-1 cells. Furthermore, immunoblotting analysis showed that 3PO inhibited LPS-induced apoptotic induction in cardiomyocytes. Taken together, these findings demonstrate that PFKFB3 participates in LPS-induced cardiac dysfunction via mediating inflammatory and apoptotic signaling pathway.

5.
ACS Nano ; 13(2): 1097-1106, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30633498

RESUMO

Polymers with superior mechanical properties are desirable in many applications. In this work, polyethylene (PE) films reinforced with exfoliated thermally reduced graphene oxide (TrGO) fabricated using a roll-to-roll hot-drawing process are shown to have outstanding mechanical properties. The specific ultimate tensile strength and Young's modulus of PE/TrGO films increased monotonically with the drawing ratio and TrGO filler fraction, reaching up to 3.2 ± 0.5 and 109.3 ± 12.7 GPa, respectively, with a drawing ratio of 60× and a very low TrGO weight fraction of 1%. These values represent by far the highest reported to date for a polymer/graphene composite. Experimental characterizations indicate that as the polymer films are drawn, TrGO fillers are exfoliated, which is further confirmed by molecular dynamics (MD) simulations. Exfoliation increases the specific area of the TrGO fillers in contact with the PE matrix molecules. Molecular dynamics simulations show that the PE-TrGO interaction is stronger than the PE-PE intermolecular van der Waals interaction, which enhances load transfer from PE to TrGO and leverages the ultrahigh mechanical properties of TrGO.

6.
J Pharmacol Exp Ther ; 370(3): 894-901, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30683666

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of cisplatin (CDDP) and gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and nontargeted delivery. More than 80% of PDAC aberrantly expresses the sialyl Tn (STn) antigen due to the loss of function of the core 1ß3-Gal-T-specific molecular chaperone, a specific chaperone for the activity of core 1 ß3-galactosyltransferase or C1GalT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen-specific antibody (TKH2 monoclonal antibody) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered a significantly higher amount of platinum into the cells and tumors expressing STn antigens. We also confirmed that a synergistic cytotoxic effect of sequential exposure of pancreatic cancer cells to Gem followed by CDDP can be mimicked by the codelivery of CDDP-loaded NGs (NG/CDDP) and free Gem. In a murine orthotopic model of PDAC, combined simultaneous treatment with Gem and targeted NG/CDDP significantly attenuated tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces highly synergistic therapeutic efficacy against pancreatic cancer. Our results offer the basis for development of combination drug regimens using targeted nanomedicines to increase treatment effectiveness and improve outcomes of PDAC therapy.

7.
Molecules ; 23(11)2018 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30423891

RESUMO

Insulin injection relies on strict blood glucose monitoring. However, existing techniques and algorithms for blood glucose monitoring cannot be completed in a timely way. In this study, we have developed a new intelligent glucose-sensitive insulin delivery system to stabilize blood glucose levels in the body. This system does not require real-time detection of blood glucose. First, we successfully synthesized a nanoscale material called PAM-PAspPBA-b-PEG by using chemical methods. We then conducted TEM, DLS, and ¹H-NMR analyses to characterize the physicochemical properties, such as size, molecular composition, and configuration of the nanomaterial. We verified the glucose responsibility of the insulin loading nanoscale material in vitro and evaluated its safety and effect on mice in vivo. Results showed that insulin-loaded PAM-PAspPBA-b-PEG is glucose-sensitive, safer and more effective than regular insulin injection. This study provides a basis for future development of smart insulin delivery systems.

8.
Artif Cells Nanomed Biotechnol ; : 1-11, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30299174

RESUMO

In our study, we have established a novel liquid-driven co-flow focusing (LDCF) process to fabricate curcumin (CUR)-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (CPMs). LDCF-CPMs of size 20.26 ± 2.37 µm have high encapsulation efficiency (>70%) and were intended for application in ovarian cancer by intraperitoneal (IP) administration. LDCF-CPMs have smooth surface with narrow size distribution and a core-shell structured verified by confocal microscopy which can be precisely controlled by changing the flow rates of focusing, outer and inner phases. The LDCF-CPMs reveal the physiochemical stability with sustained release profile corresponding to 95% CUR release over a period of 14 days in an in vitro release medium. Moreover, LDCF-CPMs were testified for cytotoxicity against SKOV-3 ovarian cancer cell lines and peritoneal delivery advantages by animal experiments. The pharmacokinetics of LDCF-CPMs in rats following IP injection shows slow systemic absorption with mean residence time (MRT) of 13.54 h in comparison with 9.82 and 6.74 h for SE-CPMs and free CUR, respectively. In addition, IP delivery of CUR can expose the ovarian tumour to higher concentration for a longer duration by programming the thickness of the shell. The study provides compelling evidence for LDCF-CPMs having high therapeutic opportunity in the treatment of peritoneal cancers, such as ovarian, that reside in the peritoneal cavity.

9.
Molecules ; 23(8)2018 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-30060618

RESUMO

Obesity and nonalcoholic fatty liver disease (NAFLD) are highly prevalent and cause numerous metabolic diseases. However, drugs for the prevention and treatment of obesity and NAFLD remain unavailable. In this study, we investigated the effects of mogrosides (luo han guo, LH) in Siraitia grosvenorii saponins on high-fat-diet-induced obesity and NAFLD in mice. We found that compared with the negative control, LH reduced body and liver weight. LH also decreased fat accumulation and increased AMP-activated protein kinase (AMPK) phosphorylation (pAMPK) levels in mouse livers. We also found that high-purity mogroside V upregulated pAMPK expression in HepG2 cells. In addition, high-purity mogroside V inhibited reactive oxygen species production and upregulated sequestosome-1 (SQSTM1, p62) expression in THP-1 cells. These results suggest that LH may affect obesity and NAFLD by enhancing fat metabolism and antioxidative defenses. Mogroside V may be a main component of LH. However, the exact molecular mechanisms and active components responsible for the inhibitory effects of LH on obesity and NAFLD require further investigation.


Assuntos
Fármacos Antiobesidade/farmacologia , Anticolesterolemiantes/farmacologia , Momordica/química , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Triterpenos/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Anticolesterolemiantes/química , Anticolesterolemiantes/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Saponinas/química , Saponinas/isolamento & purificação , Saponinas/farmacologia , Proteína Sequestossoma-1/agonistas , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Células THP-1 , Triterpenos/química , Triterpenos/isolamento & purificação
10.
Cell Mol Life Sci ; 75(21): 4021-4040, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29916093

RESUMO

Mitochondrial intracrines are extracellular signaling proteins, targeted to the mitochondria. The pathway for mitochondrial targeting of mitochondrial intracrines and actions in the mitochondria remains unknown. Megalin/LRP2 mediates the uptake of vitamins and proteins, and is critical for clearance of amyloid-ß protein from the brain. Megalin mutations underlie the pathogenesis of Donnai-Barrow and Lowe syndromes, characterized by brain defects and kidney dysfunction; megalin was not previously known to reside in the mitochondria. Here, we show megalin is present in the mitochondria and associates with mitochondrial anti-oxidant proteins SIRT3 and stanniocalcin-1 (STC1). Megalin shuttles extracellularly-applied STC1, angiotensin II and TGF-ß to the mitochondria through the retrograde early endosome-to-Golgi transport pathway and Rab32. Megalin knockout in cultured cells impairs glycolytic and respiratory capacities. Thus, megalin is critical for mitochondrial biology; mitochondrial intracrine signaling is a continuum of the retrograde early endosome-to-Golgi-Rab32 pathway and defects in this pathway may underlie disease processes in many systems.


Assuntos
Peptídeos beta-Amiloides/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mitocôndrias/genética , Proteínas rab de Ligação ao GTP/genética , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/metabolismo , Agenesia do Corpo Caloso/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Membrana Celular/genética , Glicoproteínas/genética , Células HEK293 , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Hérnias Diafragmáticas Congênitas/genética , Hérnias Diafragmáticas Congênitas/metabolismo , Hérnias Diafragmáticas Congênitas/patologia , Humanos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Mitocôndrias/metabolismo , Miopia/genética , Miopia/metabolismo , Miopia/patologia , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Síndrome Oculocerebrorrenal/patologia , Proteinúria/genética , Proteinúria/metabolismo , Proteinúria/patologia , Células RAW 264.7 , Erros Inatos do Transporte Tubular Renal/genética , Erros Inatos do Transporte Tubular Renal/metabolismo , Erros Inatos do Transporte Tubular Renal/patologia , Transdução de Sinais , Sirtuína 3/genética , Fator de Crescimento Transformador beta/genética , Proteínas rab de Ligação ao GTP/metabolismo
11.
Biochem Pharmacol ; 152: 45-59, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29551587

RESUMO

Canagliflozin (CAN) regulates intracellular glucose metabolism by targeting sodium-glucose co-transporter 2 (SGLT2) and intracellular glucose metabolism affects inflammation. In this study, we hypothesized that CAN might exert anti-inflammatory effects. The anti-inflammatory effects and action mechanisms of CAN were assayed in lipopolysaccharide (LPS)-induced RAW264.7 and THP-1 cells and NIH mice. Results showed that CAN significantly inhibited the production and release of interleukin (IL)-1, IL-6, or tumor necrosis factor-α (TNF-α) in the LPS-induced RAW264.7 and THP-1 cells, and mice. CAN also significantly inhibited intracellular glucose metabolism and 6-phosphofructo-2-kinase (PFK2) expression. CAN increased the levels of sequestosome-1 (SQSTM1/p62), upregulated the ratios of microtubule-associated protein 1A/1B-light chain 3 (LC3) II to I, promoted the formation of LC3 puncta, and enhanced the activities of lysosome. The inhibition of autophagy by 3-methyladenine (3-MA) reversed the effects of CAN on IL-1α levels. Increased autophagy might be associated with increased AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, p62 demonstrated good co-localization with IL-1α and possibly mediated IL-1α degradation. CAN-induced increase in p62 was dependent on the nuclear factor kappa B (NFκB) signaling pathway. These results indicated that CAN might exert anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy. Attenuated glucose metabolism by PFK2, increased autophagy flow by AMPK, and increased p62 levels by NFκB might be responsible for the molecular mechanisms of CAN. This drug might serve as a new promising anti-inflammatory drug for acute or chronic inflammatory diseases via independent hypoglycemic mechanisms. This drug might also be used as an important reference for similar drug research and development by targeting intracellular glucose metabolism and autophagy in immune cells.

12.
Chin J Nat Med ; 15(10): 732-739, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29103458

RESUMO

Pomegranate leaf (PGL) has a definite role in regulating lipid metabolism. However, pharmacokinetic results show the main active ingredient, ellagic acid, in PGL has lower oral bioavailability, suggesting that the lipid-lowering effect of PGL may act through inhibiting lipid absorption in the small intestine. Our results demonstrated that pomegranate leaf and its main active ingredients (i.e., ellagic acid, gallic acid, pyrogallic acid and tannic acid) were capable of inhibiting pancreatic lipase activity in vitro. In computational molecular docking, the four ingredients had good affinity for pancreatic lipase. Acute lipid overload experiments showed that a large dosage of PGL significantly reduced serum total cholesterol (TG) and triglycerides (TC) levels in addition to inhibiting intestinal lipase activity, which demonstrated that PGL could inhibit lipase activity and reduce the absorption of lipids. We also found that PGL could reverse the reduced tight-junction protein expression due to intestinal lipid overload, promote Occludin and Claudin4 expression in the small intestine, and enhance the intestinal mucosal barrier. In conclusion, we demonstrated that PGL can inhibit lipid absorption and reduce blood TG and TC by targeting pancreatic lipase, promoting tight-junction protein expression and thereby preventing intestinal mucosa damage from an overload of lipids in the intestine.


Assuntos
Inibidores Enzimáticos/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/enzimologia , Intestino Delgado/metabolismo , Lipase/metabolismo , Metabolismo dos Lipídeos , Extratos Vegetais/administração & dosagem , Punicaceae/química , Animais , Inibidores Enzimáticos/química , Humanos , Hiperlipidemias/metabolismo , Absorção Intestinal , Cinética , Lipase/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Folhas de Planta/química , Triglicerídeos/metabolismo
14.
Chin J Integr Med ; 2017 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-28795389

RESUMO

OBJECTIVE: To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels. METHODS: The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confifirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. RESULTS: PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (P<0.01) and allodynia after intra-plantar formalin (P<0.01) in mice. PA also up-regulated COX2 mRNA and protein (P<0.05) with a down-regulation of MOR (P<0.05) both in in vivo and in vitro experiments, which devote to the analgesic effect of PA. A decrease in the intracellular calcium level (P<0.05) induced by PA may play an important role in its anti-nociceptive effect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. CONCLUSIONS: Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.

15.
Sci Rep ; 7(1): 5270, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28706254

RESUMO

Diabetes is an inflammatory disease. Inflammation plays an important role in islet functions. However, the exact mechanisms by which inflammation affects islet functions remain unclear. In this study, we investigated the regulatory effects of miR-30a on inflammation and islet functions. The results indicate that miR-30a serves as an inflammation-resolving buffer factor by targeting interleukin 1a (IL-1α) in immune cells and in islet cells, which might play an important role in inflammation homeostasis. miR-30a ameliorates islet functions in an inflammatory micro-environment by targeting the IL-1α/nuclear factor kappa B (NFKB) p65 subunit (p65)/p62 (SQSTM1)/insulin axis, which can be developed into a novel antidiabetic approach. miR-30a serves as a promising inflammation-response biomarker in inflammatory diseases and is possibly activated by the toll-like receptor 4 (TLR4)/IL-1α/NFKB pathways. However, the exact molecular mechanisms by which miR-30a regulates inflammation and islet functions as well as the potential applications in transitional medicine require further elucidation.

16.
PLoS One ; 12(5): e0177964, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28562667

RESUMO

Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene. However, efficient delivery of small interfering RNA (siRNA) in vivo remains a significant hurdle for its successful therapeutic application. In this study, we first identified, on a cell-based experiment, applying a 1:1 mixture of two PTN specific siRNA engenders a higher silencing efficiency on both mRNA and protein level than using any of them discretely at the same dose. As a consequence, slower melanoma cells growth was also observed for using two specific siRNA combinatorially. To establish a robust way for siRNA delivery in vivo and further investigate how silence of PTN affects tumor growth, we tested three different methods to deliver siRNA in vivo: first non-targeted in-vivo delivery of siRNA via jetPEI; second lung targeted delivery of siRNA via microbubble coated jetPEI; third tumor cell targeted delivery of siRNA via transferrin-polyethylenimine (Tf-PEI). As a result, we found that all three in-vivo siRNAs delivery methods led to an evident inhibition of melanoma growth in non-immune deficiency C57BL/6 mice without a measureable change of ALT and AST activities. Both targeted delivery methods showed more significant curative effect than jetPEI. The lung targeted delivery by microbubble coated jetPEI revealed a comparable therapeutic effect with Tf-PEI, indicating its potential application for target delivery of siRNA in vivo.


Assuntos
Proteínas de Transporte/genética , Proliferação de Células/genética , Citocinas/genética , Inativação Gênica , Metástase Neoplásica/genética , Neoplasias/patologia , RNA Interferente Pequeno/administração & dosagem , Animais , Humanos , Melanoma Experimental/patologia , Camundongos
17.
Chin J Nat Med ; 15(3): 178-191, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28411686

RESUMO

Heat stress can stimulate an increase in body temperature, which is correlated with increased expression of heat shock protein 70 (HSP70) and tumor necrosis factor α (TNFα). The exact mechanism underlying the HSP70 and TNFα induction is unclear. Berberine (BBR) can significantly inhibit the temperature rise caused by heat stress, but the mechanism responsible for the BBR effect on HSP70 and TNFα signaling has not been investigated. The aim of the present study was to explore the relationship between the expression of HSP70 and TNFα and the effects of BBR under heat conditions, using in vivo and in vitro models. The expression levels of HSP70 and TNFα were determined using RT-PCR and Western blotting analyses. The results showed that the levels of HSP70 and TNFα were up-regulated under heat conditions (40 °C). HSP70 acted as a chaperone to maintain TNFα homeostasis with rising the temperature, but knockdown of HSP70 could not down-regulate the level of TNFα. Furthermore, TNFα could not influence the expression of HSP70 under normal and heat conditions. BBR targeted both HSP70 and TNFα by suppressing their gene transcription, thereby decreasing body temperature under heat conditions. In conclusion, BBR has a potential to be developed as a therapeutic strategy for suppressing the thermal effects in hot environments.


Assuntos
Berberina/farmacologia , Proteínas de Choque Térmico HSP70/genética , Transtornos de Estresse por Calor/tratamento farmacológico , TATA Box/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Animais , Proteínas de Choque Térmico HSP70/metabolismo , Transtornos de Estresse por Calor/genética , Transtornos de Estresse por Calor/metabolismo , Temperatura Alta , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fator de Necrose Tumoral alfa/metabolismo
18.
Sci Rep ; 7: 45155, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332601

RESUMO

Transient Receptor Potential Melastatin-8 (TRPM8) reportedly plays a fundamental role in a variety of processes including cold sensation, thermoregulation, pain transduction and tumorigenesis. However, the role of TRPM8 in inflammation under cold conditions is not well known. Since cooling allows the convergence of primary injury and injury-induced inflammation, we hypothesized that the mechanism of the protective effects of cooling might be related to TRPM8. We therefore investigated the involvement of TRPM8 activation in the regulation of inflammatory cytokines. The results showed that TRPM8 expression in the mouse hypothalamus was upregulated when the ambient temperature decreased; simultaneously, tumor necrosis factor-alpha (TNFα) was downregulated. The inhibitory effect of TRPM8 on TNFα was mediated by nuclear factor kappa B (NFκB). Specifically, cold stress stimulated the expression of TRPM8, which promoted the interaction of TRPM8 and NFκB, thereby suppressing NFκB nuclear localization. This suppression consequently led to the inhibition of TNFα gene transcription. The present data suggest a possible theoretical foundation for the anti-inflammatory role of TRPM8 activation, providing an experimental basis that could contribute to the advancement of cooling therapy for trauma patients.


Assuntos
Resposta ao Choque Frio/genética , Regulação da Expressão Gênica , Canais de Cátion TRPM/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Animais , Biomarcadores , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Cálcio/metabolismo , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Transporte Proteico , RNA Interferente Pequeno/genética , Canal de Cátion TRPA1/metabolismo
19.
Sci Rep ; 7: 41712, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28181523

RESUMO

After being studied for approximately a century, berberine (BBR) has been found to act on various targets and pathways. A great challenge in the pharmacological analysis of BBR at present is to identify which target(s) plays a decisive role. In the study described herein, a rescue experiment was designed to show the important role of mitochondria in BBR activity. A toxic dose of BBR was applied to inhibit cell proliferation and mitochondrial activity, then α-ketobutyrate (AKB), an analogue of pyruvate that serves only as an electron receptor of NADH, was proven to partially restore cell proliferation. However, mitochondrial morphology damage and TCA cycle suppression were not recovered by AKB. As the AKB just help to regenerate NAD+, which is make up for part function of mitochondrial, the recovered cell proliferation stands for the contribution of mitochondria to the activity of BBR. Our results also indicate that BBR suppresses tumour growth and reduces energy charge and mitochondrial DNA (mtDNA) copy number in a HepG2 xenograft model. In summary, our study suggests that mitochondria play an important role in BBR activity regarding tumour cell proliferation and metabolism.


Assuntos
Berberina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Butiratos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , DNA Mitocondrial , Relação Dose-Resposta a Droga , Dosagem de Genes , Humanos , Mitocôndrias/genética , Mitocôndrias/ultraestrutura , NAD/metabolismo , Ácido Pirúvico/metabolismo
20.
Cell Mol Life Sci ; 74(6): 1117-1131, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27783096

RESUMO

Nuclear paraspeckle assembly transcript 1 (NEAT1) is the crucial structural platform of paraspeckles, which is one type of nuclear bodies. As a stress-induced lncRNA, the expression of NEAT1 increases in response to viral infection, but little is known about the role of NEAT1 or paraspeckles in the replication of herpes simplex virus-1 (HSV-1). Here, we demonstrate that HSV-1 infection increases NEAT1 expression and paraspeckle formation in a STAT3-dependent manner. NEAT1 and other paraspeckle protein components, P54nrb and PSPC1, can associate with HSV-1 genomic DNA. By binding with STAT3, PSPC1 is required for the recruitment of STAT3 to paraspeckles and facilitates the interaction between STAT3 and viral gene promoters, finally increasing viral gene expression and viral replication. Furthermore, thermosensitive gel containing NEAT1 siRNA or STAT3 siRNA effectively healed the skin lesions caused by HSV-1 infection in mice. Our results provide insight into the roles of lncRNAs in the epigenetic control of viral genes and into the function of paraspeckles.


Assuntos
Genes Virais , Herpesvirus Humano 1/fisiologia , RNA Longo não Codificante/metabolismo , Transcrição Genética , Replicação Viral/genética , Animais , Sequência de Bases , Regulação Viral da Expressão Gênica , Células HeLa , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Humanos , Corpos de Inclusão Intranuclear/metabolismo , Camundongos , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição de Octâmero/metabolismo , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição STAT3/metabolismo
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