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1.
Signal Transduct Target Ther ; 6(1): 328, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471088

RESUMO

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Microambiente Celular/imunologia , Pulmão/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/patologia , Interferon-alfa/imunologia , Interleucina-6/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino
2.
Mol Pharmacol ; 100(3): 217-223, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34135098

RESUMO

Regulators of G protein signaling (RGS) proteins modulate signaling by G protein-coupled receptors. Using a knock-in transgenic mouse model with a mutation in Gαo that does not bind RGS proteins (RGS-insensitive), we determined the effect of RGS proteins on presynaptic µ opioid receptor (MOR)-mediated inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG). The MOR agonists [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and met-enkephalin (ME) inhibited evoked inhibitory postsynaptic currents (eIPSCs) in the RGS-insensitive mice compared with wild-type (WT) littermates, respectively. Fentanyl inhibited eIPSCs similarly in both WT and RGS-insensitive mice. There were no differences in opioid agonist inhibition of spontaneous GABA release between the genotypes. To further probe the mechanism underlying these differences between opioid inhibition of evoked and spontaneous GABA release, specific myristoylated Gα peptide inhibitors for Gαo1 and Gαi1-3 that block receptor-G protein interactions were used to test the preference of agonists for MOR-Gα complexes. The Gαo1 inhibitor reduced DAMGO inhibition of eIPSCs, but Gαi1-3 inhibitors had no effect. Both Gαo1 and Gαi1-3 inhibitors separately reduced fentanyl inhibition of eIPSCs but had no effects on ME inhibition. Gαi1-3 inhibitors blocked the inhibitory effects of ME and fentanyl on miniature postsynaptic current (mIPSC) frequency, but both Gαo1 and Gαi1-3 inhibitors were needed to block the effects of DAMGO. Finally, baclofen-mediated inhibition of GABA release is unaffected in the RGS-insensitive mice and in the presence of Gαo1 and Gαi1-3 inhibitor peptides, suggesting that GABAB receptor coupling to G proteins in vlPAG presynaptic terminals is different than MOR coupling. SIGNIFICANCE STATEMENT: Presynaptic µ opioid receptors (MORs) in the ventrolateral periaqueductal gray are critical for opioid analgesia and are negatively regulated by RGS proteins. These data in RGS-insensitive mice provide evidence that MOR agonists differ in preference for Gαo versus Gαi and regulation by RGS proteins in presynaptic terminals, providing a mechanism for functional selectivity between agonists. The results further define important differences in MOR and GABAB receptor coupling to G proteins that could be exploited for new pain therapies.

3.
Cell Res ; 31(8): 847-860, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34112954

RESUMO

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Assuntos
Antivirais/metabolismo , COVID-19/patologia , Proteínas do Envelope de Coronavírus/metabolismo , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/química , Antivirais/uso terapêutico , Apoptose , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteínas do Envelope de Coronavírus/antagonistas & inibidores , Proteínas do Envelope de Coronavírus/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Meia-Vida , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidade , Baço/metabolismo , Baço/patologia , Carga Viral , Virulência
4.
Zool Res ; 42(3): 350-353, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33998182

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques ( Macaca leonina, NPMs) supported SARS-CoV-2 replication. Furthermore, compared with rhesus macaques, NPMs showed rapid viral clearance in lung tissues, nose swabs, throat swabs, and rectal swabs, which may be due to higher expression of interferon (IFN)-α in lung tissue. However, the rapid viral clearance was not associated with good outcome. In the second week post infection, NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques. These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Macaca nemestrina , SARS-CoV-2/imunologia , Animais , Modelos Animais de Doenças , Interferon-alfa/análise , Interleucina-1beta/análise , Interleucina-6/análise , Pulmão/imunologia , Pulmão/virologia , Nariz/virologia , Faringe/virologia , RNA Viral/análise , Reto/virologia , SARS-CoV-2/genética
5.
Artigo em Inglês | MEDLINE | ID: mdl-34018292

RESUMO

Inorganic cesium lead halide perovskites offer a pathway towards thermally stable photovoltaics. However, moisture-induced phase degradation restricts the application of hole transport layers (HTLs) with hygroscopic dopants. Dopant-free HTLs fail to realize efficient photovoltaics due to severe electrical loss. Herein, we developed an electrical loss management strategy by manipulating poly(3-hexylthiophene) with a small molecule, i.e., SMe-TATPyr. The developed P3HT/SMe-TATPyr HTL shows a three-time increase of carrier mobility owing to breaking the long-range ordering of "edge-on" P3HT and inducing the formation of "face-on" clusters, over 50 % decrease of the perovskite surface defect density, and a reduced voltage loss at the perovskite/HTL interface because of favorable energy level alignment. The CsPbI2 Br perovskite solar cell demonstrates a record-high efficiency of 16.93 % for dopant-free HTL, and superior moisture and thermal stability by maintaining 96 % efficiency at low-humidity condition (10-25 % R. H.) for 1500 hours and over 95 % efficiency after annealing at 85 °C for 1000 hours.

6.
Proc Natl Acad Sci U S A ; 118(16)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33846240

RESUMO

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than ß-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

9.
Zool Res ; 42(2): 161-169, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33554485

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continue to impact countries worldwide. At present, inadequate diagnosis and unreliable evaluation systems hinder the implementation and development of effective prevention and treatment strategies. Here, we conducted a horizontal and longitudinal study comparing the detection rates of SARS-CoV-2 nucleic acid in different types of samples collected from COVID-19 patients and SARS-CoV-2-infected monkeys. We also detected anti-SARS-CoV-2 antibodies in the above clinical and animal model samples to identify a reliable approach for the accurate diagnosis of SARS-CoV-2 infection. Results showed that, regardless of clinical symptoms, the highest detection levels of viral nucleic acid were found in sputum and tracheal brush samples, resulting in a high and stable diagnosis rate. Anti-SARS-CoV-2 immunoglobulin M (IgM) and G (IgG) antibodies were not detected in 6.90% of COVID-19 patients. Furthermore, integration of nucleic acid detection results from the various sample types did not improve the diagnosis rate. Moreover, dynamic changes in SARS-CoV-2 viral load were more obvious in sputum and tracheal brushes than in nasal and throat swabs. Thus, SARS-CoV-2 nucleic acid detection in sputum and tracheal brushes was the least affected by infection route, disease progression, and individual differences. Therefore, SARS-CoV-2 nucleic acid detection using lower respiratory tract samples alone is reliable for COVID-19 diagnosis and study.


Assuntos
Teste para COVID-19/veterinária , COVID-19/diagnóstico , SARS-CoV-2/genética , Animais , Anticorpos Antivirais , Modelos Animais de Doenças , Haplorrinos , Humanos , Estudos Longitudinais , Faringe/virologia , Valor Preditivo dos Testes , SARS-CoV-2/imunologia , Manejo de Espécimes , Escarro/virologia
10.
Science ; 371(6536): 1374-1378, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33602867

RESUMO

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Animais , Antivirais/química , Antivirais/uso terapêutico , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Interferon beta/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Oligopeptídeos , Prolina/análogos & derivados , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico , Inibidores de Proteases/toxicidade , Ratos , Ratos Sprague-Dawley , Carga Viral/efeitos dos fármacos , Replicação Viral
11.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32772513

RESUMO

As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.


Assuntos
Envelhecimento/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Macaca mulatta/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/veterinária , Inflamação/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta/virologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/virologia , Pandemias/veterinária , Pneumonia Viral/veterinária , Pneumonia Viral/virologia , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/veterinária , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Carga Viral/imunologia , Carga Viral/veterinária , Replicação Viral/imunologia
12.
Zool Res ; 41(5): 517-526, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32701249

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/ HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here, different aged Chinese tree shrews (adult group, 1 year old; old group, 5-6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days post-inoculation (dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3, 5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase (AST) and blood urea nitrogen (BUN). Histological analysis of lung tissues from animals at 3 dpi (adult group) and 7 dpi (old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.


Assuntos
Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/diagnóstico , Modelos Animais de Doenças , Pulmão/patologia , Pneumonia Viral/diagnóstico , Tupaiidae/fisiologia , Fatores Etários , Animais , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Humanos , Pulmão/virologia , Masculino , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , SARS-CoV-2 , Tupaiidae/virologia , Eliminação de Partículas Virais/fisiologia
13.
Nanoscale ; 12(14): 7759-7765, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32211703

RESUMO

Hybrid organic-inorganic perovskite (HOIP) materials have caught significant attention in photovoltaics and photoelectronics for their outstanding photovoltaic properties. However, their instability to various environment, such as illumination, temperature, moisture and oxygen, hinders their way to commercialization. To figure out the interaction mechanism between H2O and CH3NH3PbI3 (MAPbI3), extensive theoretical studies have been carried out; however, the experimental results are insufficient and inconsistent. Here, we systematically investigate and compare the influence of H2O on MAPbI3 perovskite films with or without DMF) post-annealing in dark or light condition. The interaction between H2O and the surface of pristine MAPbI3 leads to the fusion of grain boundaries thus grain growth into micron level in short-time moisture exposure. While the penetration of H2O into MAPbI3 results in swelled crystalline whisker, cracking into smaller grains in long-time exposure upon the release of H2O. However, no degradation occurs in dark condition. As the DMF post-annealing treatment changes the surface states of MAPbI3, the interactions between the external H2O and internal MAPbI3 significantly varies from the pristine MAPbI3. Three different surface states with different topographies have influence on the interaction process and mechanism with H2O, leading to different decomposition rates, the striped surface that is the most rough among the three and experiencing the minimum change in surface potential with exposure to 80% humidity decomposes into PbI2 fastest. However, the addition of light will once again affect the aforementioned process. It is found that even ambient light could severely speed up the moisture-induced decomposition of MAPbI3, while the N,N-dimethylformamide (DMF) post-annealing treatment significantly improves the stability of MAPbI3 films upon exposure to humidity and illumination, benefiting from the MAI-deficient thus H2O resistant surface.

14.
Org Biomol Chem ; 17(34): 7854-7857, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31408075

RESUMO

A copper-catalyzed DTBP oxidative dual C-H sulfurization has been developed for the direct thiocarbamation of imidazopyridines using a combination of elemental sulfur and formamides as carbamothioyl surrogates. NBS (bromo succinimide) was found to promote the thiocarbamation in good yields. This dual C-H sulfurization strategy enables access to a wide range of carbamothioyl imidazoheterocycles without the use of highly toxic phosgene.

15.
J Pharm Biomed Anal ; 165: 18-23, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30500596

RESUMO

Many species of velvet antler have been used as traditional medicine for thousands of years; however, as medicinal materials, velvet antler derived from different animals have different clinical effects. To distinguish the differences and homologies, ultra-performance liquid chromatography-quadruple-time of flight mass spectrometry (UPLC-QTOF-MS) coupled with principal component analysis (PCA) was developed and applied to identify these antler samples derived from Cervus nippon Temminck, Cervus elaphus Linnaeus and Rangifer tarandus Linnaeus, which were first tested and compared at the molecular level of protein. The UPLC-MS data of the trypsin digested samples were subjected to PCA, and the potential markers based on peptide were depicted to illustrate their differences. With the integrated strategy combining UPLC-QTOF-MS with PCA, the results from this study indicated that the proposed methods could be successfully applied to distinguish reindeer antler from sika deer antler and red deer antler, which were prescribed in the Chinese Pharmacopoeia (2015 edition).


Assuntos
Chifres de Veado/química , Cromatografia Líquida de Alta Pressão/métodos , Cervos , Espectrometria de Massas/métodos , Animais , Cervos/classificação , Masculino , Medicina Tradicional Chinesa , Análise de Componente Principal , Especificidade da Espécie
16.
Zhongguo Zhong Yao Za Zhi ; 43(21): 4198-4202, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30583617

RESUMO

With the rapid development of traditional Chinese medicine (TCM) in China as well as the implementation of the four most strict requirements, the quality of Chinese medicinal materials and decoction pieces had beem improved in recent years, however new problems and challenges were occurred. All the data of Chinese medicinal materials and decoction piece in special inspection,supervision test and evaluation inspection of drug administration department to were summarized and analyzed evaluate and analyze of the quality of Chinese medicinal materials and decoction pieces in 2017. On this basis, the relevant quality control strategies and suggestions were put forward for the relevant departments of China Food and Drug Administration to formulate and implement regulatory measures, furthermore to improve drug standards, and ensure the safety of medication.


Assuntos
Medicamentos de Ervas Chinesas/normas , Medicina Tradicional Chinesa , China , Vigilância de Produtos Comercializados , Controle de Qualidade
17.
Front Pharmacol ; 9: 1029, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271345

RESUMO

Tubulointerstitial fibrosis is the final common pathway for all kidney diseases leading to chronic kidney disease (CKD). TGF-ß/Smad signaling pathway plays a key role in renal fibrosis. Previous studies have revealed that rhubarb extracts attenuated the increase of transforming growth factor-ß 1 (TGF-ß1) in CKD rats. To gain an in-depth insight into the mechanism of the anti-fibrotic activities of the rhubarb extracts, we investigated the influence of rhubarb extracts on TGF-ß/Smad signaling pathway and the influence on metabolome in a rat model of CKD with adenine-induced chronic tubulointerstitial nephropathy. Male Sprague-Dawley rats were divided into four groups, including control, CKD, CKD + petroleum ether extract, CKD + ethyl acetate extract, and CKD + n-butanol extract groups. Kidneys harvested on the week three were evaluated for renal fibrosis, the expression of proteins in TGF-ß/Smad signaling pathway and metabolomic study. We found rhubarb extracts suppressed TGF-ß/Smad3-mediated renal fibrosis by reducing the TGF-ß1, transforming growth factor-ß receptor I (TGF-ß RI), transforming growth factor-ß receptor II (TGF-ß RII), Smad2, p-Smad2, Smad3, p-Smad3, and Smad4, meanwhile increased Smad7. In addition, rhubarb extracts mitigated renal injury and dysfunction, and either fully or partially reversed the abnormalities of tissue metabolites. Thus, rebalancing the disorder of TGF-ß/Smad signaling and metabolic dysfunction by treatment with rhubarb extracts may represent as an effective therapy for CKD associated with fibrosis.

18.
J Pain Res ; 11: 1673-1678, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214277

RESUMO

Objective: The objective of this study was to evaluate the feasibility of percutaneous interbody fusion (PIF) using bone cement for adjacent vertebral stress fracture of ankylosing spondylitis (AS) with intervertebral pseudarthrosis formation. Patients and methods: From January 2010 to February 2018, eleven consecutive patients (seven men and four women; median age, 56.09±13.64 years; age range, 33-80 years) who underwent PIF as a treatment for adjacent stress fracture of AS with intervertebral pseudarthrosis formation were retrospectively analyzed. The Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) score were assessed before and after the procedure; meanwhile, the procedure duration, length of hospital stay and complications were assessed. Moreover, anterior/lateral and computed tomography (CT) scans were utilized for the assessment of bone cement distribution and interbody fusion. Results: Technical success was achieved in all patients, and they experienced good interbody fusion with bone cement after PIF. Mean VAS scores declined significantly from 8.82±0.87 before the procedure to 3.36±0.67 1 day after the procedure and 2.73±0.65 1 month after the procedure, while the mean ODI scores decreased from 82.91±3.02 before treatment to 31.64 ±2.66 1 day after treatment and 30.00±3.10 1 month after treatment. The mean procedure duration was 49.73±6.12 minutes (range, 42-65 minutes). The average length of hospital stay was 7.09±1.45 days (range, 5-10 days). Extraosseous cement leakage occurred in one case without causing any clinical complications. Conclusion: PIF is a feasible therapeutic technique for adjacent vertebral stress fracture of AS with intervertebral pseudarthrosis formation, which can significantly relieve pain and stabilize the fractured spine.

19.
J Neurosci ; 38(41): 8737-8744, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30150362

RESUMO

Regulators of G-protein signaling (RGS) proteins negatively modulate presynaptic µ-opioid receptor inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG). Paradoxically, we find that G-protein-coupled receptor (GPCR) activation of G-protein-gated inwardly rectifying K+ channels (GIRKs) in the vlPAG is reduced in an agonist- and receptor-dependent manner in transgenic knock-in mice of either sex expressing mutant RGS-insensitive Gαo proteins. µ-Opioid receptor agonist activation of GIRK currents was reduced for DAMGO and fentanyl but not for [Met5]-enkephalin acetate salt hydrate (ME) in the RGS-insensitive heterozygous (Het) mice compared with wild-type mice. The GABAB agonist baclofen-induced GIRK currents were also reduced in the Het mice. We confirmed the role of Gαo proteins in µ-opioid receptor and GABAB receptor signaling pathways in wild-type mice using myristoylated peptide inhibitors of Gαo1 and Gαi1-3 The results using these inhibitors indicate that receptor activation of GIRK channels is dependent on the preference of the agonist-stimulated receptor for Gαo versus that for Gαi. DAMGO and fentanyl-mediated GIRK currents were reduced in the presence of the Gαo1 inhibitor, but not the Gαi1-3 inhibitors. In contrast, the Gαo1 peptide inhibitor did not affect ME activation of GIRK currents, which is consistent with results in the Het mice, but the Gαi1-3 inhibitors significantly reduced ME-mediated GIRK currents. Finally, the reduction in GIRK activation in the Het mice plays a role in opioid- and baclofen-mediated spinal antinociception, but not supraspinal antinociception. Thus, our studies indicate that RGS proteins have multiple mechanisms of modulating GPCR signaling that produce negative and positive regulation of signaling depending on the effector.SIGNIFICANCE STATEMENT Regulators of G-protein signaling (RGS) proteins positively modulate GPCR coupling to GIRKs, and this coupling is critical for opioid- and baclofen-mediated spinal antinociception, whereas µ-opioid receptor-mediated supraspinal antinociception depends on presynaptic inhibition that is negatively regulated by RGS proteins. The identification of these opposite roles for RGS proteins has implications for signaling via other GPCRs.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Neurônios/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Proteínas RGS/metabolismo , Analgésicos/administração & dosagem , Animais , Baclofeno/administração & dosagem , Feminino , Agonistas dos Receptores de GABA-B/administração & dosagem , Locomoção/efeitos dos fármacos , Masculino , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptores de GABA-B/metabolismo , Receptores Opioides mu/agonistas
20.
Front Neurol ; 9: 339, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867745

RESUMO

Cerebral ischemia and stroke are increasing in prevalence and are among the leading causes of morbidity and mortality in both developed and developing countries. Despite the progress in endovascular treatment, ischemia/reperfusion (IR) injury is an important contributor to post-surgical mortality and morbidity affecting a wide range of neurointerventional procedures. However, pharmacological recruitment of effective cerebral protective signaling has been largely disappointing to date. In remote ischemic conditioning (RIC), repetitive transient mechanical obstruction of vessels at a limb remote from the IR injury site protects vital organs from IR injury and confers infarction size reduction following prolonged arterial occlusion. Results of pharmacologic agents appear to be species specific, while RIC is based on the neuroprotective influences of phosphorylated protein kinase B, signaling proteins, nitric oxide, and transcriptional activators, the benefits of which have been confirmed in many species. Inducing RIC protection in patients undergoing cerebral vascular surgery or those who are at high risk of brain injury has been the subject of research and has been enacted in clinical settings. Its simplicity and non-invasive nature, as well as the flexibility of the timing of RIC stimulus, also makes it feasible to apply alongside neurointerventional procedures. Furthermore, despite nonuniform RIC protocols, emerging literature demonstrates improved clinical outcomes. The aims of this article are to summarize the potential mechanisms underlying different forms of conditioning, to explore the current translation of this paradigm from laboratory to neurovascular diseases, and to outline applications for patient care.

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