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1.
Neurochem Res ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34993705

RESUMO

To explore the mechanism regarding the regulation of spinal cord ischemia (SCI) in rats by mild hypothermia. A SCI rat model was established through aorta occlusion, and in some cases, the rats were intervened with mild hypothermia, after which motor function, microglia activation, and M1/M2 polarization in rats were measured. Also, the expression of inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and neuronal apoptosis were examined. Lipopolysaccharide (LPS)-induced M1 microglia and IL-4-induced M2 microglia were intrathecally injected into rats to evaluate the effect of microglial polarization on SCI. In in vitro experiments, primary microglial cells were treated under hypothermic condition, in which M1/M2 polarization and microglia apoptosis, the levels of iNOS, CD86, CD206, Arg-1 and inflammatory cytokines were assessed. Western blot analysis detected the activation of the TLR4/NF-κB pathway to investigate the role of this pathway in M1/M2 polarization. SCI treatment impaired motor function, induced higher M1 microglia proportion, and increased the levels of pro-inflammatory cytokines in rats, and mild hypothermic treatment attenuated these trends. Moreover, injection of M1 microglia increased M1 microglia proportion and increased the levels of pro-inflammatory cytokines, while injection of M2 microglia induced the reverse results, i.e. decreased M1 microglia proportion and reduced pro-inflammatory cytokine levels. In LPS-induced microglial cells, mild hypothermia treatment increased M2 microglia proportion and decreased pro-inflammatory cytokine levels, relative to normothermia. Mild hypothermia inactivated the TLR4/NF-κB pathway in LPS-treated microglia. TLR4 overexpression reversed the function of mild hypothermia in LPS-stimulated microglia, and under normal condition, TLR4/NF-κB pathway suppressed microglial M2 polarization. Mild hypothermia inhibits TLR4/NF-κB pathway and promotes microglial M2 polarization, thus attenuating SCI-induced injury and inflammation.

2.
J Ethnopharmacol ; 284: 114753, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34662667

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pteryxin is a natural coumarin compound that is found in "Qianhu", a traditional Chinese medicine, which possesses heat-clearing and detoxifying functions according to the theory of Traditional Chinese Medicine. Despite its medicinal effects, its anti-inflammatory and mechanisms of actions have not been established. AIM OF THIS STUDY: This study aims to evaluate the anti-inflammatory property and reveal the possible anti-inflammatory mechanisms of pteryxin. MATERIAL AND METHODS: LPS-induced RAW 264.7 macrophages and LPS-induced zebrafish model were used for the anti-inflammatory activity determination of pteryxin. The level of NO, PEG2, TNF-α and IL-6 were measured by ELISA. The accumulation of NO and ROS was stained and observed by a fluorescence microscopy. The nuclear translocation of NF-κB p65 and formation of NLRP3 inflammasome complex in LPS-induced RAW 264.7 macrophage cells were analyzed by immunofluorescence assay. The expression level of iNOS, IL-6, COX-2, TNF-α, p-p38, p38, ERK, JNK, p-ERK, p-JNK, IKK, IκB-α, p-IKK, p-IκB-α, p65, NLRP3, p-p65, Caspase 1 (p 20), ASC, and GAPDH were determined by Western blotting. RESULTS: Lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) and nitric oxide (NO) secretions were found to be downregulated by pteryxin. Moreover, pteryxin significantly suppressed inflammatory factor secretion in LPS-treated RAW 264.7 cells. Mechanistically, pteryxin significantly downregulated NF-κB/MAPK activation. Moreover, pteryxin inhibited caspase-1 and NLRP3 activation and formation of ASC specks in RAW 264.7 cells, implying that pteryxin inhibits inflammasome assembly, which is a signal for NLRP3 inflammasome activation. In conclusion, pteryxin blocks NF-κB/MAPK signaling, and suppresses the initiation and activation of NLRP3 thereby preventing inflammation. CONCLUSION: Pteryxin is a potential treatment option for inflammatory-related diseases.

3.
J Ethnopharmacol ; 284: 114815, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34763039

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Jieduquyuziyin prescription (JP) is a traditional Chinese medicine (TCM) formula. According to both TCM theory and more than a decade of clinical practice, JP has been testified to be effective for systemic lupus erythematosus (SLE) treatment as an approved hospital prescription in China. AIM OF THE STUDY: To determine the effect of JP on the treatment of SLE by glucocorticoid (GC) and to further examine the molecular mechanisms. MATERIALS AND METHODS: We conducted in vivo experiments to estimate the effect of JP on hepatic gluconeogenesis in MRL/lpr mice treated with GC. Additionally, isoproterenol (ISO) induced hepatic gluconeogenesis model and GC-treated MRL/lpr mouse hepatocytes were carried out in vitro experiments to verify the effect of JP on gluconeogenesis. RESULTS: The results showed that JP combined with GC could effectively alleviate the lupus symptoms in MRL/lpr mice and improve the pathological changes of the kidney and liver. And the combination of JP reduced the side effects caused by GC, which was related to the inhibition of GC-induced hepatic gluconeogenesis in MRL/lpr mice. Specifically, JP up-regulated the expression of glucocorticoid receptor (GR) α, phosphoinositide-3-kinase (PI3K) and Akt restrained by GC to reduce the production of forkhead box O1 (FoxO1), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In vivo, the use of JP either alone or with GC could reduce spleen enlargement, high levels of serum antibodies, aggravated urine protein and renal pathological damage in MRL/lpr mice. Furthermore, the glucose content was reduced in the liver of MRL/lpr mice treated with JP, and the liver damage and steatosis were also alleviated. In vitro, the expressions of PI3K and Akt increased and the expressions of FoxO1, PGC-1α, PEPCK and G6Pase decreased after JP treatment in ISO-treated hepatocytes. Compared with MRL/MP mice, we found that JP could significantly inhibit the expression of gluconeogenesis in the hepatocytes of MRL/lpr mice induced by GC to a greater extent. CONCLUSIONS: The therapeutic effect of JP on GC-induced is likely related to hepatic gluconeogenesis, which provides a new perspective to reveal the positive role of JP in SLE.

4.
Neuroscience ; 482: 77-86, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34902496

RESUMO

Delayed paralysis occurs within some patients suffered from ischemic spinal cord injury (ISCI) due to the aorta occlusion during the repair surgery of thoracic and thoracoabdominal aortic aneurysms. Although mild hypothermia has been reported to improve ISCI and prolong the tolerance of rats to ISCI without inducing immediate paralysis, the mechanism remains unclear. Herein, the study revealed that the mild hypothermia treatment indeed partially improved the ISCI in rats caused by cross-clamping at the descending aorta. ISCI induced the excessive activation of microglia and moderate autophagy in the spinal cord tissues of rats, while mild hypothermia significantly induced autophagy and reversed the excessive activation of microglia in the spinal cord tissues of rats. In OGD-stimulated mouse microglia BV-2 cells, the excessive activation of microglia and moderate autophagy were also observed; in the rapamycin-treated OGD model in BV-2 cells, autophagy was significantly enhanced whereas the excessive activation of microglia was reversed. In both in vivo ISCI model in rats and in vitro OGD model in BV-2 cells, the PI3K/AKT/mTOR pathway showed to be inhibited, whereas the PI3K/AKT/mTOR pathway was further inhibited by mild hypothermia in ISCI rats or rapamycin treatment in OGD-stimulated BV-2 cells. In conclusion, enhanced autophagy might be the mechanism of inhibited microglia activation by hypothermia treatment in ISCI rats and by rapamycin treatment in OGD-stimulated BV-2 cells. Autophagy could be enhanced through inhibiting the PI3K/AKT/mTOR pathway.

5.
J Ethnopharmacol ; : 114669, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34600079

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sugemule-3 decoction (SD-3) is a commonly used prescription in Mongolian medicine which composed of the herbs Baidoukou (the fruit of Amomum compactum Sol. ex Maton), Baijusheng (the fruit of Lactuca sativa L.) and Biba (Piper longum L.). SD-3 has remarkable effect on the cardiovascular diseases, but its pharmacological mechanism has not been elucidated. AIM OF THIS STUDY: To evaluate the cardioprotective effects and the potential mechanisms of the ethanol extracts of SD-3 against isoproterenol (ISO)-induced heart failure (HF) in rats. MATERIAL AND METHODS: The ethanol extracts of SD-3 were prepared and analyzed by LC-ESI-MS/MS. One hundred male Wistar rats were randomly divided into five groups: control, ISO (HF) and different doses of SD-3 (0.4, 0.2, 0.1 g/kg/d) groups. HF model rats were established by intraperitoneal injecting of ISO. The left ventricular function was evaluated by echocardiography. Myocardial injury and fibrosis were examined by hematoxylin-eosin (HE) and Masson staining. Western-blot analysis was performed to determine the protein expression of apoptosis and mitochondrial dynamics in all the groups. Moreover, the structural changes in the mitochondria of cardiomyocytes were also observed by transmission electron microscopy. RESULTS: Fifteen compounds were detected in the ethanol extracts of SD-3, include piperine, piperanine, etc. Rats administered with ISO showed a significant decline in the left ventricular function. The cardiac histopathological changes such as local necrosis, interstitial oedema, and cardiac fibrosis were also observed in the ISO group. The treatment with SD-3 significantly inhibited these effects of ISO. ISO was found to increase the protein expression of Bax, cleaved-PARP and cleaved-caspase-3, -7 -9, destroy the balance between mitochondrial fusion and fission, and alter the mitochondrial morphology. The ethanol extracts of SD-3 could rebalance mitochondrial fusion and fission, and ameliorates the morphological abnormalities induced by ISO in mitochondria. CONCLUSION: The current study demonstrated that ethanol extracts of SD-3 improved isoprenaline-induced cardiac hypertrophy and fibrosis through inhibiting cardiomyocyte apoptosis and regulating the mitochondrial dynamics.

6.
Transl Vis Sci Technol ; 10(12): 29, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34665231

RESUMO

Purpose: To investigate the morphologic and histopathologic changes in allogeneic endokeratophakia using hyperopic lenticules derived from small-incision lenticule extraction (SMILE). Methods: Six New Zealand rabbits (12 eyes) were included in this experiment and randomly and evenly divided into donor and recipient groups. The donor group underwent bilateral hyperopic SMILE surgery, and the concave lenticules were implanted into eyes in the recipient group. Corneal topography and anterior segment optical coherence tomography (OCT) examinations were performed at 1 day, 1 week, 1 month, and 5 months after surgery. All eyes were enucleated 5 months after surgery. Hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM) were used to observe the corneal morphology in the recipient group. Results: No complications were observed, and the corneas remained transparent in the follow-up period. There was mild corneal edema within 1 week after surgery. Slit-lamp microscopy and OCT showed that the lenticules were gradually integrated with the surrounding corneal stroma. HE staining showed that the arrangement of corneal collagen was regular. The boundary between the lenticules and surrounding tissue could be identified with HE staining and TEM, and no inflammatory cells were found under TEM. The corneal Km values were significantly lower at 5 months postoperatively compared to preoperatively (P < 0.05). Conclusions: This pilot study showed that allogeneic hyperopic SMILE lenticule endokeratophakia seems to be safe and feasible. Translational Relevance: Allogeneic hyperopic SMILE lenticule endokeratophakia may be applicable for the correction of corneal regression, ectasia, ultra-high myopia, or keratoconus.


Assuntos
Cirurgia da Córnea a Laser , Transplante de Células-Tronco Hematopoéticas , Hiperopia , Animais , Hiperopia/cirurgia , Lasers , Projetos Piloto , Coelhos
7.
J Mol Histol ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34709489

RESUMO

The imbalance between osteogenic and adipogenic differentiation of Bone marrow-derived mesenchymal stem cells (BMSCs) is involved in the occurrence and development of osteoporosis (OP). Previous studies have indicated the potential of phosphatase and actin regulator 1 (Phactr1) in regulating osteogenic and adipogenic differentiation of BMSCs. The present study aims to investigate the function and mechanism of Phactr1 in regulating osteogenic and adipogenic differentiation of BMSCs. Herein, the expression of Phactr1 in bone and adipose tissue of OP rats was determined by immunohistochemical. BMSCs were subjected to osteogenic and adipogenic differentiation, and transfected with Phactr1 overexpression lentivirus, small interference RNA (siRNA) and KD025 (selective ROCK2 inhibitor). The relationship between Phactr1 and ROCK2 was detected by Co-IP experiment. The expression of Phactr1, Runx2, C/EBPα, RhoA and ROCK2 was detected by Western blot. Calcium nodule and lipid droplets were determined by alizarin red and Oil red O staining. Interestingly, Phactr1 increased in both bone and adipose tissue of OP rats. During osteogenic differentiation, Phactr1 decreased and active RhoA, ROCK2 increased, while overexpression Phactr1 inhibits the increase of Runx2. Phactr1 increased and active RhoA decreased, ROCK2 did not changed during adipogenic differentiation. While, Knockdown Phactr1 inhibits the increase of C/EBPα. Phactr1 and ROCK2 were combined in osteogenic differentiation, but not in adipogenic differentiation. By using KD025, the decrease of Phactr1 and increase of Runx2 were inhibited respectively in osteogenic differentiation. Meanwhile, when ROCK2 was inhibited, Phactr1, C/EBPα were significantly increased in adipogenic differentiation. These findings indicated that Phactr1 negatively regulates bone mass by inhibiting osteogenesis and promoting adipogenesis of BMSCs by activating RhoA/ROCK2.

8.
Nat Mach Intell ; 3: 306-315, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34676358

RESUMO

Hyperspectral imaging is a technique that provides rich chemical or compositional information not regularly available to traditional imaging modalities such as intensity imaging or color imaging based on the reflection, transmission, or emission of light. Analysis of hyperspectral imaging often relies on machine learning methods to extract information. Here, we present a new flexible architecture, the U-within-U-Net, that can perform classification, segmentation, and prediction of orthogonal imaging modalities on a variety of hyperspectral imaging techniques. Specifically, we demonstrate feature segmentation and classification on the Indian Pines hyperspectral dataset and simultaneous location prediction of multiple drugs in mass spectrometry imaging of rat liver tissue. We further demonstrate label-free fluorescence image prediction from hyperspectral stimulated Raman scattering microscopy images. The applicability of the U-within-U-Net architecture on diverse datasets with widely varying input and output dimensions and data sources suggest that it has great potential in advancing the use of hyperspectral imaging across many different application areas ranging from remote sensing, to medical imaging, to microscopy.

9.
Mol Ther Oncolytics ; 22: 565-573, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34553041

RESUMO

Endostatin (ES, ENDO) has been reported to suppress the growth of tumors while inducing the proliferation of lung cancer stem cells (LCSCs), causing a poor prognosis for lung cancer. In this study, we aimed to clarify whether BRM270 can inhibit the proliferation of cancer stem cells (CSCs). Endostatin + BRM270 showed anti-tumor effects by reducing tumor volume and increasing survival. Administration of BRM270 reduced the number of aldehyde dehydrogenase-positive (ALDH+) cells and the level of ALDH1A1 expression in tumors by increasing the level of miR-128 while decreasing the levels of BMI-1, ABCC-5, E2F3, and c-MET. The luciferase activity of miR-128 promoter was increased by an increasing concentration of BRM270. In addition, BMI-1, ABCC-5, E2F3, and c-MET were identified as candidate targets of miR-128, and the overexpression of miR-128 significantly reduced mRNA/protein levels of BMI-1, ABCC-5, E2F3, and c-MET in A549 and H460 cells. Administration of BRM270 inhibited the expression of BMI-1, ABCC-5, E2F3, and c-MET in a dose-dependent manner. In this study, we showed for the first time that the combined administration of endostatin and BRM270 achieved anti-tumor effects while suppressing the proliferation of stem cells.

10.
Nat Commun ; 12(1): 4422, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285219

RESUMO

The eastern North Pacific (ENP) has the highest density of tropical cyclones (TCs) on earth, and yet the controls on TCs, from individual events to seasonal totals, remain poorly understood. One effect that has not been fully considered is the unique geography of the Central American mountains. Although observational studies suggest these mountains can readily fuel individual TCs through dynamical processes, here we show that these mountains indeed play the opposite role on the seasonal timescale, hindering seasonal ENP TC activity by up to 35%. We found that these mountains significantly interrupt the abundant moisture transport from the Caribbean Sea to the ENP, limiting deep convection over the open ocean area where TCs preferentially occur. This study advances our fundamental understanding of ENP TC genesis mechanisms across the weather-to-climate timescales, and also highlights the importance of topography representation in improving the ENP regional climate simulations, as well as TC seasonal predictions and future projections.

12.
BMC Ophthalmol ; 21(1): 282, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284749

RESUMO

PURPOSE: To assess the ability of the Pentacam in predicting the corneal power after hyperopic small-incision lenticule extraction (SMILE). METHODS: Twenty-five eyes of 22 patients underwent hyperopic SMILE were prospectively followed. All patients finished at least 6 months visit. Cornea power was obtained by Pentacam HR, in the format of mean keratometry (Km), equivalent keratometry (EKR) and total cornea refractive power (TCRP). Calculation of TCRP were centered on either the corneal apex or the pupil center within a ring or zone, giving a total of four different subtypes naming AR、AZ、PR、PZ. Clinical history method (CHM) was regarded as a gold standard and was compared with other cornea power parameters. RESULTS: Center difference had no impact on the TCRP values (PR vs AR and PZ vs AZ, P > 0.05). Compared with CHM, no difference was found in Km, EKR 4.0 mm, EKR 4.5 mm, PR 3.0 mm, PR 4.0 mm, AR 3.0 mm and AR 4.0 mm. PR 4.0 mm showed the least difference with CHM (- 0.14 ± 1.03D, P > 0.05). The 95% limit of agreement (LOA) of the TCRPs and CHM was not close. The top two were PR 3.0 mm and PR 4.0 mm, LOA of which were - 2.20 to 1.84 D and - 2.18 to 1.68 D respectively. Central cornea thickness was correlated with error (TCRP - CHM) of PR 4.0 mm (r = 0.58, P = 0.003). CONCLUSIONS: The Pentacam topographer is an alternative method of measuring corneal power in eyes after hyperopic SMILE. The optimal options seem to be the TCRP (PR 4.0 mm). The agreement needs more verifications.


Assuntos
Córnea , Hiperopia , Córnea/cirurgia , Topografia da Córnea , Humanos , Hiperopia/cirurgia , Refração Ocular , Projetos de Pesquisa
13.
World Neurosurg ; 152: e589-e596, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34129986

RESUMO

BACKGROUND: Pedicle screw fixation (PSF) has been considered the preferred surgery for the treatment of severe osteoporotic vertebral compression fracture (sOVCF), and sOVCF was traditionally regarded as a relative contraindication to minimally invasive percutaneous kyphoplasty (PKP). Debate has continued regarding the selection of the best surgical method for sOVCF. In the present study, we compared the efficacy and safety between PKP and PSF. METHODS: PKP was performed in 376 patients in group 1 and PSF in 121 patients in group 2. The visual analog scale (VAS), Oswestry disability index (ODI), local kyphotic angle, fractured vertebral body height, and complications were evaluated. RESULTS: In the immediate postoperative analysis, the mean VAS score for group 1 was 2.4, significantly lower than the VAS score of 4.7 for group 2. The mean ODI score was 44.4% for group 1, lower than the ODI score of 57.1% for group 2. In addition, group 1 had had a significantly better ODI score at 1 year of follow-up. The local kyphotic angle and fractured vertebral body height had recovered better in group 2. In group 1, 113 patients had experienced cement leakage, and 29 patients had undergone PKP for adjacent new vertebral fractures. In group 2, 2 patients had developed wound infections, 4 had developed pneumonia, 2 had developed urinary tract infection, 3 had experienced asymptomatic screw loosening, and 7 had undergone PKP to treat new vertebral fractures and 1 had undergone removal of internal fixation because of back pain. CONCLUSIONS: The results of the clinical and radiological evaluations showed that PKP is comparable to PSF for the treatment of sOVCF with kyphosis, with PKP having the advantages of minimal invasion, quick postoperative pain relief, and functional recovery.


Assuntos
Fixação Interna de Fraturas/métodos , Fraturas por Compressão/cirurgia , Cifoplastia/métodos , Cifose/cirurgia , Vértebras Lombares/cirurgia , Fraturas por Osteoporose/cirurgia , Parafusos Pediculares , Fraturas da Coluna Vertebral/cirurgia , Vértebras Torácicas/cirurgia , Idoso , Estudos de Coortes , Avaliação da Deficiência , Feminino , Fraturas por Compressão/complicações , Humanos , Fixadores Internos , Cifose/complicações , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/complicações , Medição da Dor , Estado Vegetativo Persistente , Estudos Retrospectivos , Fraturas da Coluna Vertebral/complicações , Resultado do Tratamento
14.
PLoS Biol ; 19(5): e3001209, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33961621

RESUMO

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.


Assuntos
Anticorpos Neutralizantes/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/ultraestrutura , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/metabolismo , Epitopos/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Testes de Neutralização , Pandemias , Ligação Proteica , Domínios Proteicos , Receptores Virais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
15.
Psychopharmacology (Berl) ; 238(8): 2313-2324, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33932163

RESUMO

RATIONALE: Epigenetic regulation has been implicated in the incubation of drug craving (the time-dependent increase in drug seeking after prolonged withdrawal from drug self-administration). There is little information available on the role of microRNAs in incubation of heroin craving. OBJECTIVE: This study aimed to investigate the roles and mechanisms of miR-181a and methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) in incubation of heroin seeking. METHODS: MiRNA sequencing was used to predict potential miRNAs, and miRNA profiles were performed in the NAc after 1 day or 14 days after withdrawal from heroin self-administration. Following 14 days of heroin self-administration, rats were injected of lentiviral vectors into the NAc and evaluated for the effects of overexpression of miR-181a or knockdown of MeCP2 on non-reinforced heroin seeking after 14 withdrawal days. RESULTS: Lever presses during the heroin-seeking tests were higher after 14 withdrawal days than after 1 day (incubation of heroin craving). miR-181a expression in NAc was lower after 14 withdrawal days than after 1 day, and meCP2 expression in NAc was higher after 14 days than after 1 day. Luciferase activity assay showed that the 3'UTR of MeCP2 is directly regulated by miR-181a. Overexpression of miR-181a in NAc decreased heroin seeking after 14 withdrawal days and decreased MeCP2 mRNA and protein expression. Knockdown of MeCP2 expression in NAc by LV-siRNA-MeCP2 also decreased heroin seeking after 14 withdrawal days. CONCLUSIONS: Results indicate that incubation of heroin craving is mediated in part by time-dependent decreases in NAc miR181a expression that leads to time-dependent increases in MeCP2 expression. Our data suggest that NAc miR-181a and MeCP2 contribute to incubation of heroin craving.


Assuntos
Fissura/fisiologia , Comportamento de Procura de Droga/fisiologia , Heroína/administração & dosagem , Proteína 2 de Ligação a Metil-CpG/biossíntese , MicroRNAs/biossíntese , Núcleo Accumbens/metabolismo , Animais , Fissura/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Masculino , Proteína 2 de Ligação a Metil-CpG/antagonistas & inibidores , Proteína 2 de Ligação a Metil-CpG/genética , MicroRNAs/genética , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Autoadministração
16.
Nat Commun ; 12(1): 2623, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976198

RESUMO

COVID-19 pandemic caused by SARS-CoV-2 constitutes a global public health crisis with enormous economic consequences. Monoclonal antibodies against SARS-CoV-2 can provide an important treatment option to fight COVID-19, especially for the most vulnerable populations. In this work, potent antibodies binding to SARS-CoV-2 Spike protein were identified from COVID-19 convalescent patients. Among them, P4A1 interacts directly with and covers majority of the Receptor Binding Motif of the Spike Receptor-Binding Domain, shown by high-resolution complex structure analysis. We further demonstrate the binding and neutralizing activities of P4A1 against wild type and mutant Spike proteins or pseudoviruses. P4A1 was subsequently engineered to reduce the potential risk for Antibody-Dependent Enhancement of infection and to extend its half-life. The engineered antibody exhibits an optimized pharmacokinetic and safety profile, and it results in complete viral clearance in a rhesus monkey model of COVID-19 following a single injection. These data suggest its potential against SARS-CoV-2 related diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Especificidade de Anticorpos/imunologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Linhagem Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Feminino , Humanos , Macaca mulatta , Masculino , Mutação , Pandemias , Ligação Proteica , Domínios Proteicos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Resultado do Tratamento , Células Vero
17.
Ann Transl Med ; 9(5): 380, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33842601

RESUMO

Background: Investigating the impact of magnification correction in macular vessel density using optical coherence tomography angiography (OCTA) in patients with anisometropia. Methods: Cross-sectional study. Totally 47 patients (11 male, 36 female) aged >18 years with high myopia were analyzed. All patients underwent evaluation of visual acuity, subjective refraction, and axial length. Anisometropia (n=37) was defined as a refraction difference between paired eyes ≥0.75 D. The control group (n=10) consisted patients with a refraction difference ≤0.5 D. Superficial vessel density was performed using 3 mm × 3 mm Cirrus-HD OCTA protocol. The vessel length density (VLD) and foveal avascular zone area (FAZA) were analyzed before and after magnification correction using Bennett's formula. Results: The mean spherical equivalent (SE) was -10.54±3.47 D in the more myopic eye and -8.05±3.47 D in the contralateral eye (P<0.001). Before magnification correction, the mean perfusion density (PD) and VLD were both significantly lower in the more myopic eyes. After magnification correction, the VLD and PD did not differ between paired eyes. No statistical difference was found in terms of the FAZA between paired eyes regardless of magnification correction. The magnification-induced differences in both VLD and PD were positively correlated with the difference in SE (both r=0.86, P<0.001). Conclusions: In OCTA analysis, magnification correction should be performed to reduce refraction error-induced image error, which deserves attention in the clinical application.

18.
Front Med (Lausanne) ; 8: 627725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681255

RESUMO

Chronic itch is a common distressing symptom of many diseases, which reduced patient's quality of life. The mechanistic study on itch and screening for new anti-itch drugs require the development of new pre-clinical itch animal models. Herein, we established an acute itch model by intradermal (i.d.) injection of low-dose formalin into the neck or cheek in mice. In mice, i.d. injection of formalin (0.1-5%) in the nape of the neck evoked robust scratching behavior in a dose-dependent manner and the dose-response curves showed an inverted "U" shape. I.d. injection of formalin (0.3-0.6%) into the cheek evoked scratching in mice but wiping in rats, while formalin (1.25-5%) induced mixed wiping and scratching behavior in both mice and rats. Further, we found that 0.3% formalin-induced scratching was histamine-independent and significantly attenuated by transient receptor potential ion channel A1 (TRPA1) inhibitor (HC030031) or in TRPA1 knockout (KO) mice, but not affected by transient receptor potential ion channel V1 (TRPV1) inhibitor (capsazepine) or in TRPV1 KO mice. Additionally, 0.3% formalin-induced up-regulation of phosphorylation of extracellular regulated protein kinases (p-ERK) in the dorsal root ganglion (DRG) and scratching were suppressed by intrathecal injection of MEK inhibitor U0126 in mice. Incubation of 0.03% formalin induced the accumulation of intracellular reactive oxygen species (ROS) in the cultured DRG-derived cell line ND7-23, and formalin-induced itch was suppressed by antioxidants in mice. Finally, perfusion of 0.03% formalin induced elevation of intracellular calcium in a subset of primary cultured DRG neurons of mice. Thus, these results indicate that low-dose formalin induced non-histaminergic itch by activation of TRPA1 in mice, which may be employed as a useful acute itch model for screening potential anti-itch drugs.

19.
Ann Palliat Med ; 10(4): 4000-4007, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33691435

RESUMO

BACKGROUND: Osteoporotic vertebral compression fracture (OVCF) is a common disease in elderly population, which could cause serious back pain and has a substantial impact on patients' health-related quality of life (HRQoL). The aim of this study was to identify the effect of Teriparatide as a conservative treatment on reducing back pain, and improving quality of life for postmenopausal women with osteoporotic vertebral fractures. METHODS: In a 12-month, retrospective study, 112 postmenopausal women with OVCFs were assigned to Teriparatide group (20 µg Teriparatide, subcutaneous, once daily, n=38) or control group (500 mg calcium and 400-800 IU Vitamin D per day, oral administration, n=74) according to patients' choices between January 2016 and October 2018. Patient-reported outcomes scores including the visual analogue score (VAS), Oswestry disability index (ODI), and short form 36 questionnaire (SF-36) were assessed at baseline, the 3rd months, the 6th months and 1 year after treatment. RESULTS: Treatments with Teriparatide or calcium plus vitamin D supplements had significant effect on improvement of patients' back pain as well as HRQoL, with significantly reduced VAS and ODI and increased SF-36 physical component summary (PCS) and mental component summary (MCS) scores. At the endpoint, Teriparatide showed better therapeutic effect, with greater reductions in VAS and ODI and more increases in SF-36 PCS and MCS scores. However, more adverse events (AEs) were found in Teriparatide group, but symptoms were relatively mild and of short duration. CONCLUSIONS: In postmenopausal women with OVCFs, the consequent persistent back pain and impaired HRQoL, treatment with Teriparatide was associated with more profound therapeutic effects and more AEs compared with calcium plus vitamin D supplements.


Assuntos
Fraturas por Compressão , Fraturas da Coluna Vertebral , Idoso , Feminino , Fraturas por Compressão/tratamento farmacológico , Humanos , Pós-Menopausa , Qualidade de Vida , Estudos Retrospectivos , Fraturas da Coluna Vertebral/tratamento farmacológico , Teriparatida/uso terapêutico
20.
Addict Biol ; 26(5): e13013, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33619816

RESUMO

Akt is initially identified as one of the downstream targets of phosphatidylinositol-3 kinase (PI3K) and is involved in morphine reward and tolerance. However, whether phospholyration of Akt (p-Akt) mediates heroin relapse remains unclear. Here, we aimed to explore the role of p-Akt in the nucleus accumbens (NAc) in cue-induced heroin-seeking behaviors after withdrawal. First, rats were trained to self-administer heroin for 14 days, after which we assessed heroin-seeking behaviors induced by a context cue (CC) or by discrete conditioned cues (CS) after 1 day or 14 days of withdrawal. We found that the active responses induced by CC or CS after 14 days of withdrawal were higher than those after 1 day of withdrawal. Meanwhile, the expression of p-Akt in the NAc was also greatest when rats were exposed to the CS after 14 days of withdrawal. Additionally, a microinjection of LY294002, an inhibitor of PI3K, into the NAc inhibited the CS-induced heroin-seeking behaviors after 14 days of withdrawal, paralleling the decreased levels of p-Akt in the NAc. Finally, Akt1 or ß-arrestin 2 was downregulated via a lentiviral injection to assess the effect on heroin seeking after 14 days of withdrawal. CS-induced heroin-seeking behavior was inhibited by downregulation of Akt1, but not ß-arrestin 2, in the NAc. These data demonstrate that Akt phosphorylation in the NAc may play an important role in the incubation of heroin-seeking behavior, suggesting that the PI3K/Akt pathways may be involved in the process of heroin relapse and addiction.

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